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1.  Economic Consequences Incurred by Living Kidney Donors: A Canadian Multi-Center Prospective Study 
Some living kidney donors incur economic consequences as a result of donation; however, these costs are poorly quantified. We developed a framework to comprehensively assess economic consequences from the donor perspective including out-of-pocket cost, lost wages and home productivity loss. We prospectively enrolled 100 living kidney donors from seven Canadian centers between 2004 and 2008 and collected and valued economic consequences ($CAD 2008) at 3 months and 1 year after donation. Almost all (96%) donors experienced economic consequences, with 94% reporting travel costs and 47% reporting lost pay. The average and median costs of lost pay were $2144 (SD 4167) and $0 (25th–75th percentile 0, 2794), respectively. For other expenses (travel, accommodation, medication and medical), mean and median costs were $1780 (SD 2504) and $821 (25th–75th percentile 242, 2271), respectively. From the donor perspective, mean cost was $3268 (SD 4704); one-third of donors incurred cost >$3000, and 15% >$8000. The majority of donors (83%) reported inability to perform usual household activities for an average duration of 33 days; 8% reported out-of-pocket costs for assistance with these activities. The economic impact of living kidney donation for some individuals is large. We advocate for programs to reimburse living donors for their legitimate costs.
In a prospective costing study, the authors find that economic consequences incurred by living kidney donors are frequent and nontrivial, and a notable proportion of donors experience significant costs.
PMCID: PMC4285205  PMID: 24597854
Cost of illness; costs and cost analysis; kidney transplantation; living donors
2.  Metastatic renal cell carcinoma without evidence of a primary renal tumour 
Current Oncology  2014;21(3):e521-e524.
Although metastases are common in patients with renal cell carcinoma (rcc), it is extremely rare for patients to present with metastatic rcc (mrcc) without evidence of a primary mass in the kidney. Two cases of mrcc with no detectable primary renal mass are reported here. Both patients had bilateral native kidneys in situ and no significant prior urologic history. The first patient presented with a hip fracture and was found to have multiple radiologic bony and lung metastases. Biopsy of a mass involving the pubic bone demonstrated clear cell mrcc. Multiple scans by computed tomography (ct) and confirmatory imaging by magnetic resonance demonstrated no renal mass. This first patient had disease stabilization for 18 months on sunitinib and was still alive at last follow-up. The second patient was diagnosed with clear-cell mrcc after thickened synovium was discovered and biopsied during a knee arthroplasty. Multiple scans by ct in this second patient demonstrated no primary renal mass. Sunitinib and radiotherapy to the knee lesion were initiated, but unfortunately, the patient deteriorated clinically and passed away from disease progression shortly after diagnosis. Because of the rare nature of these cases, a standardized course of action has not yet been established. However, we hypothesize that it is reasonable to manage metastases in these patients by following established mrcc protocols.
PMCID: PMC4059817  PMID: 24940113
Metastatic renal cell carcinoma; kidney cancer; no primary tumour
3.  Adjuvant chemotherapy in elderly patients with pancreatic cancer 
British Journal of Cancer  2013;110(2):313-319.
Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer.
We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative.
The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ⩾70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8% P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27–2.78, P=0.002).
Patients aged ⩾70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.
PMCID: PMC3899761  PMID: 24263063
pancreatic cancer; adjuvant chemotherapy; elderly
4.  Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo 
The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on the reactivity of FVIII inhibitory antibodies, referred to as inhibitors, is still controversial.
To investigate the interaction among VWF, FVIII and FVIII inhibitory antibodies.
Three sources of inhibitors were used for in vitro studies, including the plasma from immunized VWFnullFVIIInull mice, purified plasma IgG from human inhibitor patients, or human monoclonal antibody from inhibitor patients’ B-cell clones. Inhibitors were incubated with recombinant human FVIII (rhFVIII) either with or without VWF. The remaining FVIII activity was determined by chromogenic assay and inhibitor titers were determined. For in vivo studies, inhibitors and rhFVIII were infused into FVIIInull or VWFnullFVIIInull mice followed by a tail clip survival test.
