There is an ongoing debate if and how kidney and liver volume are associated with pain and gastrointestinal (GI) symptoms in autosomal dominant polycystic kidney disease (ADPKD) patients. Since both ...kidney and liver volume could interact, we investigated whether combined total kidney and liver volume had stronger associations with ADPKD-related pain and GI symptoms than the volumes of the organs separately.
We used baseline data from the DIPAK-1 study, which included ADPKD patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2. MR imaging was performed to measure height-adjusted total kidney volume (hTKV), height-adjusted total liver volume (hTLV) and the combination of both (height-adjusted total kidney liver volume hTKLV).
Three hundred nine ADPKD patients were included with a mean age of 48 ± 7 years, 53% female, eGFR 50 ± 11 mL/min/1.73 m2 and median hTKV, hTLV and hTKLV of 1,095 (758-1,669), 1,173 (994-1,523) and 2,496 (1,972-3,352) mL/m, respectively. ADPKD-related pain and GI symptoms were present in, respectively, 27.5 and 61.2% of patients. Gender was no effect modifier in the association between kidney and/or liver volume, and symptom burden, indicating that all models could be tested in the overall study population. hTKLV and hTLV were significantly associated with pain and GI symptoms, whereas hTKV was not. Model testing revealed that the associations of pain and GI symptoms with hTKLV were significantly stronger than with hTKV (p = 0.04 and p = 0.04, respectively) but not when compared to hTLV (p = 0.2 and p = 0.5, respectively).
This study indicates that combined kidney and liver volume was associated with the presence and severity of pain and GI symptoms in ADPKD, with a more prominent role for hTLV than for hTKV.
The BIOMED-2 multiplex polymerase chain reaction (PCR) tubes for analysis of immunoglobulin and T-cell receptor (TCR) gene rearrangements have recently been introduced as a reliable and easy tool for ...clonality diagnostics in suspected lymphoproliferations. Quality and performance assessment of PCR-based clonality diagnostics is generally performed using human leukemia/lymphoma cell lines as controls. We evaluated the utility of 30 well-defined human T-cell lines for quality performance testing of the BIOMED-2 PCR primers and protocols. The PCR analyses of the TCR loci were backed up by Southern blot analysis. The clonal TCRB, TCRG and TCRD gene rearrangements were analyzed for gene segment usage and for the size and composition of their junctional regions. In 29 out of 30 cell lines, unique clonal TCR gene rearrangements could be easily detected. Besides their usefulness in molecular clonality diagnostics, these cell lines can now be authenticated based on their TCR gene rearrangement profile. This enables their correct use in molecular clonality diagnostics and in other cancer research studies.
Understanding farmers' seed quality problem will enable farmers to devise strategies to improve quality at the farm level. The study was conducted to assess the quality of seed used by farmers from ...different sources and regions. A total of 304 wheat (Trticium aestivum L. and T. durum L.) seed samples from Ethiopia and 206 wheat and 200 barley (Hordeum vulgare L.) seed samples from Syria were collected from major wheat and barley growing regions to investigate the quality of seed obtained from various sources and regions and planted by farmers. A 1 kg sample was drawn from seed lots intended for planting from each farmer. A detailed questionnaire was used to collect information on seed selection and management practices and farmers' perception of seed quality. The physical and physiological quality of seed samples was analyzed using standard testing procedures. In Ethiopia, the mean physical purity and germination of wheat seed was 98.92% and 96%, respectively, and the majority of samples (93%; n = 303) met the minimum purity and germination standards for certified seed 2. Certified seed from the formal sector seed had the highest analytical purity (99.4%), but this was not significantly different from other seed sources, such as neighbors/other farmers (98.8%), local traders/markets (98.6%), or own saved seed (98.9%). However, the mean germination for certified seed (96%) showed a weak significant difference from seed obtained from other sources (94%). In Syria, mean physical purity and germination for wheat was 97.6% and 88%, respectively, and for barley 95.5% and 86%, respectively. Seed quality was better in wheat than in barley. The majority of wheat seed samples, i.e., 70.4% (n = 206) for physical purity and 78.2% for germination, met the minimum seed quality requirements of certified seed 2. In barley, only 10% of samples for physical purity and 72% of samples for germination met this standard. Contamination with weed seeds appeared to be the major constraint for seed samples not meeting the standard of formal sector. There was no significant difference in physical and physiological quality of wheat seed samples obtained from different sources. In barley, germination from different sources was significantly different. Highly significant differences in seed quality were observed for seed samples collected from different regions and districts for wheat and barley crops in both countries. Vigor indices showed significant differences among wheat and barley seed samples from different regions and districts, but not among different sources. Simple correlation coefficients showed significant relationships among vigor tests. The standard germination, speed of germination, and seedling root length were well correlated with field emergence in wheat and barley in both countries. Farmers used local seed management practices, such as seed selection, cleaning, treatment, or separate storage to improve or maintain seed quality. A large number of seed samples managed differently by farmers met the minimum physical purity and germination standard for certified seed 2, producing seed comparable to those from the formal sector. It is imperative that national seed polices equally recognize the role of both formal and informal sectors and provide support to create an integrated seed system catering to the needs of a diverse group of farmers.
