Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine.

BACKGROUND: Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data. RESULTS: Using a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions. CONCLUSIONS: The results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria.

How can cardiothoracic and vascular medical devices stay in the market?

Surgeons, as the consumers, must engage in commercial activity regarding medical devices since it directly has impacts on surgical practice and patient outcomes. Unique features defy traditional economic convention in this specific market partly because consumers do not usually pay directly. Greater involvement with commercial activity means better post-market surveillance of medical devices which leads to improved patient safety. The medical device industry has exhibited astonishing levels of growth and profitability reaching $398 billion on a global scale with new product development focusing on unmet clinical need. The industry has rapidly emerged within the context of an ageing population and a global surge in healthcare spending. But the market remains fragmented. The split of consumer, purchaser and payer leads to clinical need driving demand for new product development. This demand contributes to potentially large profit margins mainly contained by regulatory burden and liability issues. Demographic trends, prevalence of diseases and a huge capacity to absorb technology have sustained near unparalleled growth. To stay in the market, incremental development over the short term is essentially aided by responsiveness to demand. Disruptive product development is now more likely to come from multinational companies, in an increasingly expensive, regulated industry. Understanding healthcare organization can help explain the highly complex process of diffusion of innovations in healthcare that include medical devices. The time has come for surgeons to become actively involved with all aspects of the medical device life cycle including commercial activity and post-market surveillance. This is vital for improving patient care and ensuring patient safety.

Can the Presence of Crystalluria Predict Stone Formation in Patients with Cystinuria?

OBJECTIVES: To determine the feasibility of crystalluria as a biomarker for stone disease in patients with cystinuria. PATIENTS AND METHODS: All patients attending a multidisciplinary cystinuria clinic provided early morning urine (EMU) and clinic urine (CU) samples for crystal measurement over a 2-year period (August 1, 2010, to July 31, 2012). Association between presence of crystals, presence of stone(s), and new stone growth (NSG) was determined using the chi-square test. Crystal numbers in EMU and CU were compared in patients with stones/NSG and no stones/stable disease using the Mann-Whitney U test. RESULTS: There was a statistically significant difference between the presence of crystalluria and presence of stones for CU (chi-square test = 5.86, df = 1, p = 0.02) but not EMU (chi-square test = 1.92, df = 1, p = 0.17) and between the presence of crystalluria and NSG for CU (chi-square test = 8.10, df = 1, p = 0.004) but not EMU (chi-square test = 1.32, df = 1, p = 0.25). Patients with stones and NSG have higher levels of crystalluria in CU than patients with no stones or stable disease (stones, median = 41, interquartile range [IQR] = 600 vs median = 0, IQR = 21, p = 0.01; NSG, median = 49, IQR = 525 vs median = 0, IQR = 40, p = 0.01). CONCLUSION: The presence of crystalluria in CU samples is associated with the presence of stones. Crystalluria is comparable to ultrasound and may serve as a useful adjunct to predict whether a patient with cystinuria has stones, which could guide the frequency of clinic review and imaging.

The genetic diversity of cystinuria in a UK population of patients.

OBJECTIVE: To examine the genetic mutations in the first UK cohort of patients with cystinuria with preliminary genotype/phenotype correlation. PATIENTS AND METHODS: DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to identify the mutations in 74 patients in a specialist cystinuria clinic in the UK. Patients with type A cystinuria were classified into two groups: Group M patients had at least one missense mutation and Group N patients had two alleles of all other types of mutations including frameshift, splice site, nonsense, deletions and duplications. The levels of urinary dibasic amino acids, age at presentation of disease, number of stone episodes and interventions were compared between patients in the two groups using the Mann-Whitney U-test. RESULTS: In all, 41 patients had type A cystinuria, including one patient with a variant of unknown significance and 23 patients had type B cystinuria, including six patients with variants of unknown significance. One patient had three sequence variants in SLC7A9; however, two are of unknown significance. Three patients had type AB cystinuria. Three had a single mutation in SLC7A9. No identified mutations were found in three patients in either gene. There were a total of 88 mutations in SLC3A1 and 55 mutations in SLC7A9. There were 23 pathogenic mutations identified in our UK cohort of patients not previously published. In patients with type A cystinuria, the presence of a missense mutation correlated to lower levels of urinary lysine (mean [SE] 611.9 [22.65] vs 752.3 [46.39] millimoles per mole of creatinine [mM/MC]; P=0.02), arginine (194.8 [24.83] vs 397.7 [15.32] mM/MC; P<0.001) and ornithine (109.2 [7.40] vs 146.6 [12.7] mM/MC; P=0.02). There was no difference in the levels of urinary cystine (182.1 [8.89] vs 207.2 [19.23] mM/MC; P=0.23). CONCLUSIONS: We have characterised the genetic diversity of cystinuria in a UK population including 23 pathogenic mutations not previously published. Patients with at least one missense mutation in SLC3A1 had significantly lower levels of lysine, arginine, and ornithine but not cystine than patients with all other combinations of mutations.

Outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective?

OBJECTIVES: To evaluate the safety, tolerability and effectiveness of outpatient (office-based) laser ablation (OLA), with local anaesthetic, for non-muscle-invasive bladder cancer (NMIBC) in an elderly population with and without photodynamic diagnosis (PDD). To compare the cost-effectiveness of OLA of NMIBC with that of inpatient cystodiathermy (IC). PATIENTS AND METHODS: We conducted a prospective cohort study of patients with NMIBC treated with OLA by one consultant surgeon between March 2008 and July 2011 A subgroup of patients had PDD before undergoing OLA. Safety and effectiveness were determined by complications (In the immediate post operative period, at three days and at three months), patient tolerability (visual analogue score) and recurrence rates. The long-term costs and cost-effectiveness of OLA and IC of NMIBC were evaluated using Markov modeling. RESULTS: A total of 74 OLA procedures (44 white-light, 30 PDD) were carried out in 54 patients. The mean (range) patient age was 77 (52-95) years. More than half of the patients had more than three comorbidities. Previous tumour histology ranged from G1pTa to T3. One patient had haematuria for 1 week which settled spontaneously and did not require hospital admission. There were no other complications. The procedure was well tolerated with pain scores of 0-2/10. Additional lesions were found in 21% of patients using PDD that were not found using white light. At 3 months, the percentage of patients who had recurrence after OLA with white light and OLA with PDD were 10.6 and 4.3%, respectively. At 1 year, 65.1% and 46.9% of patients had recurrence. The cost of OLA was found to be much lower than that of IC (£538 vs £1474), even with the addition of PDD (£912 vs £1844). Over the course of a patient's lifetime, OLA was more clinically effective, measured in quality-adjusted life-years (QALY), than IC (0.147 [sd 0.059]) and less costly (£2576.42 [sd £7293.07]). At a cost-effectiveness threshold of £30,000/QALY, as set by the National Institute for Health and Care Excellence, there was an 82% probability that OLA was cost-effective. CONCLUSIONS: This is the first study to demonstrate the long-term cost-effectiveness of OLA of NMIBC. The results support the use of OLA for the treatment of NMIBC, especially in the elderly.

Management of stones in renal transplant.

PURPOSE OF REVIEW: Increasingly, screening of both deceased and living donor organs has led to the early detection of kidney stones prior to donation. A number of transplant recipients will still present with donor-gifted and de-novo stones. A range of treatment modalities is available in the management of renal transplant stones. RECENT FINDINGS: Stones can be pretreated in the (living) donor prior to transplantation, managed at the time of transplantation or treated in the recipient post-transplant. The options include conservative management, extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy, ureteroscopy or open surgery depending on the size and location of the stone(s). Various techniques to deal with a transplant kidney are described. Ex-vivo ureteroscopy or pyeloscopy can safely render a kidney-stone free prior to transplantation and in living donors this means without subjecting the living donor to an additional stone removing procedure. SUMMARY: The cause of renal transplant lithiasis is multifactorial. More research is needed to understand the factors associated with de-novo stone formation. Early detection of donor-gifted stones can allow stones to be removed at the time of transplantation. Close follow up of both living donors and transplant recipients is necessary to ensure long-term safety is maintained.

Leadership in cardiac surgery.

Despite the efficacy of cardiac surgery, less invasive interventions with more uncertain long-term outcomes are increasingly challenging surgery as first-line treatment for several congenital, degenerative and ischemic cardiac diseases. The specialty must evolve if it is to ensure its future relevance. More importantly, it must evolve to ensure that future patients have access to treatments with proven long-term effectiveness. This cannot be achieved without dynamic leadership; however, our contention is that this is not enough. The demands of a modern surgical career and the importance of the task at hand are such that the serendipitous emergence of traditional charismatic leadership cannot be relied upon to deliver necessary change. We advocate systematic analysis and strategic leadership at a local, national and international level in four key areas: Clinical Care, Research, Education and Training, and Stakeholder Engagement. While we anticipate that exceptional individuals will continue to shape the future of our specialty, the creation of robust structures to deliver collective leadership in these key areas is of paramount importance.

Cardioprotection by the female sex hormone -- interaction with the beta1-adrenoceptor and its signaling pathways.

Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of beta-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/beta-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down-regulation of the beta(1)-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G(s) protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca(2+)/calmodulin kinase II deltac isoform (CaMKII-deltac), another downstream second messenger of the beta(1)-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial beta(1)-adrenoceptor and attenuate Ca(2+) influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the beta-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the beta(1)-adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection.