Nitrite directly vasodilates hypoxic vasculature via nitric oxide-dependent and -independent pathways

Background and purpose:

It is postulated that nitrite requires reduction to nitric oxide in order to exert its relaxant effect upon isolated hypoxic vessels. Herein, we evaluate the relative contribution of nitric oxide and characterize the downstream mechanisms of nitrite-induced vasorelaxation.

Experimental approach:

Aortic rings were treated with pharmacological agents and exposed to hypoxia (<1% O₂). Following pre-constriction, nitrite (10 µM final) was added to appropriate baths; isometric tension was recorded throughout.

Key results:

Nitrite (under hypoxic conditions at physiological pH) is capable of exerting physiological effects that cannot be completely inhibited by the inhibitor of soluble guanylate cyclase (sGC), 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or a nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide). Simultaneous blockade of both sGC and cyclooxygenase (COX) completely inhibited the response to nitrite. With regard to the nitric oxide-dependent component, we confirm that aldehyde oxidase, but not xanthine oxidase or endothelial nitric oxide synthase, was important for the actions of nitrite in our model.

Conclusions and implications:

Nitric oxide generated from nitrite is not exclusively responsible for the physiological actions observed in isolated hypoxic vessels. Nitrite operates via different pathways dependent on the presence or absence of endothelium to produce vasorelaxation. In intact vessels, both sGC and COX enzymes appear to be important. Irrespective of this difference in relaxation mechanism, nitrite is capable of producing the same maximum relaxation, regardless of the presence of endothelium. Having investigated possible nitrite reduction sites, we confirm that aldehyde oxidase is important for the actions of nitrite.     

Immune-driven recombination and loss of control after HIV superinfection

After acute HIV infection, CD8⁺ T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27⁺ subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8⁺ T cell responses revealed that each of these recombination sites (~50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8⁺ T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.     

Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic in South Africa and the clinical manifestation of AIDS-associated Kaposi's sarcoma (KS) represents a significant clinical problem. Whereas the positive effects of HAART on the regression of KS have been well established, less is known about the role of herpesvirus-specific cellular immunity in disease improvement. DESIGN: Thirty-three treatment-naive HIV clade C-infected individuals with KS were randomly assigned into two treatment arms (HAART plus systemic chemotherapy versus HAART alone). KSHV-specific cellular immune responses, viral loads and clinical outcome were evaluated. METHODS: KSHV, Epstein-Barr virus and HIV-specific cellular immunity was measured using an IFN-gamma enzyme-linked immunospot assay in samples obtained at baseline and up to 11 months after treatment initiation. Cell-associated KSHV viremia was determined by real-time polymerase chain reaction. RESULTS: Robust increases in CD4 cell counts and suppressed HIV viral loads were seen in parallel with significant increases in the KSHV-specific cellular immune responses over time. Although slowly increasing after 5 months, KSHV-specific T-cell responses were significantly elevated only after 11 months, with both lytic and latent antigens being more frequently targeted. A trend towards better clinical outcome with HAART plus chemotherapy treatment was observed compared with HAART alone, and was accompanied by a significant reduction in cellular KSHV viral load in the HAART plus chemotherapy-treated subjects but not those treated with HAART alone after 11 months of treatment. CONCLUSION: The data show a temporal association between the clinical improvement of KS and the re-appearance of KSHV-specific cellular immunity, and demonstrate an effective suppression of KSHV viral replication using combination therapy.     

Tracheal tear and tension pneumothorax complicating bronchoscopy-guided percutaneous tracheostomy

Percutaneous dilatational tracheostomy (PDT) is a frequently conducted procedure in critically ill patients. Bronchoscopic guidance of PDT is generally recommended to minimize the risk of unintentional tracheal injury. We present a case of tracheal tear and tension pneumothorax, a rare but potentially life-threatening complication, during continuously bronchoscopy-guided PDT. Sealing the large tracheal air fistula with the cuff of an endotracheal tube helped bridge time to definitive surgical repair in our patient. Bronchoscopic guidance may minimize, but cannot completely eliminate, the risk of tracheal injury during PDT.     

Congenital left atrial appendage ostial stenosis in an extremely premature infant diagnosed by transthoracic echocardiography

Congenital left atrial appendage ostial stenosis is a very rare congenital cardiac condition. We present the case of an extremely premature infant with congenital left atrial appendage ostial stenosis diagnosed by transthoracic echocardiographic imaging.     

A failure in the medication delivery system—how disclosure and systems investigation improve patient safety

A recent medication error at Vanderbilt University Medical Center contributed to the death of a patient. The ensuing criminal indictment of the administering nurse has shaken the medical community. This has led to clinical staff questioning whether they can disclose patient safety incidents without fear of criminal prosecution. However, because of the publicity of this case, hospitals can benefit from the lessons learned and mitigate the risk of this and similar events at their facilities. To uncover the most impactful and relevant safety recommendations, the Vanderbilt case is examined from a systems investigation perspective using the available public information gathered from media reports, the Tennessee Bureau of Investigation report, and Vanderbilt's corrective action plan submitted to CMS. We present an example of how hospitals can benefit from disclosure: Henry Ford Health used the Vanderbilt case study as part of its medication safety continuous improvement initiatives, which are underpinned by available medication safety recommendations from the Institute for Safe Medication Practices. Using this experience and the lessons learned from the Vanderbilt case, a proactive action plan is presented for hospitals nationwide to prevent the recurrence of this medication error. Without disclosure, these analyses and safety recommendations would not have been possible.     

Early-Life and Family Risk Factors for Tic Disorder Persistence into Adulthood

Background

Many children with tic disorders outgrow their tics, but little is known about the proportion of individuals who will continue to require specialist services in adulthood and which variables are associated with tic persistence.

Objectives

The aims were to estimate the proportion of individuals first diagnosed with tic disorders in childhood who continued to receive tic disorder diagnoses after age 18 years and to identify risk factors for persistence.

Methods

In this Swedish nationwide cohort study including 3761 individuals diagnosed with tic disorders in childhood, we calculated the proportion of individuals whose diagnoses persisted into adulthood. Minimally adjusted logistic regression models examined the associations between sociodemographic, clinical, and family variables and tic disorder persistence. A multivariable model was then fitted, including only variables that were statistically significant in the minimally adjusted models.

Results

Seven hundred and fifty-four (20%) children with tic disorders received a diagnosis of a chronic tic disorder in adulthood. Psychiatric comorbidity in childhood (particularly attention-deficit hyperactivity disorder, obsessive-compulsive disorder, pervasive developmental disorders, and anxiety disorders) and psychiatric disorders in first-degree relatives (particularly tic and anxiety disorders) were the strongest risk factors for persistence. We did not observe statistically significant associations with socioeconomic variables, perinatal complications, comorbid autoimmune diseases, or family history of autoimmune diseases. All statistically significant variables combined explained approximately 10% of the variance in tic disorder persistence (P < 0.0001).

Conclusions

Childhood psychiatric comorbidities and family history of psychiatric disorders were the strongest risk factors associated with tic disorder persistence into adulthood. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.