VWF has a dose-dependent protective effect on FVIII, limiting inhibitor inactivation of FVIII in both mouse and human samples. A preformed complex of VWF with FVIII provides more effective protection from inhibitors than competitive binding of antibodies and VWF to FVIII. The protective effect of VWF against FVIII inactivation by inhibitors was further confirmed in vivo by infusing inhibitors and FVIII into FVIIInull or VWFnullFVIIInull mice followed by a tail clip survival test.
Our results demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo.
PMCID: PMC3670966  PMID: 22908929
FVIII; inhibitory antibody; VWF
5.  Solid Organ Transplantation in Older Adults: Current Status and Future Research 
An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK, and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.
PMCID: PMC3459231  PMID: 22958872
transplantation; liver; kidney; heart; lung; elderly; aging
6.  Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK 
Diabetologia  2013;56(10):2238-2249.
This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}]) and physical activity.
One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40–70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMAIR), plus other risk factors, and underwent assessment of physical activity (using accelerometry), \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}, body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA1c levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMAIR and fasting glucose between South Asian and European men.
HOMAIR and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document}, lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMAIR. Lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2 \max } $$\end{document} and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose.
Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2969-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3764328  PMID: 23811809
Adiposity; Ethnicity; Fitness; Glycaemia; Insulin resistance; Maximal oxygen uptake; Obesity; Physical activity; Sedentary; South Asian
7.  Management of renal collecting duct carcinoma: a systematic review and the McMaster experience 
Current Oncology  2013;20(3):e223-e232.
Collecting duct carcinoma (cdc) is a rare, aggressive form of renal carcinoma that presents at an advanced stage and has a poor prognosis. Little is known concerning the optimal management of cdc. We present the results of a systematic review addressing the management of cdc and the McMaster University cdc series.
The medline, Cochrane Library, and embase databases and conference proceedings were searched to identify studies relating to the management of cdc. Included studies reported on a minimum of 10 subjects receiving a single intervention. Series in which an evaluation of therapeutic effectiveness was not possible were excluded. The McMaster University (Hamilton, Ontario) series of 6 cases of cdc were retrospectively reviewed.
We identified 3 studies relevant to the management of cdc that included a total of 72 patients. A gemcitabine–cisplatin or –carboplatin regimen resulted in a 26% objective response rate in 23 patients with metastatic cdc. Two additional studies indicated that 49 patients treated with immunotherapy achieved no response. In the McMaster series, cytoreductive nephrectomy was performed in 4 of 6 patients. In 2 patients, mvac therapy (methotrexate–vinblastine–doxorubicin–cisplatin) achieved no response. No significant therapeutic complications occurred, but survival was poor (median: 11 months; range: 10–33 months).
Our review and clinical experience suggest that the current standard of care for metastatic cdc is a gemcitabine–cisplatin regimen.
