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Abstract Background Fatigue is recognized as a disabling symptom in many chronic conditions including rheumatic disorders such as rheumatoid arthritis (RA) and lupus. Fatigue in osteoarthritis (OA) is not routinely evaluated and has only been considered in a very limited number of studies. To date, these studies have focused primarily on patients with OA under rheumatological care, which represent the minority of people living with OA. The purpose of this study was to increase our understanding of the fatigue experience in community dwelling people with OA. Methods In 2004, 8 focus groups were conducted with 28 men and 18 women (mean age 72.3) with symptomatic hip or knee OA recruited from a population-based cohort. Participants completed a self-administered questionnaire, which included demographics, measures of OA severity (WOMAC), depression (CES-D) and fatigue (FACIT). Sessions were audio taped and transcribed verbatim. Two researchers independently reviewed the transcripts to identify themes. Findings were compared and consensus reached. Results Mean pain, disability, depression and fatigue scores were 8.7/20, 27.8/68, 15.4/60, and 30.9/52, respectively. Participants described their fatigue as exhaustion, being tired and "coming up against a brick wall". Participants generally perceived fatigue as different from sleepiness and distinguished physical from mental fatigue. Factors believed to increase fatigue included OA pain and pain medications, aging, various types of weather and poor sleep. Mental health was identified as both affecting fatigue and being affected by fatigue. Participants described fatigue as impacting physical function, and their ability to participate in social activities and to do household chores. Rest, exercise, and avoiding or getting assistance with activities were cited as ways of coping. Participants generally did not discuss their fatigue with anyone except their spouses. Conclusion Participants with OA described experiencing notable amounts of fatigue and indicated that it had a substantial impact on their lives. Further research is required to better understand the role of fatigue in OA in order to identify strategies to reduce its impact.

OBJECTIVE: Advances in health care require that individuals participate knowledgeably and actively in their health care to realize its full benefit. Implications of these changes for the behavior of individuals and for the practice of patient education are described. METHODS: An 'engagement behavior framework' (EBF) was compiled from literature reviews and key informant interviews. To assess the focus of research and interventions on the identified engagement behaviors, the EBF was used to code scientific sessions in professional conferences relevant to patient education in the US in 2006-2007. RESULTS: Many specific behaviors constitute engagement. Professional conferences on patient education show only modest attention to the full range of relevant behaviors. CONCLUSION: People must make informed choices about insurance and clinicians, coordinate communications among providers and manage complex treatments on their own. Not doing so risks preventable illness, suboptimal outcomes and wasted resources. PRACTICE IMPLICATIONS: Increased responsibilities of individuals, sick and well, to find and actively participate in high quality health care provides an opportunity for patient education researchers and clinicians to improve health outcomes by developing innovative strategies to support all individuals to effectively participate in their care to the extent possible. [ABSTRACT FROM AUTHOR]

Background: Children are increasingly discharged directly from the PICU. Transitions have been recognized as a period of increased patient and caregiver stress and risk of adverse events. No study has evaluated patient and caregiver outcomes after direct discharge from the PICU. This study aimed to explore the family's experiences with discharge directly home (DDH) from the PICU., Methods: This exploratory mixed-methods study was conducted in the PICU of the Institution is Sainte-Justine Hospital from February to July 2021. We included families of children expected to be DDH within 12 hours. Semistructured interviews were conducted at discharge, followed by telephone interviews 7 and 28 days post-PICU discharge. We measured comfort on a 5-point Likert scale and screened for anxiety using the Generalized Anxiety Disorder-7 tool., Results: Families of 25 patients were interviewed. Thematic analysis of the interviews revealed several themes, such as feeling stress and anxiety, feeling confident, anticipating home care, and needing support. These findings complemented the quantitative findings; the median comfort score was 4 (comfortable) (interquartile range 4-5) and 8 (interquartile range 4-12) for the Generalized Anxiety Disorder-7 on the day of discharge, with 16 reporting clinically significant anxiety. In the 28-day study period, 2 patients were readmitted and 6 had visited the emergency department., Conclusions: Despite feelings of anxiety, many families felt comfortable with DDH from the PICU. Increasing our understanding of the patient and family experiences of discharge from the PICU will help to better support these patients and their families during transition., (Copyright © 2023 by the American Academy of Pediatrics.)

