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This paper highlights new research on the biomineralization of otoliths and uses a mineralogical approach to understand mechanisms of crystal growth and metal incorporation into otoliths. Petrographic observations of the nucleation of otolith growth in the core for several fish species reveals that sagittal otoliths appear to nucleate around a few or many nucleation sites (primordia) and that these sites vary in size (ranging in diameter from 1 to 20 μm), depending on the species. Spectroscopic data show a large Mn-enrichment in the primordia within the core but the reasons for this enrichment are still unclear (e.g. organic matter or possibly another material other than CaCO3). This study also provides the first multi trace-element data for endolymph fluid and the growing otolith; we found large enrichments (Ca and Sr) and depletions (Na, K, Zn and Rb) of elements in the otolith relative to the endolymph. The last part of this paper examines the effect of crystal structure on the microchemistry of otoliths. Our investigation helps understand how the chemical characteristics of the metal ions (i.e. ionic radii) and the crystalline structure interact to cause differential trace-metal uptake between the CaCO3 polymorphs, aragonite and vaterite. [ABSTRACT FROM AUTHOR]

Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials., (© 2024. The Author(s).)

Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1., Methods: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions., Results: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions., Conclusion: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.

Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency., (© 2013.)

We describe the pregnancy of a patient of French-Canadian descent with multiple Acyl-CoA dehydrogenation deficiency (MADD). The proband was found to harbor a previously reported homozygous missense mutation on EFTDH gene (p.Pro534Leu:c.1601C>T) confirming the biochemical diagnosis of MADD. This mutation was not found in 50 controls from the same ethnic background. The clinical and molecular information of all patients with ETFDH mutations reported in the literature up-to-date are summarized., (Copyright © 2012 Elsevier Inc. All rights reserved.)

N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 μM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 μM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 μM (740 and 1,572) and their levels fell below 500 μM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.

Context: Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes., Objective: The objective of the study was to report a novel syndrome with some overlapping features with MAD., Results: We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features to MAD patients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients., Conclusions: Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP syndrome remains to be elucidated.

The fractionation of metals from water to otolith is an area of research that has received relatively limited attention, especially in freshwater systems. The objectives of the present research were to study the metal partitioning between otolith and endolymph of two freshwater species: Lake trout (Salvelinus namaycush), and burbot (Lota lota). We also included the chemical analyses of water and blood from fish of the same species collected in the same area but during different years. These results provide insight regarding the partition of metals between water and fish. This is one of the first studies to provide a range of trace metal concentrations for endolymph and the growing otolith (both aragonite and vaterite) and to directly measure otolith-endolymph partition coefficients for freshwater fish. The trace elements (Mg, Sr, and Ba) most often used as otolith elemental tracers were the ones with the lowest uptake from water to blood. We found that endolymph and whole blood had similar metal concentrations, with Mg and Fe being the only elements enriched in whole blood. Results showed few significant differences in trace metal content between wild lake trout and burbot endolymph (except for K, Mg, and Ba), but significant differences existed between their aragonitic otoliths. These results suggest two different crystallization processes in these species or the presence of different proteins (and/or organic matrices) that would selectively influence elemental incorporation in the otoliths.

The mucopolysaccharidoses are a group of lysosomal storage disorders caused by defects in the degradation of glycosaminoglycans. Each disorder is characterized by progressive multi-system disease with considerable clinical heterogeneity. The clinical heterogeneity of these disorders is thought to be related to the degree of the metabolic block in glycosaminoglycan degradation which in turn is related to the underlying mutation at the respective locus. There are currently no objective means other than longitudinal clinical observation, or the detection of a recurrent genetic mutation to accurately predict the clinical course for an individual patient, particularly when diagnosed early. In addition, there are no specific disease biomarkers that reflect the total body burden of disease. The lack of specific biomarkers has made monitoring treatment responses and predicting disease course difficult in these disorders. The recent introduction of enzyme replacement therapy for MPS I, II, and VI highlights the need for objective measures of disease burden and disease responsiveness. We show that serum levels of heparin cofactor II-thrombin complex is a reliable biomarker of the mucopolysaccharidoses. Untreated patients have serum levels that range from 3- to 112-fold above control values. In a series of patients with varying severity of mucopolysaccharidosis I, the serum complex concentration was reflective of disease severity. In addition, serum heparin cofactor II-thrombin levels showed responsiveness to various treatment regimens. We propose that serum levels of heparin cofactor II-thrombin complex may provide an important assessment and monitoring tool for patients with mucopolysaccharidosis.

Leukocyte imaging performed with in-111 or Tc-99m is gaining widespread acceptance as a method for detection of osteomyelitis associated with soft tissue injury or infection. The authors present three cases in which initial imaging was suggestive of a focal infectious process in bone and soft tissue. However, repeat imaging after the removal of wound dressings, which revealed sero-sanguineous discharge in all cases, resulted in a scan appearance that was much less remarkable for focal radiotracer accumulation in the bone. The authors conclude that accumulation of labeled WBCs in wound discharge can result in scans that are false-positive for osteomyelitis. Therefore, the authors recommend that wounds should be cleaned and dressings changed before imaging in order to avoid scans that are false-positive for osteomyelitis.

