Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD).

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression.

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.

Prevalence and Risk of Dental Erosion in Patients with Gastroesophageal Reflux Disease: A Meta-Analysis.

AIM: The present paper aims to systematize data concerning the prevalence and risk of dental erosion (DE) in adult patients with gastroesophageal reflux disease (GERD) compared to controls. MATERIALS AND METHODS: Core electronic databases, i.e., MEDLINE/PubMed, EMBASE, Cochrane, Google Scholar, and the Russian Science Citation Index (RSCI), were searched for studies assessing the prevalence and risk of DE in adult GERD patients with publication dates ranging from 1 January 1985 to 20 January 2022. Publications with detailed descriptive statistics (the total sample size of patients with GERD, the total sample size of controls (if available), the number of patients with DE in the sample of GERD patients, the number of patients with DE in the controls (if available)) were selected for the final analysis. RESULTS: The final analysis included 28 studies involving 4379 people (2309 GERD patients and 2070 control subjects). The pooled prevalence of DE was 51.524% (95 CI: 39.742-63.221) in GERD patients and 21.351% (95 CI: 9.234-36.807) in controls. An association was found between the presence of DE and GERD using the random-effects model (OR 5.000, 95% CI: 2.995-8.345; I2 = 79.78%) compared with controls. When analyzing studies that only used validated instrumental methods for diagnosing GERD, alongside validated DE criteria (studies that did not specify the methodologies used were excluded), a significant association between the presence of DE and GERD was revealed (OR 5.586, 95% CI: 2.311-13.503; I2 = 85.14%). CONCLUSION: The meta-analysis demonstrated that DE is quite often associated with GERD and is observed in about half of patients with this extremely common disease of the upper gastrointestinal tract.

Focus on FOCIS: the continuing diagnostic challenge of autosomal recessive chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency of defective neutrophil oxidative burst activity due to mutations in the genes CYBA, NCF-1, NCF-2, and CYBB, which respectively encode the p22-phox, p47-phox, p67-phox, and gp91-phox subunits. CGD usually presents in early childhood with recurrent or severe infection with catalase-positive bacteria and fungi. We present an unusual case of CGD in which Burkholderia cepacia lymphadenitis developed in a previously healthy 10-year-old girl. Flow cytometric analysis of dihydrorhodamine (DHR)-labeled neutrophils performed by a CLIA-approved outside reference laboratory was reported as normal. However, we found that this patient's neutrophil oxidative burst activity in DHR assays was substantially reduced but not absent. A selective decrease in intracellular staining for p67-phox suggested the diagnosis of autosomal recessive CGD due to NCF-2 gene mutations, and a novel homozygous and hypomorphic NCF-2 gene mutation was found. The potential mechanisms for this delayed and mild presentation of CGD are discussed.

Structural and wetting properties of nature's finest silks (order Embioptera).

Insects from the order Embioptera (webspinners) spin silk fibres which are less than 200 nm in diameter. In this work, we characterized and compared the diameters of single silk fibres from nine species-Antipaluria urichi, Pararhagadochir trinitatis, Saussurembia calypso, Diradius vandykei, Aposthonia ceylonica, Haploembia solieri, H. tarsalis, Oligotoma nigra and O. saundersii. Silk from seven of these species have not been previously quantified. Our studies cover five of the 10 named taxonomic families and represent about one third of the known taxonomic family-level diversity in the order Embioptera. Naturally spun silk varied in diameter from 43.6 ± 1.7 nm for D. vandykei to 122.4 ± 3.2 nm for An. urichi. Mean fibre diameter did not correlate with adult female body length. Fibre diameter is more similar in closely related species than in more distantly related species. Field observations indicated that silk appears shiny and smooth when exposed to rainwater. We therefore measured contact angles to learn more about interactions between silk and water. Higher contact angles were measured for silks with wider fibre diameter and higher quantity of hydrophobic amino acids. High static contact angles (ranging up to 122° ± 3° for An. urichi) indicated that silken sheets spun by four arboreal, webspinner species were hydrophobic. A second contact angle measurement made on a previously wetted patch of silk resulted in a lower contact angle (average difference was greater than 27°) for all four species. Our studies suggest that silk fibres which had been previously exposed to water exhibited irreversible changes in hydrophobicity and water adhesion properties. Our results are in alignment with the 'super-pinning' site hypothesis by Yarger and co-workers to describe the hydrophobic, yet water adhesive, properties exhibited by webspinner silk fibres. The physical and chemical insights gained here may inform the synthesis and development of smaller diameter silk fibres with unique water adhesion properties.