Protein ubiquitylation is an essential post-translational modification that regulates nearly all aspects of eukaryotic cell biology. A diverse collection of ubiquitylation signals, including an extensive repertoire of polymeric ubiquitin chains, leads to a range of different functional outcomes for the target protein. Recent studies have shown that ubiquitin chains can be branched and that branched chains have a direct impact on the stability or the activity of the target proteins they are attached to. In this mini review, we discuss the mechanisms that control the assembly and disassembly of branched chains by the enzymes of the ubiquitylation and deubiquitylation machinery. Existing knowledge regarding the activities of chain branching ubiquitin ligases and the deubiquitylases responsible for cleaving branched chains is summarized. We also highlight new findings concerning the formation of branched chains in response to small molecules that induce the degradation of otherwise stable proteins and examine the selective debranching of heterotypic chains by the proteasome-bound deubiquitylase UCH37., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gregor, Xu and French.)

This study investigated shoulder complex joint kinematics and functional outcomes before and after full-thickness supraspinatus rotator cuff repair. Nine adults (mean age 63.4 ± 6.2 years) participated in three test sessions: 0-12 weeks pre-operatively, 9-12 weeks, and 22-30 weeks post-operatively. Upper extremity kinematics of the surgical arm's glenohumeral, acromioclavicular, sternoclavicular and thoracohumeral joints over the duration of a hair combing task were quantified with motion analysis using inverse kinematics. The UCLA Shoulder Rating and Simple Shoulder Test shoulder health outcomes were administered at each session to determine patients' perceived function of their surgical shoulder. Results indicated multiple significant increases over time among the three joints comprising the shoulder complex in the coronal and transverse planes, despite no increases in thoracohumeral motion, and suggest that thoracohumeral motion alone does not provide a comprehensive assessment. Interestingly, more significant increases were observed at the 6-month evaluation than the 3-month evaluation, which is not aligned with the standard rehabilitation endpoint. Thus, our findings suggest that clinicians should evaluate all joints of the shoulder complex during longer-term rehabilitation assessment. Ultimately, knowledge of patients' pre-operative and post-operative shoulder complex kinematics may help to improve rehabilitation to promote improved patient outcomes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has focused health systems on supporting patients affected by this virus. Meanwhile in the community, many other contained patients could only use self-care strategies, especially in countries that have set up a long and strict containment such as France. The study aimed to compare coping strategies deployed by patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS; a poorly recognised syndrome) to those with better known and referenced chronic conditions. An online flash survey was conducted during the containment period in partnership with French Patients Organizations including ME/CFS national association. Therefore, 'Brief COPE' version of Lazarus and Folkman's Ways of Coping Check List has been adapted to the specificity of the containment. The survey was e-distributed in France from 15 April to 11 May 2020. Differences of coping strategies were analyzed using Wilcoxon-Mann-Withney test. Amongst 637 responses, 192 were complete, presenting a wide variety of diseases, including 93 ME/CFS. The latter have significantly different coping strategies than recognised diagnosed diseases patients: similar uses of emotion focused coping but less uses of seek social support and problem-focused copings. In conclusion, coping strategies are different for those who deal with the daily experience of ME/CFS, highly disabling chronic condition with diagnostic ambiguity, low degree of medical and social recognition and without treatment. Better understanding of those strategies is needed to provide the means for health promotion researchers, managers and clinicians, to accompany those patients., (© 2021 John Wiley & Sons Ltd.)

