Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, ...XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.
Humoral immune perturbations contribute to pathogenic outcomes in persons with HIV-1 infection (PWH). Gut barrier dysfunction in PWH is associated with microbial translocation and alterations in ...microbial communities (dysbiosis), and IgA, the most abundant immunoglobulin (Ig) isotype in the gut, is involved in gut homeostasis by interacting with the microbiome. We determined the impact of HIV-1 infection on the antibody repertoire in the gastrointestinal tract by comparing Ig gene utilization and somatic hypermutation (SHM) in colon biopsies from PWH (n = 19) versus age and sex-matched controls (n = 13). We correlated these Ig parameters with clinical, immunological, microbiome and virological data. Gene signatures of enhanced B cell activation were accompanied by skewed frequencies of multiple Ig Variable genes in PWH. PWH showed decreased frequencies of SHM in IgA and possibly IgG, with a substantial loss of highly mutated IgA sequences. The decline in IgA SHM in PWH correlated with gut CD4+ T cell loss and inversely correlated with mucosal inflammation and microbial translocation. Diminished gut IgA SHM in PWH was driven by transversion mutations at A or T deoxynucleotides, suggesting a defect not at the AID/APOBEC3 deamination step but at later stages of IgA SHM. These results expand our understanding of humoral immune perturbations in PWH that could have important implications in understanding mucosal immune defects in individuals with chronic HIV-1 infection. IMPORTANCE The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4+ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation. To date, the consequences of microbial translocation on the mucosal humoral immune response (or vice versa) remains poorly integrated into the panoply of mucosal immune defects in PWH. We utilized next-generation sequencing approaches to profile the Ab repertoire and ascertain frequencies of somatic hypermutation in colon biopsies from antiretroviral therapy-naive PWH versus controls. Our findings identify perturbations in the Ab repertoire of PWH that could contribute to development or maintenance of dysbiosis. Moreover, IgA mutations significantly decreased in PWH and this was associated with adverse clinical outcomes. These data may provide insight into the mechanisms underlying impaired Ab-dependent gut homeostasis during chronic HIV-1 infection.
Breast milk is a vehicle of infection and source of protection in post-natal mother-to-child HIV-1 transmission (MTCT). Understanding the mechanism by which breast milk limits vertical transmission ...will provide critical insight into the design of preventive and therapeutic approaches to interrupt HIV-1 mucosal transmission. However, characterization of the inhibitory activity of breast milk in human intestinal mucosa, the portal of entry in postnatal MTCT, has been constrained by the limited availability of primary mucosal target cells and tissues to recapitulate mucosal transmission ex vivo. Here, we characterized the impact of skimmed breast milk, breast milk antibodies (Igs) and non-Ig components from HIV-1-infected Ugandan women on the major events of HIV-1 mucosal transmission using primary human intestinal cells and tissues. HIV-1-specific IgG antibodies and non-Ig components in breast milk inhibited the uptake of Ugandan HIV-1 isolates by primary human intestinal epithelial cells, viral replication in and transport of HIV-1- bearing dendritic cells through the human intestinal mucosa. Breast milk HIV-1-specific IgG and IgA, as well as innate factors, blocked the uptake and transport of HIV-1 through intestinal mucosa. Thus, breast milk components have distinct and complementary effects in reducing HIV-1 uptake, transport through and replication in the intestinal mucosa and, therefore, likely contribute to preventing postnatal HIV-1 transmission. Our data suggests that a successful preventive or therapeutic approach would require multiple immune factors acting at multiple steps in the HIV-1 mucosal transmission process.
Cheyne-Stokes respirations occur in 40% of patients with heart failure. Orthopnea is a cardinal symptom of heart failure and may affect the patient's sleeping angle. The objective of this study was ...to assess the respiratory and hemodynamic response to sleeping angle in a group of subjects with stable heart failure.
Twenty-five patients underwent overnight polysomnography with simultaneous and continuous impedance cardiographic monitoring. Sleeping polysomnographic and impedance cardiographic data were recorded.
The study was conducted in a sleep center.
All 25 patients had clinically stable heart failure and left ventricular ejection fractions < 40%.
The patients slept at 0 degrees, 15 degrees, 30 degrees, and 45 degrees in random order.
Seventeen patients had Cheyne-Stokes apneas (index > 5/h) and 23 patients had hypopneas (index > 5/h). The hypopnea index showed no response to sleeping angle. The Cheyne-Stokes apnea index decreased with increasing sleeping angle (P < 0.001). This effect was seen only during supine sleep and non-rapid eye movement sleep and was absent in non-supine sleep, rapid eye movement sleep, and during periods of wakefulness. Thoracic fluid content index and left ventricular hemodynamics measured by impedance cardiography showed no response to sleeping angle.