PMCID: PMC3671029  PMID: 23737692
Collecting duct carcinoma; Bellini duct carcinoma; renal cell carcinoma; cytoreductive nephrectomy; gemcitabine; cisplatin; mvac
8.  Evaluation of a Mindfulness-Based Intervention Program to Decrease Blood Pressure in Low-Income African-American Older Adults 
Hypertension affects a large proportion of urban African-American older adults. While there have been great strides in drug development, many older adults do not have access to such medicines or do not take them. Mindfulness-based stress reduction (MBSR) has been shown to decrease blood pressure in some populations. This has not been tested in low-income, urban African-American older adults. Therefore, the primary purpose of this pilot study was to test the feasibility and acceptability of a mindfulness-based program for low income, minority older adults provided in residence. The secondary purpose was to learn if the mindfulness-based program produced differences in blood pressure between the intervention and control groups. Participants were at least 62 years old and residents of a low-income senior residence. All participants were African-American, and one was male. Twenty participants were randomized to the mindfulness-based intervention or a social support control group of the same duration and dose. Blood pressure was measured with the Omron automatic blood pressure machine at baseline and at the end of the 8-week intervention. A multivariate regression analysis was performed on the difference in scores between baseline and post-intervention blood pressure measurements, controlling for age, education, smoking status, and anti-hypertensive medication use. Effect sizes were calculated to quantify the magnitude of the relationship between participation in the mindfulness-based intervention and the outcome variable, blood pressure. Attendance remained >80% in all 8 weeks of both the intervention and the control groups. The average systolic blood pressure decreased for both groups post-intervention. Individuals in the intervention group exhibited a 21.92-mmHg lower systolic blood pressure compared to the social support control group post-intervention and this value was statistically significant (p = 0.020). The average diastolic blood pressure decreased in the intervention group post-intervention, but increased in the social support group. Individuals in the intervention group exhibited a 16.70-mmHg lower diastolic blood pressure compared to the social support group post-intervention, and this value was statistically significant (p = 0.003). Older adults are at a time in life when a reflective, stationary intervention, delivered in residence, could be an appealing mechanism to improve blood pressure. Given our preliminary results, larger trials in this hypertensive study population are warranted.
PMCID: PMC3324609  PMID: 22302233
Blood pressure; Mindfulness-based stress reduction (MBSR); Older adults
9.  Aggressive renal angiomyolipoma extending into the renal vein and inferior vena cava — an uncommon entity 
The British Journal of Radiology  2011;84(1004):e166-e168.
Renal angiomyolipoma is recognised as a benign hamartomatous lesion with no obvious malignant potential. However, the tumour may show extrarenal/perinephric extension at times. Rarely, the lesion may extend into the renal vein and inferior vena cava (IVC) indicating aggressive behaviour. We present a case of an angiomyolipoma of the kidney with sonographic, CT and MRI evidence of extension into the renal vein and IVC.
PMCID: PMC3473426  PMID: 21750135
10.  The Axillary Nodal Harvest in Breast Cancer Surgery Is Unchanged by Sentinel Node Biopsy or the Timing of Surgery 
Introduction. Patients with a positive sentinel lymph node biopsy may undergo delayed completion axillary dissection. Where intraoperative analysis is available, immediate completion axillary dissection can be performed. Alternatively, patients may undergo primary axillary dissection for breast cancer, historically or when preoperative assessment suggests axillary metastases. This study aims to determine if there is a difference in the total number of lymph nodes or the number of metastatic nodes harvested between the 3 possible approaches. Methods. Three consecutive comparable groups of 50 consecutive patients who underwent axillary dissection in each of the above contexts were identified from the Portsmouth Breast Unit Database. Patient demographics, clinicopathological variables, and surgical treatment were recorded. The total pathological nodal count and the number of metastatic nodes were compared between the groups. Results. There were no differences in clinico-pathological features between the three groups for all features studied with the exception of breast surgical procedure (P < 0.001). There were no differences in total nodal harvest (P = 0.822) or in the number of positive nodes harvested (P = 0.157) between the three groups. Conclusion. The three approaches to axillary clearance yield equivalent nodal harvests, suggesting oncological equivalence and robustness of surgical technique.
PMCID: PMC3369471  PMID: 22693673
11.  The Risk of Risk Adjustment Measures for Perioperative Spine Infection after Spinal Surgery 
Spine  2011;36(9):752-758.
Study Design
Cross sectional data analysis of the Nationwide Inpatient Sample (NIS).
Develop a risk adjustment index specific for perioperative spine infection and compare this specific index to the Deyo Comorbidity Index (Deyo). Assess specific mortality and morbidity adjustments between teaching and non-teaching facilities.
Summary of Background Data
Risk adjustment measures have been developed specifically for mortality and may not be sensitive enough to adjust for morbidity across all diagnosis.
