Role of blood- and tissue-associated inducible nitric-oxide synthase in colonic inflammation

There is evidence that inducible nitric-oxide synthase (iNOS)-derived NO contributes to the pathophysiology of intestinal inflammation. The aims of this study were to assess the role of iNOS in the development of dextran sodium sulfate (DSS)-induced colonic inflammation and to define the contribution of tissue-specific iNOS expression to this inflammatory response. Study groups included: 1) wild-type (WT) mice; 2) WT=>WT bone marrow chimeras with normal iNOS function; 3) WT=>iNOS-/- chimeras (with functional blood cell iNOS, but iNOS-deficient tissue); 4) iNOS-/-=>WT chimeras (with iNOS-deficient blood cells, but normal tissue iNOS activity); and 5) iNOS-deficient mice. In WT mice and WT=>WT chimeras, DSS-induced colonic inflammation was characterized by bloody diarrhea and a high disease activity index. However, WT=>iNOS-/- and iNOS-/-=>WT chimeras and iNOS-/- mice exhibited an attenuated disease activity index, with parallel changes in histopathology. Colonic myeloperoxidase (MPO) was comparably elevated in DSS-treated WT mice (30.1+/-1.7) and WT=>WT chimeras (29.0+/-1), whereas MPO was significantly reduced in iNOS-/- mice and iNOS-/-=>WT chimeras (9.5+/-1.7 and 15.6+/-2.2, respectively). WT=>iNOS-/- chimeras exhibited the lowest MPO activity (3.7+/-0.6). Our findings implicate both blood cell- and tissue-derived iNOS in DSS-induced colonic inflammation, with tissue-associated iNOS making a larger contribution to the recruitment of inflammatory cells.     

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX-2

Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (DeltaU) or ExoU and ExoT (DeltaUT). COX-2(-/-) mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E(2) on the function of phagocytic cells. Our studies indicate that prostaglandin E(2) may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E(2) suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor(-/-) mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.     

Competitiveness among health and the health sector. A new look at the health economics paradigm

Health and the health sector have a direct impact on economic growth and competitiveness. Moreover, the health sector is experiencing increasingly strong links with the economy, which reinforces the key role that health plays in the development of individuals and economies. On the one hand, in addition to its intrinsic value health constitutes an important economic good because it contributes to increasing the capacity of individuals and nations to achieve greater levels of human, economic and social development. In addition, there is a direct relationship between health as a productive sector and the economy that will become more important as world health expenditure increases and because of recent advances in the productivity of the medical sector and the technology used in providing health services. For these reasons, a better understanding of the complex relationship between health, the health sector and economic development will help to increase competitiveness and attain higher levels of growth by enabling a more efficient health system that is in turn based on a solid, fair, equitable and sufficient financial base.     

Changes in Energy Intake and Diet Quality during an 18-Month Weight-Management Randomized Controlled Trial in Adults with Intellectual and Developmental Disabilities

Background

Previous research indicates that individuals with intellectual and developmental disabilities (IDDs) are at risk for poor diet quality.

Benign breast papilloma: Is surgical excision necessary?

In many centers internationally, current standard of care is to excise all papillomas of the breast, despite recently reported low rates of upgrade to malignancy on final excision. The objective of this study was to determine the upgrade rate to malignancy in patients with papilloma without atypia. A retrospective review of a prospectively maintained database of all cases of benign intraductal papilloma in a tertiary referral symptomatic breast unit between July 2008 and July 2018 was performed. Patients with evidence of malignancy or atypia on core biopsy and those with a history of breast cancer or genetic mutations predisposing to breast cancer were excluded. One hundred and seventy‐three cases of benign papilloma diagnosed on core biopsy were identified. Following exclusions, the final cohort comprised of 138 patients. Mean age at presentation was 51. Mean follow‐up time was 9.6 months. The most common symptom was a lump (40%). Of the 124 patients who underwent excision, three had ductal carcinoma in situ and there were no cases of invasive disease, giving an upgrade rate to malignancy of 2.4%. Upgrade to other high‐risk lesions (atypical lobular and ductal hyperplasia and lobular carcinoma in situ) was demonstrated in 15 cases (12.1%). Benign papilloma was confirmed in 100 cases (81.5%), and 6 (4.8%) had no residual papilloma found on final excision. Twelve patients (8.7%) were managed conservatively. Of those, one later went on to develop malignancy. Patients with a diagnosis of benign papilloma without atypia on core biopsy have a low risk of upgrade to malignancy on final pathology, suggesting that observation may be a safe alternative to surgical excision. Further research is warranted to determine which patients can be safely managed conservatively.     

Determinants of Repeat Curative Intent Surgery in Colorectal Liver Metastasis

Introduction

Following curative intent surgery (CIS) for colorectal liver metastasis (CRLM), repeat CIS for recurrence improves survival. The factors associated with repeat CIS are not widely reported.

Methods

An institutional database (January 2002–December 2012) was reviewed to evaluate factors influencing repeat CIS.

Results

One hundred sixty-three patients with colorectal liver metastasis (CRLM) underwent successful CIS. Median follow-up and disease-free interval (DFI) was 33 and 16 months, respectively. After initial CIS, 102 patients (63 %) recurred. Fifty-three patients (52 %) underwent a repeat CIS. After repeat CIS, 33 patients (62 %) developed a second recurrence, and in 13 patients (39 %), a third CIS was possible. DFI decreased following initial CIS (first CIS vs. second CIS vs. third CIS [20 vs. 15 vs. 8.5 months], p?Conclusion Despite high recurrence and decreasing DFI, repeat CIS provides a survival benefit. Postoperative complications, DFI, number, and pattern of recurrence influence the decision to pursue repeat CIS.     

Optimum Projection Angle for Attaining Maximum Distance in a Rugby Place Kick

This study investigated the effect of projection angle on the distance attained in a rugby place kick. A male rugby player performed 49 maximum-effort kicks using projection angles of between 20 and 50°. The kicks were recorded by a video camera at 50 Hz and a 2 D biomechanical analysis was conducted to obtain measures of the projection velocity and projection angle of the ball. The player’s optimum projection angle was calculated by substituting a mathematical expression for the relationship between projection velocity and projection angle into the equations for the aerodynamic flight of a rugby ball. We found that the player’s calculated optimum projection angle (30.6°, 95% confidence limits ± 1.9°) was in close agreement with his preferred projection angle (mean value 30.8°, 95% confidence limits ± 2.1°). The player’s calculated optimum projection angle was also similar to projection angles previously reported for skilled rugby players. The optimum projection angle in a rugby place kick is considerably less than 45° because the projection velocity that a player can produce decreases substantially as projection angle is increased. Aerodynamic forces and the requirement to clear the crossbar have little effect on the optimum projection angle.

Key Points

• The optimum projection angle in a rugby place kick is about 30°.
• The optimum projection angle is considerably less than 45° because the projection velocity that a player can produce decreases substantially as projection angle is increased.
• Aerodynamic forces and the requirement to clear the crossbar have little effect on the optimum projection angle.

Key Words: Biomechanics, kinematics, projectile     

Onset of fulminant type 1 diabetes mellitus following hypophysitis after discontinuation of combined immunotherapy. A case report

Diabetes is a rare, but potentially life-threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death-1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51-year-old man with metastatic melanoma, who developed acute-onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late-onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention.