Population Variation and Genetic Control of Modular Chromatin Architecture in Humans.

Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain.

Association of the COVID-19 pandemic with increased adherence among prevalent hemodialysis patients.

BACKGROUND: During the COVID-19 pandemic, there has been a reduction in emergency department visits and hospital admissions. We hypothesized that hemodialysis patients were decreasing their hospital visits and increasing their dialysis adherence during the COVID-19 pandemic. MATERIAL AND METHODS: This is a retrospective analysis of hemodialysis patients treated in the seven American Renal Associates (ARA) dialysis centers in the Dallas-Fort Worth metropolitan area. We conducted a "before-and-after" study using existing clinical data to examine patient adherence with hemodialysis between January 1 and March 14, 2020 (pre-COVID) and March 15 to May 18, 2020 (COVID) time periods. Data points included missed treatments, shortened treatments, post-dialysis weight, and hospital visits. Finally, we conducted an anonymous survey in which patients reported their hemodialysis adherence. RESULTS: Data analysis was performed on 556 patients. Significantly fewer patients missed a single treatment in the COVID vs. pre-COVID time periods (44.1 vs. 58.6%; p < 0.001). Significantly fewer patients finished their treatment with a post-dialysis weight more than 1 kg above their estimated dry weight in the COVID vs. pre-COVID time periods (31.7 vs. 38.9%, p = 0.01). Finally, there was a reduction in total hospital visits during the COVID vs. pre-COVID periods (12.6 vs. 19.4%; p = 0.002). The anonymous survey showed patients reporting increased adherence with hemodialysis and restriction of salt and water intake. CONCLUSION: The COVID time period was associated with increased adherence with hemodialysis and decreased hospital visits, and patients were conscious of these changes.

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kucinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder.

Uric acid nephrolithiasis is characteristically a manifestation of a systemic metabolic disorder. It has a prevalence of about 10% among all stone formers, the third most common type of kidney stone in the industrialized world. Uric acid stones form primarily due to an unduly acid urine; less deciding factors are hyperuricosuria and a low urine volume. The vast majority of uric acid stone formers have the metabolic syndrome, and not infrequently, clinical gout is present as well. A universal finding is a low baseline urine pH plus insufficient production of urinary ammonium buffer. Persons with gastrointestinal disorders, in particular chronic diarrhea or ostomies, and patients with malignancies with a large tumor mass and high cell turnover comprise a less common but nevertheless important subset. Pure uric acid stones are radiolucent but well visualized on renal ultrasound. A 24 h urine collection for stone risk analysis provides essential insight into the pathophysiology of stone formation and may guide therapy. Management includes a liberal fluid intake and dietary modification. Potassium citrate to alkalinize the urine to a goal pH between 6 and 6.5 is essential, as undissociated uric acid deprotonates into its much more soluble urate form.

Pseudohyperchloremia and Negative Anion Gap - Think Salicylate!

BACKGROUND: Pseudohyperchloremia results in a very low or negative anion gap. Historically, the most common cause of this artifact was bromide poisoning. Bromide salts have been removed from most medications and bromism has become very uncommon. More recently, the introduction of chloride ion selective sensing electrodes (Cl-ISE) has generated a new cause of pseudohyperchloremia-salicylate poisoning. We describe 5 such patients and quantitate the error generated by this measurement artifact. METHODS: The magnitude of artifactual hyperchloremia generated by high salicylate levels was quantified in 5 patients by measuring chloride concentration with several Cl-ISEs from different manufacturers and with Cl-ISEs of different "ages," and comparing these results to measurements with a chloridometer (coulometric titration), which is free of the salicylate artifact. RESULTS: Cl-ISEs from different manufacturers generated a wide range of artifactual chloride concentration elevation. Furthermore, the same Cl-ISE generated increasingly severe pseudohyperchloremia as it was repeatedly reused over time and "aged." CONCLUSIONS: Salicylate interferes with measurement of the blood chloride concentration when a Cl-ISE is used. The severity of this artifact is related to the salicylate level, the specific Cl-ISE, and the "age" of the electrode. Toxic blood salicylate levels can generate marked pseudohyperchloremia, and consequently, an artifactual very small or negative anion gap. The large anion gap metabolic acidosis typical of salicylate poisoning is masked by this artifact. Salicylate has become the most common cause of pseudohyperchloremia, and physicians should immediately consider salicylate poisoning whenever the combination of hyperchloremia and a very small or negative anion gap is reported by the laboratory.

Brown tumor complicating end-stage kidney disease.

Longstanding, severe hyperparathyroidism (HPT) can lead to the formation of "brown tumors". A brown tumor is a radiolucent bone lesion that is locally destructive; it is not a neoplasm, but rather a stromal mass consisting of fibrous tissue, poorly mineralized woven bone, and supporting vasculature. These tumors are a rare complication of advanced primary or secondary HPT. We present a young female with chronic kidney disease (CKD) on hemodialysis with uncontrolled secondary HPT (SHPT). The patient presented with progressive lower extremity weakness and back pain. CT imaging showed multiple lytic bone lesions involving several ribs and the spine. Subsequent MRI imaging of the thoracic and lumbar spine confirmed expansile bone lesions consistent with brown tumors. One mass protruded into the spinal canal causing severe stenosis at T3 with underlying cord edema. The other lesion at T12 caused only moderate spinal canal stenosis. Our patient underwent urgent neurosurgical resection of the tumor at T3 followed by subtotal parathyroidectomy (PTX).

A young man with recurrent kidney stones and renal failure.

Dent disease is an inherited proximal renal tubulopathy leading to low molecular weight proteinuria, hypercalciuria with nephrocalcinosis and nephrolithiasis, and progressive renal failure. Two genetic mutations have been identified. The disease usually presents in childhood or early adult life and may be associated with other proximal tubular defects, which can lead to significant morbidity, especially in children. The disorder can extend to interstitial and glomerular cells, which contributes to progression to end-stage kidney disease. The pathophysiologic process remains incompletely understood, and no specific treatment is available. Dent disease is likely under-recognized. It needs to be included in the differential, especially in young males, presenting with recurrent kidney stones, proteinuria, and impaired renal function.

Tinea cruris in children.

Tinea cruris is an intensely pruritic fungal infection of the groin and adjacent skin. Also known as crotch rot and jock itch, it can be a troubling important entity that at times is a clinical, diagnostic, and therapeutic challenge. Predisposing factors include heat, humidity, and hyperhidrosis, common accompaniments of high school-aged athletes. Furthermore, obesity and diabetes mellitus, additional risk factors for tinea cruris, are reaching unprecedented levels in adolescents. Treatment options range from improving hygiene to topical antifungal agents and systemic antifungal agents, the latter with potentially dangerous side effects.

Case report: Patiromer-induced hypercalcemia.

Patiromer is a novel potassium-binding compound which has recently received FDA approval. This ion exchange resin releases calcium when it binds potassium. We describe the development of hypercalcemia after initiation of patiromer. The calcium levels fell when the drug was stopped but recurred when it was later resumed. Patiromer was again discontinued, and the serum calcium level fell back into the normal range. We believe this patient manifested patiromer-induced hypercalcemia.

Acute neurological syndrome complicating secondary hyperparathyroidism.

Longstanding severe hyperparathyroidism can lead to the formation of "brown tumors," benign but locally aggressive neoplasms. We present the case of a young woman with end-stage renal disease on hemodialysis with uncontrolled secondary hyperparathyroidism. The patient presented with progressive lower extremity weakness and back pain. Imaging showed multiple lytic bone lesions, the most impressive being a T3 spinal lesion causing cord compression. She underwent urgent neurosurgical resection of the tumor at T3 followed by subtotal parathyroidectomy. Our case touches upon the pathophysiology, consequences, and treatment of secondary hyperparathyroidism in patients with end-stage renal disease.

Hypertension and the kidney.

Hypertension is an important and widely prevalent risk factor for the development of chronic kidney disease (CKD), which unfortunately may progress to end-stage renal disease. CKD is a progressive condition that causes significant morbidity and mortality. Diabetes is the leading cause of end-stage renal disease in the Western world. Both hypertension and diabetes are the causative factors for the occurrence of CKD and its consequences. Aggressive control of hypertension and diabetes is indicated to reduce the risk for kidney disease in the community. Certainly, effective control of hypertension is a proven modality to prevent renal disease. The concept of decreasing the systemic blood pressure as well as the intraglomerular pressure has led to the application of rational therapeutic options in patients with renal insufficiency. Although treatment of hypertension alone is critical, drugs that block the renin-angiotensin system have been shown to have special renal (and cardiovascular) benefits. Early detection and treatment of microalbuminuria is an integral part of disease management. This article reviews the pathophysiologic and therapeutic implications of the link between hypertension and the kidney.

Collapsing glomerulopathy: a cause of noncardiogenic pulmonary edema.

Collapsing glomerulopathy is a pathologic diagnosis characterized by obliteration of glomerular capillary lumina, seen most commonly as a primary glomerular disease in young black men. A secondary form with almost identical pathologic features is described in association with human immunodeficiency virus infection. The disease is characterized by heavy proteinuria with variable renal insufficiency at the onset followed by rapid progression to end-stage renal disease with no documented effective therapy. We describe a patient who presented with systemic manifestations, including fever, acute renal failure with massive proteinuria, and noncardiogenic pulmonary edema. Renal biopsy showed classic collapsing glomerulopathy. All known causes of noncardiogenic pulmonary edema were ruled out. The pulmonary syndrome resolved, but the renal disease progressed to end-stage renal disease. We propose consideration of collapsing glomerulopathy in the differential diagnosis of any patient presenting with a multisystem disease including acute renal failure and pulmonary edema.

Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription.

DNA sequence variation has been associated with quantitative changes in molecular phenotypes such as gene expression, but its impact on chromatin states is poorly characterized. To understand the interplay between chromatin and genetic control of gene regulation, we quantified allelic variability in transcription factor binding, histone modifications, and gene expression within humans. We found abundant allelic specificity in chromatin and extensive local, short-range, and long-range allelic coordination among the studied molecular phenotypes. We observed genetic influence on most of these phenotypes, with histone modifications exhibiting strong context-dependent behavior. Our results implicate transcription factors as primary mediators of sequence-specific regulation of gene expression programs, with histone modifications frequently reflecting the primary regulatory event.

Cellular delivery of pyrenyl-arene ruthenium complexes by a water-soluble arene ruthenium metalla-cage.

Three pyrenyl-arene ruthenium complexes (M(1)-M(3)) of the general formula [Ru(η(6)-arene-pyrenyl)Cl(2)(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane) have been synthesised and characterised. Prior to the coordination to ruthenium, pyrene was connected to the arene ligand via an alkane chain containing different functional groups: ester (L(1)), ether (L(2)) and amide (L(3)), respectively. Furthermore, the pyrenyl moieties of the M(n) complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; donq = 5,8-dioxydo-1,4-naphthoquinonato), while the arene ruthenium end was pointing out of the cage, thus giving rise to the corresponding host-guest systems [M(n)⊂Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([M(n)⊂cage](6+)). The antitumor activity of the pyrenyl-arene ruthenium complexes (M(n)) and the corresponding host-guest systems [M(n)⊂cage][CF(3)SO(3)](6) were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M(2), which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(η(6)-p-cymene)Cl(2)(pta)] (RAPTA-C). All host-guest systems [M(n)⊂cage](6+) showed good anticancer activity with IC(50) values ranging from 2 to 8 µM after 72 h exposure. The fluorescence of the pyrenyl moiety allowed the monitoring of the cellular uptake and revealed an increase of uptake by a factor two of the M(2) complex when encapsulated in the metalla-cage [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+).

Secondary mucinous carcinoma of the skin: metastatic breast cancer.