The avascular nature of cartilage makes it a unique tissue
, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular ...invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two ...independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.
Abstract Background This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. Patients ...and methods Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 – T 100 mg/m2 ) or six cycles of TAC (75/50/500 mg/m2 ) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. Results In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67–3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). Conclusions With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.
Abstract Background Dissociative disorders encompass a range of symptoms varying from severe absent-mindedness and memory problems to confusion about one's own identity. Recent studies suggest that ...these symptoms may be the by-products of a labile sleep–wake cycle. Methods In the current study, we explored this issue in patients suffering from insomnia ( N = 46). We investigated whether these patients have raised levels of dissociative symptoms and whether these are related to objective sleep parameters. Patients stayed for at least one night in a specialized sleep clinic, while sleep EEG data were obtained. In addition, they completed self-report measures on dissociative symptoms, psychological problems, and sleep characteristics. Results Dissociative symptom levels were elevated in patients suffering from insomnia, and were correlated with unusual sleep experiences and poor sleep quality. Longer REM sleep periods and less time spent awake during the night were predictive of dissociation. Conclusions This is the first study to show that insomnia patients have raised dissociative symptom levels and that their dissociative symptoms are related to objective EEG parameters. These findings are important because they may inspire sleep-related treatment methods for dissociative disorders.
Analysis of spatial diversity, temporal diversity and coefficient of parentage (COP) were carried out along with measurements of agronomic and morphological traits to explain on-farm diversity of ...modern varieties or landraces of wheat (Triticum aestivum L. and Triticum durum L.) grown by farmers in Ethiopia. Farm level surveys showed low spatial diversity of wheat where only a few dominant varieties appeared to occupy a large proportion of wheat area. The five top wheat varieties were grown by 56% of the sample farmers and these varieties were planted on 80% of the total wheat area. The weighted average age of wheat varieties was high with an average of 13.8 years for bread wheat showing low temporal diversity or varietal replacement by farmers. The COP analysis showed that average and weighted diversity of bread wheat was 0.76 and 0.66, respectively variance component analysis showed significant variations for agronomic characters such as plant height, grain yield, and yield components (kernels spike-1, thousand seed weight) among modern varieties and/or landraces. The principal component analysis explained better the variation among varieties and landraces. Cluster analysis based on agro-morphological traits grouped modern varieties and landraces into separate clusters. The present study describes the diversity of wheat crop available on the farm using different indicators. The variation among modern varieties and landraces offered opportunities for using genotypes with desired agronomic characters in plant breeding to develop varieties suitable for different agro-ecological zones in the country.
Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy ...sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD.
We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations.
Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 interquartile range (IQR) 495-1327 mL/m and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68-147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B = 0.35 mL/min/1.73 m2 95% confidence interval (CI) 0.09 to 0.61, P = .007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33 mL/min/1.73 m2 (95% CI 0.09 to 0.57, P = .008).
These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD.
Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need ...revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of “CLL-biased” features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
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