Ubiquitylation is a critical post-translational modification that controls a wide variety of processes in eukaryotes. Ubiquitin chains of different topologies are specialized for different cellular functions and control the stability, activity, interaction properties, and localization of many different proteins. Recent work has highlighted a role for branched ubiquitin chains in the regulation of cell signaling and protein degradation pathways. Similar to their unbranched counterparts, branched ubiquitin chains are remarkably diverse in terms of their chemical linkages, structures, and the biological information they transmit. In this review, we discuss emerging themes related to the architecture, synthesis, and functions of branched ubiquitin chains. We also describe methodologies that have recently been developed to identify and decode the functions of these branched polymers.

As the proportion of older adults in the United States is projected to increase dramatically in the coming decades, it is imperative that public health address and maintain the cognitive health of this growing population. More than 5 million Americans live with Alzheimer's disease and related dementias (ADRD) today, and this number is projected to more than double by 2050. The public health community must be proactive in outlining the response to this growing crisis. Promoting cognitive decline risk reduction, early detection and diagnosis, and increasing the use and availability of timely data are critical components of this response. To prepare state, local, and tribal organizations, CDC and the Alzheimer's Association have developed a series of Road Maps that chart the public health response to dementia. Since the initial Healthy Brain Initiative (HBI) Road Map release in 2007, the Road Map has undergone two new iterations, with the most recent version, The HBI's State and Local Public Health Partnerships to Address Dementia: The 2018-2023 Road Map , released in late 2018. Over the past several years, significant advances were made in the science of risk reduction and early detection of ADRD. As a result, the public health response requires a life-course approach that focuses on reducing risk and identifying memory issues earlier to improve health outcomes. The most recent Road Map was revised to accommodate these strides in the science and to effect change at the policy, systems, and environment levels. The 2018-2023 Road Map identifies 25 actions that state and local public health agencies and their partners can implement to promote cognitive health and address cognitive impairment and the needs of caregivers. The actions are categorized into four traditional domains of public health, and the Road Map can help public health and its partners chart a course for a dementia-prepared future., (Published by Oxford University Press on behalf of The Gerontological Society of America 2020.)

H omologous to E 6AP C - t erminal (HECT) ubiquitin (Ub) ligases (E3s) are a large class of enzymes that bind to their substrates and catalyze ubiquitination through the formation of a Ub thioester intermediate. The mechanisms by which these E3s assemble polyubiquitin chains on their substrates remain poorly defined. We report here that the Nedd4 family HECT E3, WWP1, assembles substrate-linked Ub chains containing Lys-63, Lys-48, and Lys-11 linkages (Lys-63 > Lys-48 > Lys-11). Our results demonstrate that WWP1 catalyzes the formation of Ub chains through a sequential addition mechanism, in which Ub monomers are transferred in a successive fashion to the substrate, and that ubiquitination by WWP1 requires the presence of a low-affinity, noncovalent Ub-binding site within the HECT domain. Unexpectedly, we find that the formation of Ub chains by WWP1 occurs in two distinct phases. In the first phase, chains are synthesized in a unidirectional manner and are linked exclusively through Lys-63 of Ub. In the second phase, chains are elongated in a multidirectional fashion characterized by the formation of mixed Ub linkages and branched structures. Our results provide new insight into the mechanism of Ub chain formation employed by Nedd4 family HECT E3s and suggest a framework for understanding how this family of E3s generates Ub signals that function in proteasome-independent and proteasome-dependent pathways., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Hereditary Parkinson's disease is commonly caused by mutations in the protein kinase PINK1 or the E3 ubiquitin ligase Parkin, which function together to eliminate damaged mitochondria. PINK1 phosphorylates both Parkin and ubiquitin to stimulate ubiquitination of dozens of proteins on the surface of the outer mitochondrial membrane. However, the mechanisms by which Parkin recognizes specific proteins for modification remain largely unexplored. Here, we show that the C-terminal GTPase (cGTPase) of the Parkin primary substrate human Miro is necessary and sufficient for efficient ubiquitination. We present several new X-ray crystal structures of both human Miro1 and Miro2 that reveal substrate recognition and ubiquitin transfer to be specific to particular protein domains and lysine residues. We also provide evidence that Parkin substrate recognition is functionally separate from substrate modification. Finally, we show that prioritization for modification of a specific lysine sidechain of the cGTPase (K572) within human Miro1 is dependent on both its location and chemical microenvironment. Activation of Parkin by phosphorylation or by binding of pUb is required for prioritization of K572 for modification, suggesting that Parkin activation and acquisition of substrate specificity are coupled.

