Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.     

Dealing with man-made trauma: the relationship between coping style, posttraumatic stress, and quality of life in resettled, traumatized refugees in the Netherlands

This study investigated the relationship between coping style, posttraumatic stress disorder (PTSD) symptoms, and quality of life in traumatized refugees (N = 335). Participants had resettled in the Netherlands on average 13 years prior and were referred to a Dutch clinic for the treatment of posttraumatic psychopathology resulting from persecution, war, and violence. The majority (85%) of the research sample met diagnostic criteria for PTSD. Path analysis suggested a model in which PTSD symptoms (β = -.61, p < .001), social support seeking (β = .12, p < .05), and emotion-focused coping (β = .13, p < .01) have a direct effect on quality of life. The role of avoidant and problem-focused coping could be interpreted in 2 ways. Either these coping styles are influenced by PTSD severity and have no effect on quality of life, or these coping styles influence PTSD severity and therefore have an indirect effect on quality of life. Intervention strategies aimed at modifying coping strategies and decreasing PTSD symptoms could be important in improving the quality of life of traumatized refugees.     

Cytoreduction and Hyperthermic Intraperitoneal Chemoperfusion in Women with Heavily Pretreated Recurrent Ovarian Cancer

Background

Limited data are available on the use of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC) in patients with recurrent stage III ovarian cancer.

Methods

Patients with recurrent, heavily pretreated ovarian cancer were enrolled onto a phase II multimodal protocol consisting of extensive cytoreduction followed by HIPEC.

Results

Forty-two women were treated from October 2002 until January 2009. Chemoperfusion was performed with cisplatin in 59% and oxaliplatin in 41% of patients. A macroscopically complete resection was achieved in 50% of patients. No mortality occurred, and the major morbidity rate was 21%. After a mean follow-up of 21?months, median overall survival (OS) was 37?months (95% confidence interval 12.2?C61.8) and median progression-free survival was 13?months (95% confidence interval 6.9?C19.1). In univariate analysis, OS was influenced by completeness of cytoreduction, type of chemoperfusion drug, nodal status, and tumor grade. In a Cox regression model, only completeness of cytoreduction (hazard ratio 0.06?C0.8, P?=?.022) and tumor grade (hazard ratio 1.23?C12.6, P?=?.021) were independent predictors of OS.

Conclusions

In selected patients with heavily pretreated recurrent ovarian cancer, cytoreduction combined with HIPEC may provide a meaningful OS with acceptable morbidity. Optimal results are achieved in patients with a macroscopically complete resection and biologically favorable disease.     

A Sad but Forgotten Truth: The Story of Slow‐Moving Solutes in Fast Hemodialysis

When trying to optimize hemodialysis adequacy, it can be questioned whether one should focus on the dialyzer or on the patient. Another crucial question is whether the currently applied dialysis adequacy parameter, Kt/V_urea, is a reliable marker. For the small and water‐soluble solutes, recent advances in convective strategies and/or new dialyzer designs do not add much removal capacity. Depending on their specific kinetics, generally quite different from those of urea, small solute removal benefits from longer or more frequent dialysis. Clearance of beta‐2‐microglobulin (β₂M), a marker of middle molecule removal pattern, is improved with dialysis using more open and permselective membranes, as well as by using high convective volume strategies. Furthermore, longer and more frequent dialyses have highly favorable removal characteristics because they facilitate the retarded transport between plasmatic and extraplasmatic compartments over which these molecules are distributed. As β₂M may not be representative of other middle molecules, future kinetic analyses of alternative middle molecules will be of the utmost interest. Protein‐bound solute clearance is improved by convective techniques, but not by more open dialyzer pores. Knowledge of their kinetics should be helpful in interpreting the observation that frequent (but not longer) dialysis enhances protein‐bound solute removal. Hence, further technical improvements in dialyzers will have only a minor impact on dialysis adequacy, as retarded solute movement in the patient plays a decisive role. As urea kinetics is not representative of the kinetics of protein‐bound compounds, middle molecules, nor even of other small and water‐soluble solutes, it becomes self‐evident that urea clearance is a poor predictor of many aspects of dialysis adequacy.     

Predicting discharge location of hip fracture patients; the new discharge of hip fracture patients score

Purpose

This paper reports on the development and validity of a new instrument, called the discharge of hip fracture patients score (DHP), that predicts at admission the discharge location in patients living in their own home prior to hip fracture surgery.

Methods

A total of 310 patients aged 50 years and above were included. Risk factors for discharge to an alternative location (DAL) were analysed with a multivariable regression analysis taking the admission variables into account with different weights based on the estimates. The score ranged from 0–100 points. The cut-off point for DAL was calculated using a ROC analysis. Reliability of the DHP was evaluated.

Results

Risk factors for DAL were higher age, female gender, dementia, absence of a partner and a limited level of mobility. The cut-off point was set at 30 points, with a sensitivity of 83.8%, a specificity of 64.7% and positive predictive value of 79.2%.

