Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.

The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a "Trojan horse" mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.

Laparoscopic revision paraesophageal hernia repair: a 16-year experience at a single institution.

BACKGROUND: Laparoscopic paraesophageal hernia repair (PEHr) is a safe and effective procedure for relieving foregut symptoms associated with paraesophageal hernias (PEH). Nonetheless, it is estimated that about 30-50% of patients will have symptomatic recurrence requiring additional surgical intervention. Revision surgery is technically demanding and may be associated with a higher rate of morbidity and poor patient-reported outcomes. We present the largest study of perioperative and quality-of-life outcomes among patients who underwent laparoscopic revision PEHr. METHODS: A retrospective review of all patients who underwent laparoscopic revision paraesophageal hernia repair between February 2003 and October 2019, at a single institution was conducted. All revisions of Type I hiatal hernias were excluded. The following validated surveys were used to evaluate quality-of-life outcomes: Reflux Symptom Index (RSI) and Gastroesophageal Reflux Disease Health-Related QOL (GERD-HRQL). Patient demographic, perioperative, and quality-of-life (QOL) data were analyzed using univariate analysis. RESULTS: One hundred ninety patients were included in the final analysis (63.2% female, 90.5% single revision, 9.5% multiple revisions) with a mean age, BMI, and age-adjusted Charlson score of 56.6 ± 14.7 years, 29.7 ± 5.7 kg/m2, and 2.04 ± 1.9, respectively. The study cohort consisted of type II (49.5%), III (46.3%), and IV hiatal hernia (4.2%), respectively. Most patients underwent either a complete (68.7%) or partial (27.7%) fundoplication. A Collis gastroplasty was performed in 14.7% of patients. The median follow-up was 17.6 months. The overall morbidity and mortality rate were 15.8% and 1.1%, respectively. The 30-day readmission rate was 9.5%. Additionally, at latest follow-up 47.9% remained on antireflux medication. At latest follow-up, there was significant improvement in mean RSI score (46.4%, p < 0.001) from baseline within the study population. Furthermore, there was no significant difference in QOL between patients who had a history of an initial repair only or history of revision surgery at latest review. The overall recurrence rate was 16.3% with 6.3% requiring a surgical revision. CONCLUSION: Laparoscopic revision PEHr is associated with a low rate of morbidity and mortality. Revision surgery may provide improvement in QOL outcomes, despite the high rate of long-term antireflux medication use. The rate of recurrent paraesophageal hernia remains low with few patients requiring a second revision. However, longer follow-up is needed to better characterize the long-term recurrence rate and symptomatic improvements.

Biological depletion of neutrophils attenuates pro-inflammatory markers and the development of the psoriatic phenotype in a murine model of psoriasis.

Although neutrophils are considered a histologic hallmark of psoriasis, their pathophysiologic role in psoriasis remains unclear. We characterized the effects of neutrophil depletion via injection of monoclonal antibody 1A8 on the development of imiquimod (IMQ)-induced psoriatic lesions in a murine model. Lesions were followed with photographs and histologic analysis, revealing reduced psoriasiform scale and epidermal hyperplasia in neutrophil-depleted. ELISA and flow cytometry were used to determine relative levels of cytokines and immune cells. Compared to controls, IMQ-treated neutropenic mice had significantly lower levels of macrophages in tissue samples (P < .05) and displayed significantly lower numbers of CD4+ T-cells (P < .05). Neutropenic animals exhibited lower levels of TNF-α, IFN-γ, and IL-1ß than controls (P < .05). These results show that neutropenia reduces the development of psoriasiform skin lesions and substantially decreases infiltration of pro-inflammatory cytokines and immune cells to IMQ-induced cutaneous lesions, suggesting an active role of neutrophils in maintaining inflammation in psoriasis.

Is there a role for bariatric surgery in patients with severe obesity and type 1 diabetes?

BACKGROUND: The prevalence of obesity in type 1 diabetes has been increasing over the past decades. Multiple studies have demonstrated suboptimal outcomes with dietary control and medical management for obesity and type 2 diabetes. This study's objective was to evaluate insulin and diabetic medication requirements in patients with type 1 diabetes 2 years after bariatric surgery. METHODS: This was a retrospective medical-record review study from 2002 to 2019 at Geisinger Health System. Of 4549 total bariatric surgeries, 38 bariatric surgery patients were confirmed to have type 1 diabetes. Type 1 diabetes was confirmed by medical-record review and/or the presence of C-peptide <5 ng/mL. RESULTS: The patient cohort had a mean age of 41 years, with 87% being female. The mean body mass index was 43.0 kg/m2, with a mean HbA1C of 8.4% before surgery. During follow-up, the insulin requirements improved from 114 units preoperatively to 60 units at 1 year postoperatively (SD = 54.5, P = .0018) and 60 units at 2 years postoperatively (SD = 60.3, P = .0033). Though not significant, the number of patients on more than 1 diabetic medication decreased from 66% preoperatively to 53% 1 year postoperatively (P = .343) and 52% at 2 years (P = .149). CONCLUSION: This study demonstrated significant improvement in the insulin and total number of diabetic medication requirements after bariatric surgery, suggesting that bariatric surgery may be a viable treatment for patients with type 1 diabetes.