Purpose: To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML)., Methods: This was an open label, multi-center phase II clinical trial. Courses were defined as consecutive 28-day intervals. Oral imatinib was administered daily at 340 mg/m² without interruption in the absence of toxicity., Results: Fifty-one children received 978 28-day courses of imatinib. The most common toxicities encountered were hematologic. Forty-one patients (80%) achieved a complete hematologic response by the end of course 2. Nineteen children (38%) obtained a complete cytogenetic response (CCyR) at the end of course 3. Overall, 72% achieved CCyR at a median time of 5.6 months. The rate of complete molecular response (>3 log reduction) was 27%. Progression-free and overall survival at 3 years were 72%  ± 6.4% and 92%  ± 3.9%, respectively., Conclusions: Daily oral imatinib at a dose of 340 mg/m² is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. (This study was registered at ClinicalTrials.gov under identifier NCT00030394.)., Competing Interests: Nothing to declare., (Copyright © 2011 Wiley-Liss, Inc.)

Rsp5 is a homologous to E6AP C terminus (HECT) ubiquitin ligase (E3) that controls many different cellular processes in budding yeast. Although Rsp5 targets a number of different substrates for ubiquitination, the mechanisms that regulate Rsp5 activity remain poorly understood. Here we demonstrate that Rsp5 carries a noncovalent ubiquitin-binding site in its catalytic HECT domain. The N-terminal lobe of the HECT domain mediates binding to ubiquitin, and point mutations that disrupt interactions with ubiquitin alter the ability of the Rsp5 HECT domain to assemble polyubiquitin chains in vitro. Point mutations that disrupt ubiquitin binding also result in temperature-sensitive growth defects in yeast, indicating that the Rsp5 ubiquitin-binding site is important for Rsp5 function in vivo. The Nedd4 HECT domain N-lobe also contains ubiquitin-binding activity, suggesting that interactions between the N-lobe and ubiquitin are conserved within the Nedd4 family of ubiquitin ligases. We propose that a subset of HECT E3s are regulated by a conserved ubiquitin-binding site that functions to restrict the length of polyubiquitin chains synthesized by the HECT domain.

SH3 domains are modules of 50-70 amino acids that promote interactions among proteins, often participating in the assembly of large dynamic complexes. These domains bind to peptide ligands, which usually contain a core Pro-X-X-Pro (PXXP) sequence. Here we identify a class of SH3 domains that bind to ubiquitin. The yeast endocytic protein Sla1, as well as the mammalian proteins CIN85 and amphiphysin, carry ubiquitin-binding SH3 domains. Ubiquitin and peptide ligands bind to the same hydrophobic groove on the SH3 domain surface, and ubiquitin and a PXXP-containing protein fragment compete for binding to SH3 domains. We conclude that a subset of SH3 domains constitutes a distinct type of ubiquitin-binding domain and that ubiquitin binding can negatively regulate interaction of SH3 domains with canonical proline-rich ligands.

Ultraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor (VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A(1229) (SNP 1), A/G(3944) (SNP 2), T/C(30875) (SNP 3), C/T(48200) (SNP 4) and C/T(65013) (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41-0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1-2, G-G (odds ratio = 0.63, p = 0.039), SNPs 2-3 G-C (odds ratio = 0.45, p = 0.008) and SNPs 1-2-3 G-G-C (odds ratio = 0.44, p = 0.006), but not SNPs 1-3, G-C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes). These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2.