Unlabelled: Abbreviated acquisition protocols were designed for stress and rest to decrease stress and rest SPECT image acquisition times but maintain the high count density of 99mTc-sestamibi separate-day cardiac images., Methods: Scan findings were compared visually and quantitatively with standard SPECT for 12 rest and 32 stress patient studies., Results: Of 29 stress defects detected by standard SPECT, 27 were present with the fast technique; of 8 resting SPECT defects, all were detected with fast SPECT. Two stress and no resting false-positive defects occurred with fast SPECT. Linear correlations (r) between standard and fast quantitative defect extent and severity were 0.76 and 0.86, respectively for stress SPECT, and 0.88 and 0.96 for rest SPECT. Stress fast defects were slightly less severe (p = 0.02) than those observed using standard acquisition., Conclusion: We conclude that these fast protocols for separate-day 99mTc-MIBI SPECT accurately detect and characterize perfusion defects and provide a means to improve patient tolerance and increase laboratory throughput.

Unlabelled: Generally performed in a single anterior or right anterior oblique (RAO) view, first-pass radionuclide angiocardiography (RNA) is limited due to its inability to evaluate septal and posterior wall motion., Methods: Thirty-five patients undergoing stress/rest sestamibi SPECT (22 mCi/22 mCi 2-day protocol) underwent biplane RNA at the time of resting injection. The stress SPECT images (acquired with the patient at rest) were ECG-gated to evaluate resting regional myocardial wall thickening. By this means wall motion assessed by RNA was compared to the presence of a resting SPECT perfusion defect accompanied by a localized decrease in wall thickening., Results: In 16 patients in whom both resting perfusion and wall thickening were normal one demonstrated apical hypokinesis by RNA in the RAO view. In the other 29 patients, a total of 58 resting segmental perfusion defects with abnormal wall thickening were present (12 anterior, 13 inferior, 14 apical, 11 septal and 8 posterolateral). Wall motion abnormalities were detected in all these patients and in 57/58 segments (98%) by biplane RNA. Septal and posterolateral wall motion abnormalities were detected in only the LAO RNA study. In three patients, wall motion abnormalities were detected by LAO imaging only. Of the remaining 87 normally perfused segments in these 29 patients, RNA wall motion was normal in 85. Two posterolateral segments demonstrated apparent hypokinesis, probably due to left atrial overlap in the LAO projection., Conclusion: Simultaneous biplane RNA accurately detects wall motion abnormalities frequently missed by single-plane RAO imaging.

In a previous study we reported low values of taurine and aspartic acid in the CSF of patients with Friedreich's ataxia, when the results were compared to the literature. Further studies have revealed that unforetold difficulties with the advertised methodology of sequential multi-sample amino acid analysis were responsible for low values in the determination of these two amino acids in the small volumes necessary for CSF. A corrected method is presented. With the latter method the differences disappear for CSF taurine and aspartic acid, but they remain valid for the previously reported blood and urine values in Friedreich's ataxia. GABA levels are also normal in Friedreich's ataxia CSF.

Our prospective survey of 50 ataxic patients confirms the previous finding of frequent clinical or chemical diabetes in Friedreich's ataxia. Eighteen percent of our typical cases have clinical diabetes and 40% at least an abnormal glucose tolerance curve. However, this finding does not appear to be specific to that form of ataxia. Furthermore, we have shown that most patients with ataxia have normal or low fasting insulin levels, but a hyperinsulinic response to a glucose load.

Classical Friedreich ataxia, a progressive, neurodegenerative disorder involving both the central and peripheral nervous systems, has been subclassified according to the observed clinical heterogeneity. The variations in the age at onset and in the spectrum and severity of symptoms have previously been interpreted as evidence of genetic heterogeneity. We have studied the linkage between the disorder and closely linked DNA markers in families of distinct ethnic origins, including the "typical" French-Canadians and the Acadian population of Louisiana. The disease in these two populations, both of continental French origin, has a very similar initial clinical picture. However, a marked difference in the rate of progression of the obligatory symptoms after 10 years of apparent disease is observed. A total of 553 individuals from 80 families with 202 affected members have been typed with the chromosome 9 marker MCT112, which we have previously shown to be closely linked to the disease locus. Evidence for linkage was observed in all families with the generation of a combined total lod score of 25.09 at a recombination fraction of theta = .00, providing strong evidence for genetic homogeneity at this locus for the classical form of this disease.

We studied free plasma catecholamines in 23 patients with Friedreich's ataxia, having a mean age of 22 +/- 9.6 (SD) years. Conjugated catecholamines were also studied in 10 patients. Mean plasma norepinephrine and epinephrine were significantly higher than controls both in the supine and standing positions. In total 15 out of 23 patients (65%) had increase free and/or conjugated plasma catecholamines. The increased in plasma catecholamines was more marked in patients with severe neuromotor impairment. Among the patients with left ventricular concentric hypertrophy (wall thickness greater than 12 mm), only 3 had no demonstrable sympathetic hyperfunction. Since the high local concentrations of norepinephrine at the site of release from sympathetic nerve terminals may serve as a trigger for the hypertrophic response of the myocardial cell, it is suggested that early pharmacological intervention could prevent or limit the cardiomyopathic process or its clinical consequences.