Characteristics of 5-aminolaevulinic acid-induced protoporphyrin IX fluorescence in human skin in vivo

BACKGROUND/PURPOSE: Topical photodynamic therapy (PDT) is increasingly being used to treat skin cancers. Knowledge of the detailed characteristics of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence in diseased and normal skin is incomplete. Understanding the characteristics of PpIX fluorescence in normal skin may facilitate optimization of PDT regimes while minimizing side effects in the surrounding normal skin. We investigated the characteristics of ALA-induced PpIX fluorescence in normal skin. METHODS: ALA was applied to the arm, back and leg skin of 21 healthy volunteers for 1-6 h, and PpIX fluorescence was measured for up to 24 h after ALA application using a fluorescent spectrometer. The effect of tape stripping on fluorescence was also examined. RESULTS: Considerable inter-subject variation was observed in the time to reach peak PpIX fluorescence. Intra-subject variation in the time to peak fluorescence was dependent on ALA application time. Six hours after ALA application, no significant difference was observed in the degree of fluorescence achieved irrespective of ALA application times ranging between 1 and 6 h. PpIX fluorescence was reduced on the leg and increased by tape stripping. CONCLUSIONS: Marked inter- and intra-subject variation in ALA-induced PpIX fluorescence occurs in normal human skin. ALA application time, body site and the state of the stratum corneum are all determinants of PpIX fluorescence within subjects and these factors need to be taken into account in optimization of PDT regimes.     

Biplanar Low-Dose Radiography Is Accurate for Measuring Combined Anteversion After Total Hip Arthroplasty

HSS Journal ® - Acetabular component position alone has not been predictive of stability after total hip arthroplasty (THA). Combined anteversion of the acetabulum and femur has the potential...     

Loss of NADPH Oxidase–Derived Superoxide Skews Macrophage Phenotypes to Delay Type 1 Diabetes

Macrophages are early islet-infiltrating cells seen in type 1 diabetes (T1D). While proinflammatory M1 macrophages induce T1D, M2 macrophages have been shown to delay this autoimmune disease in nonobese diabetic (NOD) mice, but the environmental cues that govern macrophage polarization and differentiation remain unresolved. We previously demonstrated the importance of reactive oxygen species (ROS) in T1D, as NOD mice deficient in NADPH oxidase (NOX)-derived superoxide (Ncf1^m1J) were protected against T1D partly because of blunted Toll-like receptor–dependent macrophage responses. We provide evidence that NOX-derived ROS contribute to macrophage differentiation in T1D. During spontaneous diabetes progression, T1D-resistant NOD.Ncf1^m1J islet-resident macrophages displayed a dampened M1 and increased M2 phenotype. The transfer of diabetogenic T cells into NOX-deficient NOD.Rag.Ncf1^m1J recipients resulted in decreased TNF-α⁺ and IL-1β⁺ islet-infiltrating M1 macrophages and a concomitant enhancement in arginase-1⁺ M2 macrophages. Mechanistic analysis of superoxide-deficient bone marrow–derived macrophages revealed a marked diminution in a proinflammatory M1 phenotype due to decreased P-STAT1 (Y701) and interferon regulatory factor 5 compared with NOD mice. We have therefore defined a novel mechanistic link between NOX-derived ROS and macrophage phenotypes, and implicated superoxide as an important factor in macrophage differentiation. Thus, targeting macrophage redox status may represent a promising therapy in halting human T1D.     

Patient-Reported Outcome Measures of Total Knee Arthroplasties for Post-Traumatic Arthritis versus Osteoarthritis: A Short-Term (5- to 10-year) Retrospective Matched Cohort Study

Background

The objective of the study was to compare the patient-reported outcome measures (PROM) of patients with post-traumatic arthritis (PTA) versus patients with osteoarthritis (OA) undergoing total knee arthroplasty (TKA) and compare the rates of revision among these two groups.

The familial occurrence of lymphocytic thyroiditis in borzoi dogs

A group of related borzoi dogs were studied over a 6-year period to ascertain the cause of primary hypothyroidism. Four generations of dogs were analyzed. Two littermates with lymphocytic thyroiditis were mated and the 10 offspring were all diagnosed, on the basis of thyroid biopsy evaluation, as having lymphocytic thyroiditis by age 2.5 years. A wide range of thyroid gland lesions was demonstrated in this litter of dogs. This report documents the occurrence of lymphocytic thyroiditis in three successive generations of an inbred group of borzoi dogs. An autosomal recessive mode of inheritance for the trait in this group of dogs is proposed.     

Analogues of 1,3-dipropyl-8-phenylxanthine: enhancement of selectivity at A1-adenosine receptors by aryl substituents

The effect of a variety of aryl substituents on the potency and selectivity of 19 analogues of 1,3-dipropyl-8-phenylxanthine as antagonists at A1- and A2-adenosine receptors in brain tissue was determined. The 4-sulfamoylphenyl and 4-carbamoylphenyl analogues are potent and somewhat selective for the A1 receptor. None of the dihydroxyphenyl analogues are remarkably potent, but all are selective for the A1 receptor. 1,3-Dipropyl-8-(2-hydroxy-4-methoxyphenyl)xanthine is the most selective A1 antagonist of the analogues with a A1/A2 potency ratio of about 90.     

Riboflavin: Inhibitory Effects on Receptors, G-Proteins, and Adenylate Cyclase

Riboflavin inhibited binding of both agonist and antagonist radioligands to rat brain A(1)-adenosine receptors with K(i) values of approximately 10 μM. In an adenylate cyclase assay with membrane preparations from either rat adipocytes or DDT MF-2 cells, both of which contain A(1)-adenosine receptors, riboflavin inhibited isoproterenol-stimulated cyclase activity with an IC(50) of approximately 20 μM. However, the inhibition of cyclase by riboflavin was not reversed by an A(1)-selective antagonist, nor by pretreatment with pertussis toxin. Thus, neither A(1)-receptors nor G(i)-proteins appear critically involved in the inhibition of cyclase by riboflavin. Riboflavin did block the stimulation by an adenosine analog of [(35)S]GTPγS binding in rat cerebral cortical membranes. However, riboflavin also inhibited the stimulation by fMLP of [(35)S]GTPγS binding in HL-60 cell membranes. Riboflavin inhibited forskolin-stimulated cyclase in membranes from DDT MF-2 cells > rat adipocytes > PC12 cells, hamster CHO M2 cells, and wild-type S49 cells. There was virtually no inhibition of forskolin-stimulated cyclase in membranes of human platelets, rat cerebral cortex, or cyc(-)S49 cells lacking G(s)-proteins. The calcium-stimulated cyclase in rat cerebral cortical membranes was inhibited by riboflavin. A preincubation of membranes with riboflavin markedly enhanced the inhibition for DDT MF-2 and wild-type and cyc(-)S49 membranes. The extent of inhibition in the different cell lines was dependent on the agent used to stimulate cyclase. Riboflavin, like the P-site inhibitor 2′,5′-dideoxyadenosine, was more potent and efficacious when manganese instead of forskolin was used as the stimulant. However, unlike the P-site inhibitor, riboflavin did not markedly inhibit GppNHp- or fluoride-stimulated cyclase. Riboflavin at low micromolar concentrations appears to have three possibly interrelated effects on second messenger systems subserved by G-proteins. These are antagonism at A(1)-adenosine receptors, inhibition of turnover of guanyl nucleotides at G-proteins, and inhibition of adenylate cyclase.