Purpose: To characterize employers' coverage of clinical preventive services., Design: Mercer Human Resource Consulting Inc. included questions on clinical preventive services as part of its National Survey of Employer-Sponsored Health Plans, 2001., Setting: A national sample of employers of a large, medium, and small number of employees, including governments., Subjects: Respondents self-identified as most knowledgeable about the organization's health benefits., Measures: Weighted analyses of responses to eight survey questions on health promotion., Results: The survey was completed by 2180 employers, and the response rate was 21%. More than 90% of employers included increased productivity and decreased health care costs among their most important reasons for coverage of clinical preventive services. Within health insurance, coverage of physical examinations, immunizations, and screenings generally exceeded 50%, but coverage of lifestyle modification services was less than 20%. Only 20% of employers covered tobacco cessation services, and only 4% of employers provided an "optimal" benefit. We compared employers' offerings with a published ranking, by impact and value, of clinical preventive services. We found the biggest discrepancy in tobacco cessation services and alcohol problem prevention, which ranked high in terms of impact and value but are offered by only 20% and 18% of employers, respectively., Conclusions: Employers seek financial return from their offerings of clinical preventive services to employees, but they are least likely to offer the services most likely to provide this return.

Unlabelled: Conventionally poorly functioning hydronephrotic kidneys have been removed if they are symptomatic. In our unit, patients are offered renal artery embolization as an alternative treatment option., Patients and Methods: Fifteen patients (11 male, 4 female) with a mean age of 32.9 yr (20-51 yrs) have undergone renal artery embolization for symptomatic hydronephrosis with poor function. Mean follow-up was 64.13 weeks (range 14-200). All patients had loin pain and hydronephrosis. Twelve patients had primary pelvi-ureteric junction obstruction (PUJO). Two patients had poorly functioning hydronephrotic kidneys secondary to chronic calculous obstruction. One patient had chronic pain in an obstructed but reasonably functioning kidney following a previous pyeloplasty for PUJO which demanded intervention. Mean split function on renography was 11% (range 0-46%). Selective renal artery embolization was carried out under antibiotic cover using a 7 Fr balloon occlusion catheter and absolute alcohol, steel coils, and polyvinyl alcohol particles., Results: Nine patients developed post-embolization syndrome of self-limiting pain and pyrexia with no evidence of sepsis. One patient required readmission with this condition. One patient developed a hematoma at the puncture site. Mean hospital stay was 2.3 days. Fourteen patients are happy with the result and are completely pain free. One patient has minor discomfort but is delighted with the result. Nine patients have had follow-up ultrasound confirming resolution of the hydronephrosis., Conclusion: Renal artery embolization is an effective, safe, well-tolerated minimally invasive treatment option in end-stage hydronephrosis and we routinely offer it as an alternative to nephrectomy.

Ultraviolet radiation (UVR) exposure may protect against prostate cancer development via a mechanism involving vitamin D. The vitamin D receptor (VDR) gene is therefore a candidate susceptibility factor for prostate cancer. This possibility has been previously investigated with conflicting results. We examined the association of VDR genotypes (variants at the CDX-2, Fok1, and Taq1 sites), haplotypes, and genotype combinations with risk by studying 368 prostate cancer and 243 benign prostatic hypertrophy (BPH) patients. CDX-2, Fok1, and Taq1 genotype and haplotype frequencies were not significantly different in cancer and BPH patients. As the impact of VDR polymorphisms may depend on UVR exposure, we studied associations of variants with risk in men stratified into low (below median) and high (above median) cumulative exposure/year groups. In men with UVR exposure above the median (1,100 hr/year), CDX-2 GA and AA (odds ratios [OR] = 2.11 and 2.02, respectively) and Fok1 ff (OR = 2.91) were associated with increased prostate cancer risk. No associations were observed for Taq1 genotypes. Of the genotype combinations, relative to all other CDX-2 and Taq1 and combinations, GGTT (P = 0.022, OR = 0.30), and relative to all other Fok1 and Taq1 combinations, FFTT (P = 0.026, OR = 0.35) were associated with reduced prostate cancer risk in the presence of the main effects. None of the other two- or three-genotype combinations was associated with risk. These data indicate that VDR variants influence prostate cancer risk and that this association is dependent on the extent of UVR exposure., (Copyright 2004 Wiley-Liss, Inc.)