This condition specific index was developed using the NIS in a two step process to determine confounders and weighting. Crude and adjusted point estimates for the Deyo and condition specific index were compared for routine discharge, death, length of stay and total hospital charges then stratified by teaching hospital status
A total of 23,846 perioperative spinal infection events occurred in the NIS database between 1988 and 2007 out of 1,212,241 procedures. Twenty-three diagnoses made up this condition specific index. Significant differences between the Deyo and the condition specific index were seen among total charges and length of stay at non-teaching hospitals (p<0.001) and death, length of stay and total charges (p<0.001) for teaching hospitals.
This study demonstrates several key points. One, condition specific measures may be useful when morbidity is of question. Two, a condition specific perioperative spine infection adjustment index appears to be more sensitive at adjusting for comorbidities. Finally, there are inherent differences in hospital disposition characteristics for perioperative spine infection across teaching and non-teaching hospitals even after adjustment.
PMCID: PMC3075312  PMID: 21217444
12.  The prognostic and predictive value of serum CA19.9 in pancreatic cancer 
Annals of Oncology  2012;23(7):1713-1722.
Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.
We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.
By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P = 0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels >90 U/ml did not benefit from adjuvant chemotherapy (P = 0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P = 0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P = 0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.
Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.
PMCID: PMC3387824  PMID: 22241899
adjuvant chemotherapy; CA19.9; pancreatic cancer; prognosis
13.  Ureteric sarcoidosis — a rare entity 
The British Journal of Radiology  2010;83(996):e247-e248.
Primary ureteric involvement in sarcoidosis is very rare; to our knowledge, only a few cases have been reported in the literature. We present here a rare case of ureteric sarcoidosis presenting with obstructive uropathy.
PMCID: PMC3473606  PMID: 21088080
14.  Genomic and Functional Analyses of Rhodococcus equi Phages ReqiPepy6, ReqiPoco6, ReqiPine5, and ReqiDocB7 ▿  
The isolation and results of genomic and functional analyses of Rhodococcus equi phages ReqiPepy6, ReqiDocB7, ReqiPine5, and ReqiPoco6 (hereafter referred to as Pepy6, DocB7, Pine5, and Poco6, respectively) are reported. Two phages, Pepy6 and Poco6, more than 75% identical, exhibited genome organization and protein sequence likeness to Lactococcus lactis phage 1706 and clostridial prophage elements. An unusually high fraction, 27%, of Pepy6 and Poco6 proteins were predicted to possess at least one transmembrane domain, a value much higher than the average of 8.5% transmembrane domain-containing proteins determined from a data set of 36,324 phage protein entries. Genome organization and protein sequence comparisons place phage Pine5 as the first nonmycobacteriophage member of the large Rosebush cluster. DocB7, which had the broadest host range among the four isolates, was not closely related to any phage or prophage in the database, and only 23 of 105 predicted encoded proteins could be assigned a functional annotation. Because of the relationship of Rhodococcus to Mycobacterium, it was anticipated that these phages should exhibit some of the features characteristic of mycobacteriophages. Traits that were identified as shared by the Rhodococcus phages and mycobacteriophages include the prevalent long-tailed morphology and the presence of genes encoding LysB-like mycolate-hydrolyzing lysis proteins. Application of DocB7 lysates to soils amended with a host strain of R. equi reduced recoverable bacterial CFU, suggesting that phage may be useful in limiting R. equi load in the environment while foals are susceptible to infection.
PMCID: PMC3020559  PMID: 21097585
15.  WolffParkinsonWhite syndrome and persistent azygous drainage of the inferior vena cava 
BMJ Case Reports  2009;2009:bcr2006101022.
PMCID: PMC3105787  PMID: 21687173
left-sided accessory pathway; persistent azygous vein; RF ablation; WolffParkinsonWhite
18.  Wolff–Parkinson–White syndrome and persistent azygous drainage of the inferior vena cava 
Heart  2007;93(10):1166.
PMCID: PMC2000946  PMID: 17890686
left‐sided accessory pathway; persistent azygous vein; RF ablation; Wolff–Parkinson–White
19.  Gross genomic damage measured by DNA image cytometry independently predicts gastric cancer patient survival 
British Journal of Cancer  2009;101(6):1011-1018.