The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation.

BACKGROUND: The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection. METHODS: Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%). RESULTS: Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection. CONCLUSIONS: A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease.

BACKGROUND: Asymptomatic cytomegalovirus (CMV) replication is frequent after cardiac transplantation in recipients with pretransplantation CMV infection. How subclinical viral replication influences cardiac allograft disease remains poorly understood, as does the importance of T-cell immunity in controlling such replication. METHODS AND RESULTS: Thirty-nine cardiac recipients who were pretransplantation CMV antibody positive were longitudinally studied for circulating CMV-specific CD4 and CD8 T-cell responses, CMV viral load in blood neutrophils, and allograft rejection during the first posttransplantation year. Nineteen of these recipients were also analyzed for changes of coronary artery intimal, lumen, and whole-vessel area. All recipients received early prophylactic therapy with ganciclovir. No recipients developed overt CMV disease. Those with detectable levels of CMV-specific CD4 T cells in the first month after transplantation were significantly protected from high mean and peak posttransplantation viral load (P<0.05), acute rejection (P<0.005), and loss of allograft coronary artery lumen (P<0.05) and of whole-vessel area (P<0.05) compared with those who lacked this immune response. The losses of lumen and vessel area were both significantly correlated with the time after transplantation at which a CD4 T-cell response was first detected (P<0.05) and with the cumulative graft rejection score (P<0.05). CONCLUSIONS: The early control of subclinical CMV replication after transplantation by T-cell immunity may limit cardiac allograft rejection and vascular disease. Interventions to increase T-cell immunity might be clinically useful in limiting these adverse viral effects.

Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2.

Vascular proliferative disorders are characterized by the proliferation of vascular smooth muscle cells (SMCs) and excessive extracellular matrix synthesis. We found that bone morphogenetic protein-2 (BMP-2) inhibited serum-stimulated increases in DNA synthesis and cell number of cultured rat arterial SMCs in a fashion quite different from that in the case of transforming growth factor-beta1 (TGF-beta1). In addition, TGF-beta1 stimulated collagen synthesis in SMCs, whereas BMP-2 did not. In an in vivo rat carotid artery balloon injury model, the adenovirus-mediated transfer of the BMP-2 gene inhibited injury-induced intimal hyperplasia. These results indicate that BMP-2 has the ability to inhibit SMC proliferation without stimulating extracellular matrix synthesis, and suggest the possibility of therapeutic application of BMP-2 for the prevention of vascular proliferative disorders.

Actomyosin extracted from bovine aortic intima.

Actomyosin extracted from bovine aortic intima with a KCl-ATP medium of low ionic strength, but not with a KCl medium of high ionic strength, exhibited Ca2+ sensitivity. Aortic medial actomyosin extracted with a medium of high ionic strength retained the Ca2+ sensitivity. These differences in extractability suggest that actomyosin of the aortic intima is different from that of the aortic media.

Inducing peripheral sympathetic nerve activity by therapeutic electrical stimulation.

PURPOSE: To examine whether the activity of peripheral sympathetic nerves in animals with spinal cord injury can be controlled using therapeutic electrical stimulation. METHODS: The spinal cords of 6 Wistar rats were severed at T12/T13 disk level and were given continuous therapeutic electrical stimulation. Microneurography was used to record sympathetic nerve activity at 24, 48, and 72 hours after severing the spinal cord. RESULTS: Integrated values of muscle sympathetic nerve activity after 72 hours of therapeutic electrical stimulation revealed significantly larger potentials on the stimulated side than the non-stimulated side. Skin sympathetic nerve activity showed no difference between the 2 sides. CONCLUSION: Therapeutic electrical stimulation was found to have a facilitatory effect on the muscle sympathetic nerve activity, whereas regulatory function was activated by the sympathetic nerves.

Transmembrane TNF (pro-TNF) is palmitoylated.