Low sunlight exposure confers increased prostate cancer risk. In a study conducted in northern England, we investigated how combinations of exposure measures affect this risk. Recursive partitioning was used to identify combinations of exposure parameters that distinguished 453 prostate cancers from 312 benign hypertrophy patients. Sunbathing score most significantly defined cancer patients; 78.7% men with low scores (8.0) had cancer. These subgroups were stratified by childhood sunburning, holidays in a hot climate and skin type such that subgroups with a 13.0-fold increased risk of cancer were identified.

Recent studies have proposed that exposure to ultraviolet radiation (UVR) protects against development of some internal cancers including that in prostate. This effect may be mediated by UVR-induced cutaneous synthesis of vitamin D. It is also proposed that ability to pigment in response to UVR will influence susceptibility to prostate cancer through its effects on vitamin D synthesis. We wished to determine first, whether ability to pigment, as assessed by skin type, influences the extent of exposure to UVR, secondly, whether skin type is associated with prostate cancer susceptibility and thirdly, whether such an effect is mediated by the extent of UVR exposure. We studied 453 prostatic adenocarcinoma and 312 benign prostatic hypertrophy (BPH) patients using a validated questionnaire to assess two parameters of exposure; months of cumulative exposure per year and adult sunbathing score. We used analysis of variance to show that cancer cases with sun-sensitive skin (skin type 1) had lower cumulative exposure per year (P = 0.014) and sunbathing scores (P < 0.0001) than those with type 4, possibly because of a tendency to avoid exposure. Further, cumulative exposure per year and sunbathing score were significantly lower in cancer compared with BPH patients (P < 0.001 and P < 0.001, respectively). While the proportion of subjects with skin types 1 and 2 was lower in cancer than BPH patients, these were not significantly different (logistic regression analysis, skin type 1 versus type 4; P = 0.11). We used recursive partitioning to determine if skin type influenced susceptibility to prostate cancer in subgroups stratified by exposure. Analysis of the data showed that in men with low sunbathing scores, skin type 1 conferred protection compared with skin types 2-4 (OR = 4.78, 95% CI 3.01-8.25, P < 0.0009). These findings indicate that susceptibility to prostate cancer is in part determined by extent of exposure to UVR and that ability to pigment mediates this effect.

We determined whether the glutathione S-transferase GSTP1 Ile105 --> Val105 substitution is associated with response to androgen ablation therapy in patients with advanced prostate cancer. As response may be associated with tumor grade, Gleason score, clinical T stage and presence of metastases we also determined if GSTP1 genotypes were associated with these prognostic parameters. We speculated that GSTP1 Ile105/Ile105 would be linked with good response to androgen ablation therapy and, low/moderate tumor grade, 1/2 clinical T-stage, Gleason score < 6 and, no metastases. Genotype frequencies in cases and controls were not significantly different (P = 0.70) indicating that allelism in GSTP1 is not associated with susceptibility. There was no association between GSTP1 (Ile105/Ile105 versus Ile105/Val105 and Val105/Val105) and grade (P = 0.28, OR = 0.92), Gleason score (P = 0.84, OR = 0.94) or metastatic state (P = 0.68, OR = 0.88) though the frequency of GSTP1 Ile105/Ile105 was higher in cases with stage 1/2 tumors than those with stage 3/4 tumors (P = 0.03, OR = 1.89). GSTP1 Val105/Val105 was also associated with response to hormone ablation therapy. Thus, the GSTP1 Ile105/Ile105 frequency was significantly higher in 86/118 patients who demonstrated a good response than in those with poor response (P = 0.03, OR = 2.70). We speculate that the association of GSTP1 with response results from an effect of the gene product early in carcinogenesis.

Exposure to ultraviolet radiation may reduce prostate cancer risk, suggesting that polymorphism in genes that mediate host pigmentation will be associated with susceptibility to this cancer. We studied 210 prostate cancer cases and 155 controls to determine whether vitamin D receptor (VDR, Taql and Fokl variants), tyrosinase (TYR, codon 192 variant) and melanocortin-1 receptor (MC1R, Arg151Cys, Arg160Trp, Val92Met, Asp294His and Asp84Glu variants) genotypes are associated with risk. UV exposure was determined using a questionnaire. MC1R Arg(160)/Arg(160) homozygotes were at increased risk (P = 0.027, odds ratio = 1.94) while TYR A2/A2 homozygotes were at reduced risk of prostate cancer (P = 0.033, odds ratio = 0.48). These associations remained significant after correction for UV-exposure. Stratification of cases and controls by quartiles of exposure, showed that the protective effect of TYR A1A2 (P = 0.006, odds ratio 0.075) and A2A2 (P = 0.003, odds ratio 0.055) was particularly strong in subjects who had received the greatest exposure. Our data show for the first time, that allelism in genes linked with skin pigment synthesis is associated with prostate cancer risk possibly because it mediates the protective effects of UV. Importantly, susceptibility is associated with an interaction between host predisposition and exposure.

Epidemiological studies have suggested that UV exerts a protective effect on prostate cancer. Accordingly, we determined, in 210 prostate cancer cases, whether parameters of exposure, skin type and polymorphism in MC1R, VDR and TYR were associated with the outcome parameters, histological grade, clinical stage and presence of bone metastases. We used logistic regression analysis, with correction for age and metastases, stage and grade in the models, to determine if the frequencies of individual factors were different in the patient groups. The development of metastases was not associated with UV exposure parameters. Paradoxically, patients with skin type 1 were at significantly reduced risk [P = 0.027, odds ratio (OR) 0.17, 95% CI 0.03-0.82] of developing metastases compared with cases with skin type 4. MC1R Val92/Val92 and VDR ff were associated with increased risk of metastases (ORs 4.30 and 4.98, respectively). Further, cumulative exposure (P = 0.005, OR 0.85/year) and increasing proportion of outdoor occupation (P = 0.001, OR 0.84/unit) were associated with reduced risk of advanced stage tumours. Skin types, MC1R or VDR genotypes were not significantly associated with advanced stage. None of the exposure parameters, skin types or genotypes were associated with tumour grade. While MC1R Val92/Val92 and VDR ff were only associated with bone metastases, TYR genotypes were associated with each of the outcome parameters. Thus, in logistic regression models that included age, but not advanced stage and high grade histology, TYR A1A2 was significantly associated with reduced risk of metastases (P = 0.033, OR 0.41). Similarly, in models that included age but not the other outcome parameters, associations between TYR A2A2 and high-grade and advanced stage were significant (P = 0.040, OR 0.41) or approached significance (P = 0.052, OR 0.44), respectively. These data indicate for the first time that pigmentation response to UV is associated with outcome in prostate cancer.

Our standard policy for the management of retention of urine due to prostatic hypertrophy is that the patient is catheterised and sent home, later to be seen and assessed in the Out-patient Department where he is given an admission date for operation. A detailed audit of 166 patients cared for in this way is presented and the results compared with those in 25 patients who remained in hospital in the interval between catheterisation and operation and in 402 patients not previously catheterised. Although the mortality rate was significantly higher in the retention group (3.3 vs 0.25%), we feel that this is a reflection of the fitness of the patients with retention rather than a consequence of the management policy. The advantages of the "catheterise and send home" policy are discussed.