DNA aneuploidy reflects gross genomic changes. It can be measured by flow cytometry (FCM-DNA) or image cytometry (ICM-DNA). In gastric cancer, the prevalence of DNA aneuploidy has been reported to range from 27 to 100%, with conflicting associations with clinicopathological variables. The aim of our study was to compare the DNA ploidy status measured using FCM-DNA and ICM-DNA in gastric cancer and to evaluate its association with clinicopathological variables.
Cell nuclei were isolated from 221 formalin-fixed, paraffin-embedded gastric cancer samples. DNA ploidy was assessed using FCM-DNA and ICM-DNA.
A total of 178 (80.5%) gastric cancer samples were classified as DNA aneuploid using FCM-DNA, compared with 172 (77.8%) gastric cancer samples when using ICM-DNA. Results obtained from both methods were concordant in 183 (82.8%) cases (κ=0.48). Patients with ICM-DNA diploid gastric cancer survived significantly longer than those with ICM-DNA aneuploid gastric cancer (log rank 10.1, P=0.001). For FCM-DNA data, this difference did not reach statistical significance. The multivariate Cox model showed that ICM-DNA ploidy status predicted patient survival independently of tumour-node-metastasis status.
ICM-DNA ploidy status is an independent predictor of survival in gastric cancer patients and may therefore be a more clinically relevant read out of gross genomic damage than FCM-DNA.
PMCID: PMC2743350  PMID: 19738619
gastric cancer; image cytometry; flow cytometry; DNA ploidy; prognosis
20.  In vivo cartilage contact deformation in the healthy human tibiofemoral joint 
Rheumatology (Oxford, England)  2008;47(11):1622-1627.
Objectives. In vivo cartilage contact deformation is instrumental for understanding human joint function and degeneration. This study measured the total deformation of contacting articular cartilage in the human tibiofemoral joint during in vivo weight-bearing flexion.
Methods. Eleven healthy knees were magnetic resonance (MR) scanned and imaged with a dual fluoroscopic system while the subject performed a weight-bearing single-leg lunge. The tibia, femur and associated articulating cartilage were constructed from the MR images and combined with the dual fluoroscopic images to determine in vivo cartilage contact deformation from full extension to 120° of flexion.
Results. In both compartments, minimum peak compartmental contact deformation occurred at 30° of flexion (24 ± 6% medial, 17 ± 7% lateral) and maximum peak compartmental deformation occurred at 120° of flexion (30 ± 13% medial, 30 ± 10% lateral) during the weight-bearing flexion from full extension to 120°. Average medial contact areas and peak contact deformations were significantly greater than lateral compartment values (P < 0.05). In addition, cartilage thickness in regions of contact was on average 1.4- and 1.1-times thicker than the average thickness of the tibial and femoral cartilage surfaces, respectively (P < 0.05).
Conclusions. These data may provide base-line knowledge for investigating the effects of various knee injuries on joint contact biomechanics and the aetiology of cartilage degeneration.
PMCID: PMC2569133  PMID: 18775967
Compartmental cartilage deformation; Knee joint; Biomechanics; Magnetic resonance; Cartilage thickness
21.  Genetic alteration of the D2 domain abolishes von Willebrand factor multimerization and trafficking into storage 
The large von Willebrand factor (VWF) propeptide (VWFpp) plays a critical role in the multimerization and regulated storage of the mature VWF protein. Although our laboratory and others have identified mutations in von Willebrand disease patients that disrupt VWF multimerization, little is known about the affect of mutations on the regulated storage of VWF.
We identified a heterozygous 18 base pair, in-frame deletion in exon 12 of the VWF gene in a patient with an unusual, dimer-intense multimer pattern. This deletion results in loss of amino acids 436–442 of VWFpp, which include one cysteine.