Human transmembrane tumor necrosis factor (pro-TNF) was examined for protein acylation. The cDNA encoding pro-TNF was expressed in both COS-1 cells and Sf9 cells and metabolic labeling with [(3)H]myristic or [(3)H]palmitic acid was attempted. The 17 kDa mature TNF secreted from the transfected cells was not labeled, whereas the 26 kDa pro-TNF was specifically labeled with [(3)H]palmitic acid. The [(3)H]palmitic acid labeling of pro-TNF was eliminated by treatment with hydroxylamine, indicating that the labeling was due to palmitoylation of a cysteine residue via a thioester bond. Site-directed mutagenesis of the two cysteine residues residing in the leader sequence of pro-TNF demonstrated that palmitoylation of pro-TNF occurs solely at Cys-47, located at the boundary between the transmembrane and cytoplasmic domains of pro-TNF. Thus, pro-TNF interacts with the plasma membrane via both its proteinaceous transmembrane domain and a lipid anchor.

Hypoxic induction of adrenomedullin in cultured human umbilical vein endothelial cells.

OBJECTIVES: The current study evaluated the hypoxic induction of adrenomedullin gene expression and secretion, and its mechanism in cultured human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC were exposed to hypoxia or normoxia as controls for 1 to 24 h. Using Northern blot analysis and a radioimmunoassay, we evaluated adrenomedullin expression in HUVEC. The transcriptional component of adrenomedullin gene regulation was assessed by nuclear run-off experiments, and adrenomedullin mRNA half-life was measured by actinomycin D experiments. RESULTS: We found that hypoxic conditions (1-3% oxygen) significantly increased adrenomedullin mRNA and protein in HUVEC. This increase was inversely proportional to oxygen tension and was reversible upon re-exposure to a 21% oxygen environment Nuclear run-off experiments revealed the enhanced transcriptional rate of adrenomedullin gene. Next, actinomycin D experiments revealed the enhanced adrenomedullin mRNA stability. CONCLUSIONS: These results indicate that hypoxia increases adrenomedullin gene expression and secretion in HUVEC by transcriptional and post-transcriptional mechanisms. Hypoxic induction of adrenomedullin may play a pathophysiological role in the vascular systems.

Acute effects of nicotine content in cigarettes on coronary flow velocity and coronary flow reserve in men.

We investigated the acute effects of smoking on coronary flow reserve in terms of the nicotine content of cigarettes in 21 smokers. Coronary flow velocity was measured with a Doppler flow wire. Subjects smoked cigarettes containing >1 mg nicotine (n = 8, group 1) or <1 mg (n = 6, group 2). Subjects in the control group mimicked smoking without a cigarette (n = 7). Coronary flow reserve decreased after smoking in group 1, but not in group 2 or the control group. This reduction may have mediated nicotine or some other unknown substances influenced by smoking.

Sympathetic skin response evoked by respiratory stimulation as a measure of sympathetic function.

OBJECTIVES: To compare respiratory and electrical methods of evoking a sympathetic skin response (SSR). METHODS: SSRs evoked by both electrical and respiratory stimulation were recorded from the palms of 47 healthy volunteers. Expiration and inspiration were used as separate stimuli. The correlation coefficients between the amplitude and latency of the SSR from the palm electrodes and the various components of heart rate variability were calculated. RESULTS: Waveform patterns of the SSRs obtained from electrical stimulation showed varied responses to and habituation to this type of stimulation. On the other hand, no subjects showed a phase change in SSR waveform patterns between the first and last expiratory stimuli. The potentials recorded after expiratory stimulation had significantly greater amplitudes than those recorded after electrical stimuli. The low frequency component of heart rate variability induced by expiratory stimulation was significantly greater than that induced by electrical stimulation. The SSR may also correlate strongly with the change of respiratory rate since a more rapid pressure change occurs during expiratory movement than during inspiratory movements. CONCLUSIONS: The SSR evoked by expiratory stimulation is more reliable than either electrical stimulation or inspiratory stimulation for determining sympathetic function.

Identification of putative gene encoded on ORF16 of the 81 kb contig of Arabidopsis thaliana chromosome III as alpha-mannosidase.

We isolated cDNA corresponding to open reading frame (ORF) 16 of the 81 kb contig of Arabidopsis thaliana chromosome III [Quigley., Nucleic Acids Res., 24, 4313-4318 (1996)] and expressed alpha-mannosidase activity in tobacco suspension-cultured cells, which revealed that ORF16 encodes alpha-mannosidase. We also suggested that Arabidopsis harbors three genes encoding alpha-mannosidase by homology search against the database.