Azathioprine and steroids (prednisone or prednisolone) form the basis of conventional immunosuppression after renal transplantation. Most of the morbidity in the early months after transplantation. Most of the attributed to steroids, which are normally give in high doses. The only justification for giving high doses is a historical one. For this reason a randomised controlled trial was carried out to compare the efficacy of high dose (39 patients) and low dose (33 patients) oral prednisolone, both in combination with azathioprine, in patients given cadaveric renal allografts. Patients were followed up for at least two years after the transplantation. Patient and graft survival were identical in the two groups and the morbidity associated with steroids was impressively lower in patients receiving a low steroid dose. Although the optimal dose of steroids is still unknown, there seems little justification for continued use of high doses of oral steroids with azathioprine after cadaveric renal transplantation.

In 138 mongrel dogs given renal transplants, 10 developed postoperative intussusceptions. The sites were jejunojejunal (seven), ileo-ileal (two) and ileocolic (one). In 30 puppies given intrasplenic autografts of dispersed pancreatic fragments after total pancreatectomy, five developed jejunojejunal intussusceptions. Presenting signs included vomiting, failure to eat, periodic attacks of pain, straining with the passage of bloodstained mucous, dehydration, weight loss, abdominal wall rigidity and an abdominal mass. The majority of dogs presented within the first seven days following transplantation, occasionally as late as the third week. Early operative intervention was essential to save the dogs and at laparotomy eight of nine intussusceptions were successfully reduced manually; one small bowel resection was performed for irreducibility. Recurrence was not observed in this series but reoperation in the puppies was invariably fatal. Factors contributing to the development of intussusception in the puppies included round worm infestation, recent dietary change following weaning, malabsorption and diarrhoea due to pancreatic insufficiency following pancreatectomy and respiratory infections suggesting an infective origin for the intussusceptions.

The effect of peroperative transfusion was studied in 27 patients who had never had a blood-transfusion or been pregnant and who were receiving their first cadaver renal allograft. 13 patients in the treatment group were given 2 units of whole stored blood at transplantation, whereas 14 patients in the control group were given no blood. Actuarial analysis after 2 years showed a graft survival of 85% at 1 year in the treated group compared with 34% at 1 year in the control group (p = 0.03). Transfusion of non-transfused patients during transplantation may be as effective as pregraft transfusion.

Dose and time response studies of the new immunosuppressive agent, cyclosporin A, have been performed in a dog renal allograft model. Rejection of a renal allograft only occurred in one of six dogs receiving 20 mg/kg/day continuously, but in 10 of 11 dogs receiving 10 mg/kg/day. Doses of 10 or 20 mg/kg/day given for 2 or 3 weeks delayed rejection, but rejection occurred in all animals when the drug was stopped. This suggests that the drug does not produce clonal deletion of the lymphocytes engaged in the immune reaction against the graft, but merely their suppression. The histological picture of rejection was markedly improved by therapeutic doses of cyclosporin A. No consistent histological or biochemical evidence for heptatoxicity or nephrotoxicity was found even in the higher doses tested. One fatal and four non-fatal infectious complications were seen in 29 dogs receiving doses of 5 mg/kg/day or higher.

Thirty-five patients given an HLA-DR-incompatible cadaver kidney that was diuresing immediately after transplantation were randomly allocated to treatment with cyclosporine alone for 3 months followed by conversion to azathioprine and prednisolone (AP), or to conventional treatment with AP. Although many patients had to be converted to AP before 90 days because of rejection requiring more than two treatment courses of high-dose i.v. methylprednisolone, 16 of 21 grafts were functioning at 3 months, and 12 of 14 grafts in the control group were functioning. However 3 further grafts were lost from chronic rejection in the control group, and none were lost from chronic rejection in the cyclosporine group. All but one patient on cyclosporine had depressed renal function, and in all these patients function improved on conversion to AP. This depression of renal function is attributed both to cyclosporine nephrotoxicity and to a low-grade rejection reaction, the latter suggesting that the addition of steroids to cyclosporine might be beneficial in some patients. The strategy of a three-month course of cyclosporine followed by conversion to AP provides satisfactory immunosuppression, and it may be of value if long-term side effects of cyclosporine emerge with further experience.