Through expression studies, we demonstrate reduced secretion, loss of VWF multimerization, and defective regulated storage of the variant VWF. The loss of VWF storage is secondary to loss of propeptide storage resulting from an apparently defective sorting signal on VWFpp. Suprisingly, coexpressed wild-type VWF or VWFpp functioned in trans to partially restore multimerization of VWF from the variant allele.
The deletion of six amino acids in VWFpp results in defects in VWF processing, regulated storage, and function. Although VWFpp may usually function in a homotypic fashion, acting on its own mature VWF subunit, VWFpp may retain the ability to function in trans on VWF expressed from the variant allele.
PMCID: PMC2745278  PMID: 19192112
von Willebrand disease; von Willebrand factor; Weibel–Palade body
22.  Exercise training has greater effects on insulin sensitivity in daughters of patients with type 2 diabetes than in women with no family history of diabetes 
Diabetologia  2008;51(10):1912-1919.
Sedentary offspring of patients with type 2 diabetes are often more insulin-resistant than persons with no family history of diabetes, but when active or fit offspring of type 2 diabetic patients are compared with non-diabetic persons, differences in insulin resistance are less evident. This study aimed to determine the effects of an exercise training intervention on insulin sensitivity in both groups.
Women offspring (n = 34) of type 2 diabetic patients (offspring age 35.6 ± 7.0 years, BMI 28.1 ± 5.1 kg/m2) and 36 matched female controls (age 33.6 ± 6.1 years, BMI 27.3 ± 4.7 kg/m2) participated. Body composition, fitness and metabolic measurements were made at baseline and after a controlled 7 week exercise intervention.
At baseline, insulin sensitivity index (ISI) was 22% lower in offspring than controls (p < 0.05), despite similar body fat and maximal oxygen uptake \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( {\dot VO_{2\max } } \right)$$\end{document} values in the two groups. ISI increased by 23% (p < 0.05) in offspring following the exercise intervention, compared with 7% (NS) in the controls. Increases in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot VO_{2\max } $$\end{document} were similar in both groups (controls 12%, offspring 15%, p < 0.05 for both). Plasma leptin concentrations decreased significantly in the offspring (−24%, p < 0.01) but not in controls (0%, NS). Change in ISI correlated significantly with baseline ISI (r = −0.47, p < 0.0005) and change in leptin (r = −0.43, p < 0.0005). The latter relationship was not attenuated by adjustment for changes in body fat.
Offspring, but not controls, significantly increased ISI in response to an exercise intervention, indicating that insulin sensitivity is more highly modulated by physical activity in daughters of patients with type 2 diabetes than in women with no family history of the disease.
Trial registration: NCT00268541
Funding: British Heart Foundation (PG/03/145).
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-008-1097-6) contains supplementary material, which is available to authorised users.
PMCID: PMC2584356  PMID: 18663427
Diabetes family history; Exercise; Insulin resistance; Insulin sensitivity; Leptin; Offspring; Training; Women
23.  Metabolic syndrome and risk of coronary heart disease in a Pakistani cohort 
Heart  2005;91(8):1003-1007.
Objective: To assess the relation of the metabolic insulin resistance syndrome (M-IRS) with coronary heart disease (CHD) in Pakistani patients.
Subjects: 200 patients with angiographic disease (CHD(+)) matched with 200 patients with chest pain without occlusive disease (CHD(−)).
Design: Prospective case–control study.
Setting: Tertiary referral cardiology unit in Pakistan.
Results: M-IRS was present in 37% of CHD(+) versus 27% of CHD(−) patients by criteria for white patients or 47% versus 42%, respectively, by Asian criteria (p < 0.001). After adjustment for other risk factors, M-IRS was not a significant predictor for CHD or angiographic disease. Age (p  =  0.03), smoking (p < 0.001), diabetes-years (p = 0.003), sialic acid (p  =  0.01), and creatinine (p  =  0.008) accounted for the excess risk of CHD. Similarly, age (p  =  0.005), creatinine (p < 0.001), cigarette pack-years (p  =  0.02), diabetes-years (p  =  0.003), and sialic acid (p  =  0.08) were predictors of greater angiographic disease. M-IRS differed between Pakistani and white patients, as waist circumference correlated weakly (r  =  −0.03–0.08, p  =  0.45–0.52) with triglycerides, high density lipoprotein cholesterol, systolic blood pressure, or glucose. Sialic acid was the only inflammatory marker associated with M-IRS.
