Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.     

Interrelationships of quantitative asthma-related phenotypes in the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy

BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.     

Direct aperture optimization for online adaptive radiation therapy

This paper is the first investigation of using direct aperture optimization (DAO) for online adaptive radiation therapy (ART). A geometrical model representing the anatomy of a typical prostate case was created. To simulate interfractional deformations, four different anatomical deformations were created by systematically deforming the original anatomy by various amounts (0.25, 0.50, 0.75, and 1.00 cm). We describe a series of techniques where the original treatment plan was adapted in order to correct for the deterioration of dose distribution quality caused by the anatomical deformations. We found that the average time needed to adapt the original plan to arrive at a clinically acceptable plan is roughly half of the time needed for a complete plan regeneration, for all four anatomical deformations. Furthermore, through modification of the DAO algorithm the optimization search space was reduced and the plan adaptation was significantly accelerated. For the first anatomical deformation (0.25 cm), the plan adaptation was six times more efficient than the complete plan regeneration. For the 0.50 and 0.75 cm deformations, the optimization efficiency was increased by a factor of roughly 3 compared to the complete plan regeneration. However, for the anatomical deformation of 1.00 cm, the reduction of the optimization search space during plan adaptation did not result in any efficiency improvement over the original (nonmodified) plan adaptation. The anatomical deformation of 1.00 cm demonstrates the limit of this approach. We propose an innovative approach to online ART in which the plan adaptation and radiation delivery are merged together and performed concurrently-adaptive radiation delivery (ARD). A fundamental advantage of ARD is the fact that radiation delivery can start almost immediately after image acquisition and evaluation. Most of the original plan adaptation is done during the radiation delivery, so the time spent adapting the original plan does not increase the overall time the patient has to spend on the treatment couch. As a consequence, the effective time allotted for plan adaptation is drastically reduced. For the 0.25, 0.5, and 0.75 cm anatomical deformations, the treatment time was increased by only 2, 4, and 6 s, respectively, as compared to no plan adaptation. For the anatomical deformation of 1.0 cm the time increase was substantially larger. The anatomical deformation of 1.0 cm represents an extreme case, which is rarely observed for the prostate, and again demonstrates the limit of this approach. ARD shows great potential for an online adaptive method with minimal extension of treatment time.     

Impact of front line relative dose intensity for methotrexate and comorbidities in immunocompetent elderly patients with primary central nervous system lymphoma

Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7–73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3–60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2–46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate >?75% were associated with increased OS (p?=?0.006 and p?=?0.003, respectively) and PFS (p?=?0.003 and p?=?0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥?8, were associated with decreased OS and PFS (p?=?0.02 and p?=?0.04, respectively). A high MSKCC score was associated with decreased OS (p?=?0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p?=?0.02 and p?=?0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.     

Measurement of radiographic joint space width in the tibiofemoral compartment of the osteoarthritic knee: comparison of standing anteroposterior and Lyon schuss views

OBJECTIVE: To evaluate progression of joint space narrowing in radiographs of osteoarthritic (OA) knees imaged in both the standing anteroposterior (AP) and the Lyon schuss positions, using alternative methods to measure joint space width (JSW). METHODS: Standing AP (extended view) and Lyon schuss (posteroanterior [PA] view, with 20-30 degrees of flexion) radiographic images of 58 OA knees were obtained twice (at baseline and 2 years later). With both methods, fluoroscopy was used to align the anterior and posterior margins of the medial or lateral tibial plateau with the central x-ray beam. Minimum JSW, mean JSW, and joint space area (JSA) of the medial or lateral femorotibial joint space were measured using a new digital image analysis system. The effects of knee flexion versus extension and parallel versus nonparallel tibial plateau alignment were evaluated with respect to the reproducibility of JSW in repeated examinations (intraclass correlation coefficient [ICC]), the mean of within-knee standard deviations of repeated measurements (SD(m)), and the sensitivity to changes in JSW in serial radiographs (standardized response mean [SRM]). RESULTS: The performance of the new software, as assessed by the reproducibility of repeated measurements of minimum JSW on the same image, was excellent in both the standing AP (ICC = 0.98) and Lyon schuss radiographs (2 SD(m) = 0.5 mm, ICC = 0.98). The reproducibility in different radiographs of the same knee was not evaluated. However, over 2 years, the mean (+/- SD) decrease in the minimum JSW of OA knees was 0.17 +/- 0.75 mm in standing AP radiographs (P not significant) and 0.24 +/- 0.50 mm in Lyon schuss views (P = 0.007), with SRMs of 0.23 and 0.48, respectively. The quality of alignment of the tibial plateau was satisfactory (<1 mm between anterior and posterior margins of the medial tibial plateau) in 66% of the pairs of Lyon schuss radiographs and in 57% of the pairs of standing AP radiographs. In the Lyon schuss radiographs, SRM was highly dependent on tibial plateau alignment. Minimum JSW was more sensitive to change than was mean JSW or JSA, in paired Lyon schuss radiographs that exhibited satisfactory alignment. CONCLUSION: Compared with the standing AP radiograph, PA imaging of the knee in 20-30 degrees flexion (the schuss position) increases the reproducibility of radiographic JSW measurements in OA knees and the sensitivity to change in JSW in serial radiographs. Sensitivity to change in minimum JSW is notably increased by aligning the medial tibial plateau with the central x-ray beam in the Lyon schuss radiograph.     

COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy.     

Factors associated with the designation of a health care proxy and writing advance directives for patients suffering from haematological malignancies

Background

During the last few decades, patients’ rights have been reinforced in many countries by acts of law. Measures now include health care proxies to uphold the doctor-patient relationship and advance directives for end-of-life patients. These could be relevant tools as early as the initial diagnosis of haematological malignancies because of the uncertain disease course. The aim of this research was to assess the factors associated with the designation of a proxy and writing advance directives by patients in a haematology department in France.

Methods

After a specific programme to encourage discussions about end-of-life preferences, we conducted a mixed-methods study comprising retrospective analysis of a random sample of 200 patients’ medical records, crossed with a qualitative analysis of the content of advance directives. Statistical analysis was performed by the RKward V 0.6.1 software with 0.05 denoting significance. The study was performed and presented in accordance with the STROBE guidelines. A thematic analysis of the advance directives was performed by two researchers.

Results

A total of 197 medical records were evaluable. The mean age of the patients was 66 years (range: 18–91). Nearly 2/3 of them (64.5%) designated a proxy, 6.1% wrote advance directives, and 8.1% and 4.6% expressed a wish to meet a religious representative or a volunteer, respectively. The 2-year survival rate was 78.4% [95%CI: 68.2-90.2]. Patients who wrote advance directives were statistically older (p <0.00025). Patients who wrote an advance directive were more likely to have expressed a wish to meet a religious representative (p <0.001) or a volunteer (p = 0.003). Marital status was a significant factor in appointing a proxy (p = 0.04).

Conclusions

To the best of our knowledge, this is the first paper to identify influencing factors for proxies and advance directives in a homogenous population of patients with haematological malignancies. Most patients chose a proxy. However, despite several training programmes for the carers and a care planning programme, few patients wrote advance directives. Our findings suggest that influencing factors are advanced age and a wish to see a religious representative. This study highlights the importance of oral communication about end-of-life issues between carers, patients and their relatives.

     

Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver

Cold ischemia-warm reperfusion (CI-WR) injury of the liver is characterized by marked alterations of sinusoidal endothelial cells (SECs), whereas hepatocytes appear to be relatively unscathed. However, the time course and mechanism of cell death remain controversial: early versus late phenomenon, necrosis versus apoptosis? We describe the occurrence and nature of cell death after different periods of CI with University of Wisconsin (UW) solution and after different periods of WR in the isolated perfused rat liver model. After 24- and 42-hour CI (viable and nonviable livers, respectively), similar patterns of liver cell death were seen: SEC necrosis appeared early after WR (10 minutes) and remained stable for up to 120 minutes. After 30 minutes of WR, apoptosis increased progressively with WR length. Based on morphological criteria, apoptotic cells were mainly hepatocytes within liver plates or extruded in the sinusoidal lumen. In addition, only after 42-hour CI were large clusters of necrotic hepatocytes found in areas of congested sinusoids. In these same livers, the hepatic microcirculation, evaluated by means of the multiple-indicator dilution technique, revealed extracellular matrix disappearance with no-flow areas. In conclusion, different time courses and mechanisms of cell death occur in rat livers after CI-WR, with early SEC necrosis followed by delayed hepatocyte apoptosis. These processes do not appear to be of major importance in the mechanism of graft failure because they are similar under both nonlethal and lethal conditions; this is not the case for the loss of the extracellular matrix found only under lethal conditions and associated with hepatocyte necrosis.