Changing the heart failure patient's sleeping angle from 0 degrees to 45 degrees results in a significant decrease in Cheyne-Stokes apneas. This decrease occurs on a constant base of hypopneas. The changes in Cheyne-Stokes apneas are not related to changes in lung congestion and left ventricular hemodynamics.
We had the opportunity to implant the first leadless pacemakers in Hawai‘i. This device represents a major change in pacemaker technology. This is a report of the first five cases and a review of the ...literature. All these devices were implanted via femoral venous access (versus conventional upper chest axillary/subclavian/cephalic routes), with an unique fixation mechanism allowing direct attachment to the ventricular myocardium (dispensing the usage of long transvenous electrode leads). The miniature generator can is over an order of magnitude smaller and lighter than the currently available ones. This article provides an understanding of the device design, implantation technique, the advantages and limitations, and the potential of this new pacemaker.
Comparison of the three-dimensional structures of folylpolyglutamate synthetase (FPGS) and the bacterial cell wall ligase UDP-N-acetylmuramoyl-l-alanine:d-glutamate ligase (MurD) reveals that these ...two enzymes have a remarkable structural similarity despite a low level of sequence identity. Both enzymes have a modular, multi-domain structure and catalyse a similar ATP-dependent reaction involving the addition of a glutamate residue to a carboxylate-containing substrate, tetrahydrofolate in the case of FPGS, and UDP-N-acetylmuramoyl-l-alanine in the case of MurD. Site-directed mutations of selected residues in the active site of Lactobacillus casei FPGS (P74A, E143A, E143D, E143Q, K185A, D313A, H316A, G411A and S412A) showed that most of these changes resulted in an almost complete loss of activity. Several of these amino acid residues in FPGS are found in structurally equivalent positions to active-site residues in MurD. Some insights into the function of these residues in FPGS activity are proposed, based on the roles surmised from the structures of two MurD. UDP-N-acetylmuramoyl-l-alanine.ADP complexes and a MurD. UDP-N-acetylmuramoyl-l-alanine-d-glutamate complex. Furthermore, the comparison has led us to propose that conformational changes induced by substrate binding in the reaction mechanism of FPGS result in a movement of the domains towards each other to more closely resemble the orientation of the corresponding domains in MurD. This relative domain movement may be a key feature of this new family of ADP-forming amide bond ligases.
Two hundred twenty-four patients underwent ventricular programmed stimulation (VPS) without prior documentation of the clinical occurrence of sustained ventricular tachycardia (VT) or ventricular ...fibrillation-flutter (VF). Indications for VPS were: palpitations or nonsustained VT during ambulatory monitoring (85 patients), syncope or presyncope (137 patients), and a family history of sudden death (two patients). Sustained VF requiring transthoracic defibrillation was initiated by VPS in 18 patients (8.0%). Four patients were treated for inducible VF with antiarrhythmic agents directed by electropharmacologic testing; five patients were treated empirically; nine patients received no therapy. No patient has had a cardiac arrest or sudden death during a follow-up period 25.2 +/- 13.8 months (mean +/- standard deviation). VF was initiated by two ventricular extrastimuli in three patients and by three extrastimuli in 15 patients. The incidence of VF was similar in patients with and without previous symptoms (8.8% vs 6.9%) or heart disease (7.1% vs 9.6%). It was significantly higher when VPS at three ventricular sites with a current of 5 mA (pulse width 2 msec) was compared to programmed stimulation at two ventricular sites with a current twice diastolic threshold (pulse width 2 msec) (15.2% vs 3.0%, p less than 0.05). VF initiated by VPS in patients without prior VT or VF appears to be a nonspecific finding. Antiarrhythmic therapy for VF may not be necessary in these patients.
We had the opportunity to implant the first leadless pacemakers in Hawai'i. This device represents a major change in pacemaker technology. This is a report of the first five cases and a review of the ...literature. All these devices were implanted via femoral venous access (versus conventional upper chest axillary/subclavian/cephalic routes), with an unique fixation mechanism allowing direct attachment to the ventricular myocardium (dispensing the usage of long transvenous electrode leads). The miniature generator can is over an order of magnitude smaller and lighter than the currently available ones. This article provides an understanding of the device design, implantation technique, the advantages and limitations, and the potential of this new pacemaker.
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