Aortic perfusion pressure and protein synthesis.

The effect of increased pressure load on cardiac protein synthesis has been studied in Langendorff preparations and working hearts supplied glucose as substrate. During the second hour of perfusion, elevation of perfusion pressure from 60 to 120 mmHg in Langendorff preparations accelerated protein synthesis by approximately 40% while induction of cardiac work and development of a systolic pressure of 145 mmHg increased synthesis by 22%, as compared to a Langendorff preparation perfused at 60 mmHg. In Langendorff preparations, increased perfusion pressure still accelerated protein synthesis when a drain was placed in the ventricle and intraventricular pressure development was prevented or when the heart was arrested with tetrodotoxin and the ventricle drained. These results suggest that the enhancement of protein synthesis with a pressure load may be induced by passive stretch of the cardiac muscle cell secondary to increased perfusion pressure.

High incidence of mitral and tricuspid regurgitation in patients with Graves' disease detected by two-dimensional color Doppler echocardiography.

With two-dimensional (2D) color Doppler echocardiography, the cardiac and valvular function of 24 consecutive patients with a history of Graves' disease (17 were hyperthyroid and 7 were euthyroid at the time of the examination) were evaluated. The incidences of mitral regurgitation (MR), tricuspid regurgitation (TR) and MR plus TR were significantly higher in the patients with Graves' disease than in the age-matched control group of patients without this disease. In the patients who had signs of congestive heart failure (CHF) while they were hyperthyroid, a significantly higher incidence of severe TR was observed. This is the first report of a 2D color Doppler echocardiography study on the incidences of TR and/or MR in patients with Graves' disease. Our data indicate that in Graves' disease valvular dysfunction can be caused by systemic disorders and that severe TR is a possible risk factor for CHF.

Ascitic fluid cytology of adenosarcoma of the ovary: a case report.

Extrauterine adenosarcoma is very rare and originates in the ovary, adnexa, or myometrium. Cytologic study of ascites is very important to determine clinical staging of malignant ovarian tumors and provide adequate therapy for recurrence. The cytomorphologic features of adenosarcoma have been only rarely described. A 77-yr-old woman visited a hospital with a complaint of lower abdominal pain for 1 mo. A tumor originating from the right adnexa in the pelvis, and involving the rectum, was found in surgery. In the ascitic fluid cytology, a few dispersed tumor cells with large cytoplasm and nuclei were oval-shaped, with nuclear invagination. The chromatin was finely granular; one or two nucleoli were conspicuous. To our knowledge, this is the fifteenth reported case of adenosarcoma of the ovary, and there have been no prior reports describing the cytological features of ascitic fluid cells in adenosarcoma of the ovary.

Sympathetic skin response in patients with spinal cord injury.

PURPOSE: To assess the effectiveness of sympathetic skin response in evaluating peripheral sympathetic nerve activity of patients with spinal cord injury, and to report on the basic properties of sympathetic skin response. METHODS: Sympathetic skin response evoked by electrical stimulation was recorded from the palms and soles of healthy volunteers and patients with spinal cord injury. RESULTS: Sympathetic skin response was recorded in 17 healthy volunteers and 14 patients with spinal cord injury. Of the 4 waveforms, the shortest latency was obtained from the palm; the sympathetic skin response was 1.2 to 1.4 ms at all stimulated sites, 1.9 to 2.0 ms at the sole, with a difference of about 0.6 ms between the palm and the sole. None of the patients with spinal cord injury responded at either the upper or lower limbs. In patients with a thoracic cord injury, some responded at the upper limbs but none at the lower limbs; some responded at neither upper nor the lower limbs; and some responded at both upper and lower limbs. The conducting pathway of sympathetic skin response in the spinal cord for the upper limbs descends to the upper thoracic cord (T4-6), and the conducting pathway for the lower limbs departs from the spinal cord at the lower thoracic cord (T9-10). CONCLUSION: It appears that sympathetic skin response should be used for the evaluation and morbid investigation of the functional abnormalities of the sympathetic nervous system in patients with spinal cord lesions such as spinal cord injuries, cervical spondylosis, and spinal canal stenosis.