Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance.

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty-nine percent of patients with end-stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A-I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post-RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.

The evolution of the phage shock protein response system: interplay between protein function, genomic organization, and system function.

Sensing the environment and responding appropriately to it are key capabilities for the survival of an organism. All extant organisms must have evolved suitable sensors, signaling systems, and response mechanisms allowing them to survive under the conditions they are likely to encounter. Here, we investigate in detail the evolutionary history of one such system: The phage shock protein (Psp) stress response system is an important part of the stress response machinery in many bacteria, including Escherichia coli K12. Here, we use a systematic analysis of the genes that make up and regulate the Psp system in E. coli in order to elucidate the evolutionary history of the system. We compare gene sharing, sequence evolution, and conservation of protein-coding as well as noncoding DNA sequences and link these to comparative analyses of genome/operon organization across 698 bacterial genomes. Finally, we evaluate experimentally the biological advantage/disadvantage of a simplified version of the Psp system under different oxygen-related environments. Our results suggest that the Psp system evolved around a core response mechanism by gradually co-opting genes into the system to provide more nuanced sensory, signaling, and effector functionalities. We find that recruitment of new genes into the response machinery is closely linked to incorporation of these genes into a psp operon as is seen in E. coli, which contains the bulk of genes involved in the response. The organization of this operon allows for surprising levels of additional transcriptional control and flexibility. The results discussed here suggest that the components of such signaling systems will only be evolutionarily conserved if the overall functionality of the system can be maintained.

Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation.

OBJECTIVES: Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation. DESIGN: Retrospective evaluation of patients with ALys. SETTING: UK National Amyloidosis Centre. PATIENTS: All 16 patients with ALys followed at the centre. RESULTS: A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx. CONCLUSIONS: Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival.

Solid organ transplantation in AL amyloidosis.

Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2-13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.

Uterine artery pulsatility and resistivity indices in pregnancy: Comparison of MRI and Doppler US.

OBJECTIVE: The aim of this work was to evaluate whether the uterine arteries (UtA) could be identified and their flow profiles measured during a fetal MRI examination. A comparison was performed against same day sonographic Doppler assessment. METHODS: 35 normal, healthy, singleton pregnancies at 28-32 weeks gestation underwent routine Doppler examination, followed by MRI examination. The resistivity index (RI) and pulsatility index (PI) of the left and right UtA were measured using phase contrast MRI. Bland Altman statistics were used to compare MRI and ultrasound results. RESULTS: Sixty-nine comparable vessels were analysed. Six vessels were excluded due to artefact or technical error. Bland-Altman analysis demonstrated the ultrasound indices were comparable, although systematically lower than the MRI indices; Right UtA RI bias -0.03 (95% limits of agreement (LOA) -0.27 to +0.20), and left UtA RI bias -0.06 (95% LOA -0.26 to +0.14); Right UtA PI bias -0.06 (95% LOA -0.50 to +0.38), Left UtA PI bias -0.11 (95% LOA -0.54 to +0.32). The inter-rater agreement for the MRI derived PI and RI analysis was good. CONCLUSION: This study demonstrates that in the majority of early third trimester pregnancies, the uterine arteries can be identified, and their flow profiles measured using MRI, and that the derived PI and RI values are comparable with Doppler ultrasound values.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

Reducing smoking at the workplace: implementing a smoking ban and hypnotherapy.

Smoking cessation programs may be an important component in the implementation of worksite smoking policies. This study examines the impact of a smoke-free policy and the effectiveness of an accompanying hypnotherapy smoking cessation program. Participants in the 90-minute smoking cessation seminar were surveyed 12 months after the program was implemented (n = 2642; response rate = 76%). Seventy-one percent of the smokers participated in the hypnotherapy program. Fifteen percent of survey respondents quit and remained continuously abstinent. A survey to assess attitudes toward the policy was conducted 1 year after policy implementation (n = 1256; response rate = 64%). Satisfaction was especially high among those reporting high compliance with the policy. These results suggest that hypnotherapy may be an attractive alternative smoking cessation method, particularly when used in conjunction with a smoke-free worksite policy that offers added incentive for smokers to think about quitting.

Review and needs assessment of materials designed to prevent tobacco use.

Over the past 25 years, numerous educational materials and strategies have been developed for the prevention and control of tobacco use. However, there has been no comprehensive assessment of the available materials designed to educate the public to avoid the use of tobacco. A search for materials and a review process was conducted in the fall of 1993, and a panel of experts reviewed the materials that were collected. In conducting the search, 240 persons and organizations associated with tobacco control efforts across the United States were contacted, and 207 materials were identified and evaluated. All materials were assessed by at least two members of the expert panel. Of the 207 items, 188 were found to be acceptable according to standardized review criteria. The authors drew conclusions about the current availability of tobacco use prevention materials and present recommendations for increasing the availability of materials to community-level and other control programs.