Conclusion

The DHP is a valid, simple and short instrument to be used at admission to predict discharge location of hip fracture patients.     

Contralateral hip fractures and other osteoporosis-related fractures in hip fracture patients: incidence and risk factors. An observational cohort study of 1,229 patients

Purpose

To report risk factors, 1-year and overall risk for a contralateral hip and other osteoporosis-related fractures in a hip fracture population.

Methods

An observational study on 1,229 consecutive patients of 50?years and older, who sustained a hip fracture between January 2005 and June 2009. Fractures were scored retrospectively for 2005–2008 and prospectively for 2008–2009. Rates of a contralateral hip and other osteoporosis-related fractures were compared between patients with and without a history of a fracture. Previous fractures, gender, age and ASA classification were analysed as possible risk factors.

Results

The absolute risk for a contralateral hip fracture was 13.8?%, for one or more osteoporosis-related fracture(s) 28.6?%. First-, second- and third-year risk for a second hip fracture was 2, 1 and 0?%. Median (IQR) interval between both hip fractures was 18.5 (26.6) months. One-year incidence of other fractures was 6?%. Only age was a risk factor for a contralateral hip fracture, hazard ratio (HR) 1.02 (1.006–1.042, p?=?0.008). Patients with a history of a fracture (33.1?%) did not have a higher incidence of fractures during follow-up (16.7?%) than patients without fractures in their history (14?%). HR for a contralateral hip fracture for the fracture versus the non-fracture group was 1.29 (0.75–2.23, p?=?0.360).

Conclusion

The absolute risk of a contralateral hip fracture after a hip fracture is 13.8?%, the 1-year risk was 2?%, with a short interval between the 2 hip fractures. Age was a risk factor for sustaining a contralateral hip fracture; a fracture in history was not.     

Deep hypothermic circulatory arrest and antegrade selective cerebral perfusion during ascending aorta-hemiarch replacement: a retrospective comparative study

OBJECTIVE: We sought to compare the results of ascending aorta-hemiarch replacement by using 2 different methods of cerebral protection in terms of hospital mortality, neurologic outcome, and systemic morbidity and to determine predictive risk factors associated with hospital mortality and neurologic outcome after ascending aorta-hemiarch replacement. METHODS: Between January 1995 and September 2001, 289 patients (mean age, 62.2 +/- 13.2 years; urgent status, 122/289 [42.2%]) underwent ascending aorta-hemiarch replacement with the aid of antegrade selective cerebral perfusion (161 patients) or deep hypothermic circulatory arrest (128 patients). RESULTS: Overall hospital mortality was 11.4% (deep hypothermic circulatory arrest group, 13.3%; antegrade selective cerebral perfusion group, 9.9%; P =.375). A logistic regression analysis revealed acute type A dissection (P =.001; odds ratio, 4.3) and age of greater than 70 years (P =.019; odds ratio, 2.5) to be independent predictors of hospital mortality. The permanent neurologic dysfunction rate was 9.3% (deep hypothermic circulatory arrest group, 12.5%; antegrade selective cerebral perfusion group, 7.6%; P =.075). Logistic regression analysis revealed acute type A dissection (P =.001; odds ratio, 6.7) and history of cerebral infarction-transient ischemic attack (P =.038; odds ratio, 3.4) to be independent predictors of permanent neurologic dysfunction. The transient neurologic dysfunction rate was 8.0% (deep hypothermic circulatory arrest group, 7.1%; antegrade selective cerebral perfusion group, 8.7%; P =.530). Acute type A dissection (P =.001; odds ratio, 5.1) was indicated as an independent predictor of transient neurologic dysfunction by means of logistic regression. Renal dysfunction (postoperative creatinine level of >250 micromol/L; deep hypothermic circulatory arrest, 10 [7.8%]; antegrade selective cerebral perfusion, 6 [3.7%]; P =.030), as well as prolonged intubation time (deep hypothermic circulatory arrest, 3.8 +/- 6.3 days; antegrade selective cerebral perfusion, 2.2 +/- 2.5 days; P =.005) were more common in the deep hypothermic circulatory arrest group. CONCLUSION: The use of antegrade selective cerebral perfusion and deep hypothermic circulatory arrest during ascending aorta-hemiarch replacement resulted in acceptable hospital mortality and neurologic outcome. Reduced postoperative intubation time and better renal function preservation were observed in the antegrade selective cerebral perfusion group.     

The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials

Introduction  Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. Methods  A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). Discussion  This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. Conclusion  The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine. An erratum to this article can be found at     

Differential Effect of Diarrhea on FK506 Versus Cyclosporine A Trough Levels and Resultant Prevention of Allograft Rejection in Renal Transplant Recipients

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.     

Reporting the results of meta-analyses: a plea for incorporating clinical relevance referring to an example

Background Context

The results of meta-analyses are frequently reported, but understanding and interpreting them is difficult for both clinicians and patients. Statistical significances are presented without referring to values that imply clinical relevance.