Are psoriasis and psoriatic arthritis the same disease? The IL-23/IL-17 axis data

Psoriatic arthritis (PsA) is a psoriasis (Ps)-associated inflammatory joint disease that affects peripheral joints, entheses, spine, and eyes. PsA and Ps are likely to be the same disease. PsA develops in nearly 70% of patients with Ps, and the hallmark of the disease is bone erosions and bone formation. Both innate and adaptive immunity appear to contribute to pathogenesis of PsA and Ps. Trauma may be a trigger factor for both PsA and Ps. The same T cell clones were reported to be present in both synovial tissues and skin lesions suggesting that a common antigen drives T cell immune response in the joints and skin lesions of patients with PsA. The IL-23/IL-17 axis plays a critical pathogenic role for both PsA and Ps, and biologics neutralizing IL-17A or IL-23/IL-12 are effective therapies for PsA and Ps. The differential expression of Th17 cytokines IL-17 and IL-22 at various sites could explain the different manifestations of the disease. IL-17 is highly expressed in peripheral joints and skin lesions and causes bone erosions. IL-22 is highly expressed in skin lesions and entheses, not peripheral joints, and cause bone formation. Finally, mannan from baker's yeast caused PsA-like arthritis and Ps-like skin lesions that were blocked by IL-17 treatment. These data suggest that PsA and Ps are likely to be the same disease exhibiting different manifestations depending on the local cytokine production.     

Chronic exposure to cocaine binging predisposes to an accelerated course of dilated cardiomyopathy in conscious dogs following rapid ventricular pacing

Despite extensive study, the extent to which cocaine use predisposes to cardiac injury remains unknown. We hypothesized that chronic cocaine binging would increase susceptibility to a subsequent cardiac insult, even in the absence of demonstrable effects on baseline hemodynamics. We studied progression of dilated cardiomyopathy (DCM) induced by rapid ventricular pacing (240 beats per minute) in five conscious, chronically instrumented dogs, after exposure to repetitive cocaine binging (COC) in the form of four consecutive 1 mg/kg i.v. boluses daily for 8 days, to simulate human cocaine abuse. We compared the results with nine control dogs (CON) undergoing the exact pacing protocol, without prior cocaine exposure. Baseline hemodynamics were not significantly altered by chronic cocaine exposure. Following 2 weeks of pacing, COC dogs exhibited accelerated progression to DCM, depressed plasma nitric oxide levels (CON, 17 +/- 2 microM; COC, 10 +/- 2 microM, p < 0.05), and a significantly greater increase in plasma epinephrine (CON, 33 +/- 6 pg/ml; COC, 104 +/- 24 pg/ml). After only 2 weeks of pacing, COC dogs demonstrated progressive DCM of a magnitude comparable with end-stage pacing-induced DCM. Chronic cocaine binging increases susceptibility to a subsequent myocardial insult and accelerates progression of DCM in conscious dogs following rapid pacing. These data suggest that although chronic cocaine use alone may not affect myocardial function, it predisposes to greater susceptibility to a superimposed insult.     

Extent of nuclear DNA damage in ejaculated spermatozoa impacts on blastocyst development after in vitro fertilization

OBJECTIVE: To determine whether the extent of ongoing apoptotic cell death measured as the presence of DNA strand breaks in spermatozoa affects embryo development to the blastocyst stage in IVF. DESIGN: A prospective comparative study. SETTING: A university IVF clinic and a private IVF clinic. PATIENT(S): Men (n = 49) undergoing infertility treatment with IVF. INTERVENTION(S): After density gradient centrifugation preparation, part of the sperm sample was used for infertility treatment, and the rest was fixed in paraformaldehyde. Strand breaks in DNA that are indicative of apoptosis were detected by the in situ DNA nick end labeling (TUNEL) technique. A total of 15,000 spermatozoa from each sample were evaluated for TUNEL reactivity by flow cytometry. MAIN OUTCOME MEASURE(S): Percentage of ejaculated spermatozoa with DNA strand breaks indicative of apoptosis, blastocyst development rate, and pregnancy rate. RESULT(S): Blastocyst development showed a significant negative correlation with percentage TUNEL positivity in spermatozoa. When 20% was used as a cutoff for TUNEL positivity in sperm samples, the percentage of blastocyst development was 50% higher in the <20% TUNEL-positivity group (n = 27) compared with those with >/=20% TUNEL positivity (n = 22; 44.7% blastocyst development vs. 29.8%). Clinical pregnancy rates in these two groups were 52% vs. 44%, respectively. CONCLUSION(S): The extent of nuclear DNA fragmentation in prepared ejaculated spermatozoa used in IVF negatively correlates with blastocyst development. A larger series of patients needs to be assessed to determine whether this paternal effect on blastocyst development may also affect pregnancy outcome.     

Reduced Senescence and Retained Nuclear DNA Integrity in Human Spermatozoa Prepared by Density Gradient Centrifugation

PURPOSE: To investigate whether removal of extraneous cells and immotile spermatozoa from a sperm preparation by density gradient centrifugation could help to maintain normal spermatozoa in a viable state and retain their deoxyribonucleic acid integrity. METHODS: Sperm motility was assessed on a daily basis in aliquots of neat semen, extended semen, and spermatozoa prepared on a PureSperm density gradient. At the same time, aliquots of each sperm sample were preserved for TUNEL assay and nick translation. RESULTS: Spermatozoa prepared using density gradient centrifugation survived three times as long as spermatozoa in neat semen or in extended semen. Both deoxyribonucleic acid integrity and sperm motility were retained in the gradient preparations. CONCLUSIONS: Preparing spermatozoa by density gradient centrifugation is advantageous in prolonging sperm survival and maintaining deoxyribonucleic acid integrity, presumably by removing sources of reactive oxygen species. Stored spermatozoa could be used for a second attempt at fertilization if oocyte immaturity was suspected.