A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.

Despite improvements in therapy amyloid light-chain (AL) amyloidosis, there are few studies comparing different regimens. Here we present a matched comparison with 69 patients in each cohort examining upfront therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) vs cyclophosphamide, thalidomide and dexamethasone (CTD). On an intention-to-treat basis, the overall response rates were 71.0% vs 79.7% in the CVD and CTD arms, respectively, (P=0.32). A higher complete response (CR) rate was observed in the CVD arm (40.5%) vs CTD (24.6%), P=0.046. One-year overall survival (OS) was 65.2% and 66.7% for CVD and CTD, respectively (P=0.87). The median progression-free survival (PFS) was 28.0 and 14.0 m for CVD and CTD, respectively (P=0.039). In a landmark analysis assessing outcomes performed at 6 months, the CR rate with CVD was 59.6% vs 34.0% for CTD (P=0.03). The 1-year OS was 96% with CVD and 92% with CTD (P=0.40). The median PFS with CVD was not reached and was 19.2 m with CTD, P=0.028). In summary, both regimens are unable to overcome the high rate of early deaths in AL amyloidosis. However, CVD correlates with improved depth of response and superior PFS supporting its use in the frontline setting. Further optimisation and better supportive-care strategies are required to increase the proportion of patients fully benefiting from therapy.

Fulminant hepatitis following primary herpes simplex virus infection.

Fulminant hepatic failure (FHF) is a rare but well-recognized complication of primary herpes simplex virus (HSV) infection in immunocompromised patients. Here, we report two cases of acute hepatitis and FHF secondary to primary HSV type 1 infection following renal transplantation in the absence of any mucocutaneous manifestation. High levels of HSV type-1 DNA were detected in the blood. Both patients were seronegative for HSV 1 and HSV 2 immunoglobulin G (IgG) before transplantation, whereas the donor of patient 1 was HSV 1 IgG-positive but had no viremia and the donor of patient 2 was HSV-seronegative. Patient 1 recovered with acyclovir and immunoglobulin whereas patient 2 did not respond and succumbed to death. HSV-seronegative patients are potentially at risk of developing severe primary HSV disease following transplantation, particularly in the absence of routine anti-viral prophylaxis. HSV infection should always be excluded in transplant patients with hepatic dysfunction.

The emergence of Dutch casinos: A case study of mismarketing?

Ostensibly, the approval of legalized casino type gambling in the Netherlands was intended to combat illegal and uncontrolled gambling. Very early on, however, the plan conceived and implemented by the Netherlands Parliament demonstrated serious mismarketing strategies and tactics. The new legal casinos were appealing to people other than those engaged in illegal gambling, in particular foreign tourists and local "high rollers." This paper attempts to analyze the ultimate process of goal displacement, as the state casino industry allowed economic objectives to supplant desires to utilize legal casinos primarily as controls over illegal gambling.

Petri Net representations in systems biology.

The mathematical structures known as Petri Nets have recently become the focus of much research effort in both the structural and quantitative analysis of all kinds of biological networks. This review provides a very brief summary of these interesting new research directions.

Effects of a worksite nonsmoking policy: evidence for increased cessation.

A random sample of employees was surveyed 20 months after a non-smoking policy was implemented at the New England Telephone Company in 1986. Overall, 21 percent of respondents who were smoking at the time they heard about the policy had quit smoking; 42 percent of quitters said they stopped smoking because of the policy. Cessation was highest among those who reported less smoke in their work area, but was not related to participation in cessation programs. This study suggests that worksite nonsmoking policies may have favorable effects on smoking cessation.

Employee knowledge and attitudes about a work-site nonsmoking policy: rationale for further smoking restrictions.

This study examines employee knowledge of and satisfaction with a nonsmoking policy instituted at approximately 600 work sites of the New England Telephone company in 1986. A stratified random sample of employees was surveyed 20 months after the policy was implemented; 1120 (74.5%) returned surveys. Awareness of the rules about smoking in most areas was high, especially where smoking was totally banned. Respondents were highly satisfied with the policy, but half preferred additional restrictions on smoking. The policy was effective in reducing perceived environmental tobacco smoke exposure in work areas where smoking was banned but not in nonwork areas where smoking was allowed in designated areas. This study suggests that a highly restrictive nonsmoking policy--including a total ban on smoking--may be more easily and successfully implemented than are less restrictive policies.