BACKGROUND: Breast cancer is the most common cancer in women. Its involvement of skin is the most frequent of visceral cancers in women. In cutaneous metastatic disease, including breast cancer, the clinical and histologic pattern may be specific or nonspecific. Specific clinical patterns of cutaneous metastatic disease are linked with breast cancer but occur less often with other cancers metastatic to skin. Likewise, specific histologic patterns of cutaneous metastatic disease are linked with breast cancer but occur less often with other cancers metastatic to skin. OBJECTIVE: To present a case of a mucinous breast cancer metastatic to skin where the histologic pattern is similar to the primary tumor. METHODS: This is a case report and a literature review. RESULTS: Metastatic breast cancer may rarely resemble primary skin cancer, in this case primary mucinous carcinoma of the skin. We describe a 60-year-old woman with breast cancer with the incidental finding of a nonspecific, soft, solitary nodule on her back. It was found to contain mucinous material and on close examination was found to be a metastatic mucinous carcinoma of the skin from a primary adenocarcinoma of the breast. CONCLUSION: One usually considers that hard, firm nodules are more suggestive of cutaneous metastatic disease than soft, nondescript ones, but one should be careful to consider secondary mucinous carcinoma of the skin and a histologically similar solitary cutaneous metastasis.

Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients.

BACKGROUND: Chronic metabolic acidosis (CMA) in normal adults results in complex endocrine and metabolic alterations including growth hormone (GH) insensitivity, hypothyroidism, hyperglucocorticoidism, hypoalbuminaemia and loss of protein stores. Similar alterations occur in chronic renal failure, a prototypical state of CMA. We evaluated whether metabolic acidosis contributes to the endocrine and metabolic alterations characteristic of end-stage renal disease. METHODS: We treated 14 chronic haemodialysis patients with daily oral Na-citrate for 4 weeks, yielding a steady-state pre-dialytic plasma bicarbonate concentration of 26.7 mmol/l, followed by 4 weeks of equimolar Na-chloride, yielding a steady-state pre-dialytic plasma bicarbonate of 20.2 mmol/l. RESULTS: Blood pressure, body weight and dialysis adequacy were equivalent in the two protocols. Na-citrate treatment corrected CMA, improved GH insensitivity, increased and normalized plasma free T(3) concentration, and improved plasma albumin. Correction of CMA had no significant effect on measured cytokines (interleukin-1 beta and -6, tumour necrosis factor-alpha) or acute phase reactants (C-reactive protein, serum amyloid A, alpha(2)-macroglobulin). CONCLUSION: CMA contributes to the derangements of the growth and thyroid hormone axes and to hypoalbuminaemia, but is not a modulator of systemic inflammation in dialysis patients. Correcting CMA may improve nutritional and metabolic parameters and thus lower morbidity and mortality.

Peculiar unilateral fixed drug eruption of the breast.

BACKGROUND: Fixed drug eruption (FDE) is a common cutaneous disorder which develops within hours of taking the offending drug and recurs at the same site with subsequent exposure to the same drug. Non-steroidal anti-inflammatory drugs (NSAIDs) are common offending drugs. METHODS: A 14-year-old girl initially presented with a 1-year history of a recurrent reddish-brown plaque around her right areola. The lesion became pruritic and raised during menses, and subsided during the remainder of her menstrual cycle with the exception of persistent residual hyperpigmentation. The patient had a pattern of naproxen use during menses for dysmenorrhea. RESULTS: The skin biopsy specimen revealed focal bullae formation and scattered necrotic keratinocytes in epidermis, hydropic degeneration of the basal cell layer, pigmentary incontinence and a perivascular infiltrate composed of lymphocytes and eosinophils. These changes confirmed the diagnosis of fixed drug eruption. CONCLUSION: Fixed drug eruption to nonsteroidal anti-inflammatory drugs is common. However, FDE due to naproxen, one of the NSAIDs, is rarely reported. We describe an unusual case of FDE, which recurred at each menses.