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Autosomal recessive Alport syndrome the result of a story COL4A4 substance heterozygous mutation: In a situation document.
The treatment goal of LDL-C ( less then 135 mg/dL, 3.5 mmol/L) was achieved in 69% of children treated. The achievement of the treatment targets correlated positively with male sex and inversely with the Dutch Lipid Clinic Network Score, baseline total, LDL-C and apoB levels. No clinically significant changes in liver or muscle-related laboratory tests were reported; no effect on growth or sexual maturation was noted. Conclusions This study confirms that lipid-lowering treatment in HeFH children initiated in the setting of a specialized tertiary hospital-based outpatient lipid clinic is efficacious and safe. Children of male sex and low baseline lipid values had a better achievement of treatment target.Background Monitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens. learn more Methods We examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS. Results A good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates. Conclusions In summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.Background Accumulating evidence indicates that trimethylamine-N-oxide (TMAO) may play a causal role in cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D). TMAO plasma concentrations show considerable intra- and inter-individual variation, underscoring the need for a reference interval in the general population to identify elevated TMAO concentrations. Methods TMAO concentrations were determined using an LC-MS/MS assay in a community-based sample of the PopGen control cohort consisting of 694 participants (54% men; aged 25-82 years) free of clinical CVD, CKD and T2D. We defined reference intervals for TMAO concentrations in human plasma using the 2.5th and 97.5th percentiles. Using multivariable regression analysis we analyzed the association of estimated glomerular filtration rate (eGFR), sex, and dietary intake and TMAO plasma concentrations. Results TMAO plasma concentrations were positively skewed and differed by sex. The median TMAO plasma concentration in men was 3.91 (Q1-Q3 2.87-6.10) μmol/L and the reference interval 1.28-19.67 μmol/L (2.5th-97.5th percentile). In women median TMAO plasma concentration was 3.56 (Q1-Q3 2.41-5.15) μmol/L and the reference interval 1.08-17.12 μmol/L. In multivariable regression analysis plasma TMAO was associated with sex, renal function and diet. The association of TMAO and diet was significant for intake of fish and shellfish in men only. Conclusions In a community-based sample free of apparent CVD and renal disease, we report the distribution of TMAO plasma concentrations with sex, renal function and diet as factors associated with plasma TMAO, and suggest reference intervals. These data may facilitate standardized comparisons of TMAO across populations.Background Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assays are employed in more and more clinical laboratories to quantify steroids. The steroid quantification by LC-MS/MS shows great value in screening or diagnosing endocrine disorders; however, the number of functional steroids included in the LC-MS/MS methods is still limited. Methods Here, we describe the performance and validation of a 20-steroid plasma panel by LC-MS/MS. The panel included progestogens (including mineralocorticoids and glucocorticoids), androgens and estrogens biosynthesized in steroid metabolic pathways. The LC-MS/MS method was validated according to guidance documents, and subsequently employed to profile steroid changes in endocrine disorders. Results Using LC-MS/MS, 20 steroids were separated and quantified in 8 min. Coefficients of variation (CVs) of the 20 analytes at the lower limit of quantification (LLoQ) were all less than 15% (ranging from 1.84% to 14.96%). The linearity of the assay was demonstrated by all the R2 values greater than 0.995. Individual plasma steroids changed significantly in patients with subclinical Cushing's syndrome (SCS) and polycystic ovary syndrome (PCOS) - 17-hydroxypregnenolone (17-OH-PR), testosterone (T) and dihydrotestosterone (DHT) were significantly decreased in SCS patients, while in PCOS patients, pregnenolone, corticosterone (CORT), androstenedione (A4) and T were significantly increased and DHT was decreased. Conclusions The LC-MS/MS method we developed for the quantification of 20 plasma steroids is clinical practicable. The steroid profiling data using this assay indicate its screening value for endocrine disorders. To further explore the value of the assay, more investigations are however needed.Familial isolated pituitary adenomas (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.The study of extreme acidophiles, broadly defined as microorganisms that grow optimally at pH values below 3, was initiated by the discovery by Waksman and Joffe in the early 1900s of a bacterium that was able to live in the dilute sulfuric acid it generated by oxidizing elemental sulfur. The number of known acidophiles remained relatively small until the second half of the 20th century, but since then has greatly expanded to include representatives of living organisms from within all three domains of life on earth, and notably within many of the major divisions and phyla of Bacteria and Archaea. Environments that are naturally acidic are found throughout the world, and others that are man-made (principally from mining metals and coal) are also widely distributed. These continue to be sites for isolating new species, (and sometimes new genera) which thrive in acidic liquor solutions that contain concentrations of metals and metalloids that are lethal to most life forms. The development and application of molecular techniques and, more recently, next generation sequencing technologies has, as with other areas of biology, revolutionized the study of acidophile microbiology. Not only have these studies provided greater understanding of the diversity of organisms present in extreme acidic environments and aided in the discovery of largely overlooked taxa (such as the ultra-small uncultivated archaea), but have also helped uncover some of the unique adaptations of life forms that live in extremely acidic environments. Thanks to the relatively low biological complexity of these ecosystems, systems-level spatio-temporal studies of model communities have been achieved, laying the foundations for 'multi-omic' exploration of other ecosystems. This article introduces the subject of acidophile microbiology, tracing its origins to the current status quo, and provides the reader with general information which provides a backdrop to the more specific topics described in Quatrini and Johnson (2016).Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non-small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.PURPOSE No established treatments exist for relapsed/refractory systemic light-chain (AL) amyloidosis. Bendamustine has shown potential in the treatment of multiple myeloma. We conducted a phase II, multicenter trial to assess the efficacy and safety of bendamustine with dexamethasone (ben-dex) in patients with persistent or progressive AL amyloidosis after ≥ 1 prior therapy. METHODS The trial enrolled 31 patients who received bendamustine on days 1 and 2 (100 mg/m2 intravenously) with 40 mg of weekly dexamethasone in 28-day cycles until disease progression or up to 6 cycles after complete hematologic response. The primary objective was the rate of partial hematologic response (PR) or better. RESULTS Patients received a median of 4 cycles (range, 2-12 cycles) with 57% of patients achieving a PR or better (11% complete response, 18% very good PR). The overall organ response was 29% among the 24 patients who had measurable organ involvement. Treatment was well tolerated with no grade 5 treatment-related adverse events (AEs).
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