Conclusions: Despite strong associations between individual risk factors associated with M-IRS and a univariate association between M-IRS and CHD in native Pakistanis, the principal discriminant risk factors in this group are age, smoking, inflammation, diabetes-years, and impaired renal function. The poor sensitivity of M-IRS for CHD reflects the high underlying prevalence of M-IRS, thus reducing sensitivity, confounding by other urban lifestyle traits, or a lack of association of waist circumference with M-IRS risk factors. The definition of M-IRS may have to be revised to increase its power as a discriminant risk factor for CHD in Pakistani populations.
PMCID: PMC1769029  PMID: 16020583
coronary heart disease; Indian Asian; insulin resistance; metabolic syndrome; risk
24.  Rational Genomics I: Antisense Open Reading Frames and Codon Bias In Short Chain Oxido Reductase Enzymes and the Evolution of the Genetic Code. 
Proteins  2005;61(4):900-906.
The short chain oxidoreductase (SCOR) family of enzymes includes over 6000 members, extending from bacteria and archaea to humans. Nucleic acid sequence analysis reveals that significant numbers of these genes are remarkably free of stop codons in reading frames other than the coding frame, including those on the antisense strand. The genes from this subset also use almost entirely the GC-rich half of the 64 codons. Analysis of a million hypothetical genes having random nucleotide composition shows that the percentage of SCOR genes having multiple open reading frames exceeds random by a factor of as much as 1×106. Nevertheless screening the content of the SWISS-PROT TrEMBL database reveals that 15% of all genes contain multiple open reading frames. The SCOR genes having multiple open reading frames and a GC-rich coding bias exhibit a similar GC bias in the nucleotide triple composition of their DNA. This bias is not correlated with the GC content of the species in which the SCOR genes are found. One possible explanation for the conservation of multiple open reading frames and extreme bias in nucleic acid composition in the family of Rossman folds is that the primordial member of this family was encoded early using only very stable GC-rich DNA and that evolution proceeded with extremely limited introduction of any codons having two or more adenine or thymine nucleotides. These and other data suggest that the SCOR family of enzymes may even have diverged from a common ancestor before most of the AT-rich half of the genetic code was fully defined.
PMCID: PMC1476703  PMID: 16245321
25.  The Extended Learning Curve for Laparoscopic Fundoplication: A Cohort Analysis Of 400 Consecutive Cases 
Many studies have looked at the learning curve associated with laparoscopic Nissen fundoplication (LNF) in a given institution. This study looks at the learning curve of a single surgeon with a large cohort of patients over a 10-year period. Prospective data were collected on 400 patients undergoing laparoscopic fundoplication for over 10 years. The patients were grouped consecutively into cohorts of 50 patients. The operating time, the length of postoperative hospital stay, the conversion rate to open operation, the postoperative dilatation rate, and the reoperation rate were analyzed. Results showed that the mean length of operative time decreased from 143 min in the first 50 patients to 86 min in the last 50 patients. The mean postoperative length of hospital stay decreased from 3.7 days initially to 1.2 days latterly. There was a 14% conversion to open operation rate in the first cohort compared with a 2% rate in the last cohort. Fourteen percent of patients required reoperation in the first cohort and 6% in the last cohort. Sixteen percent required postoperative dilatation in the first cohort. None of the last 150 patients required dilatation. In conclusion, laparoscopic fundoplication is a safe and effective operation for patients with gastroesophageal reflux disease. New techniques and better instrumentation were introduced in the early era of LNF. The learning curve, however, continues well beyond the first 20 patients.
PMCID: PMC1852390  PMID: 17436134
Laparoscopic Nissen fundoplication; Learning curve

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