Immunocytochemical detection of leptin in non-mammalian vertebrate stomach

Leptin is a hormone produced and secreted mainly by adipocytes, but also by other tissues such as placenta, brain, mammary, and pituitary glands. The gastric epithelium has also been reported as a source of leptin in mammals. In this study we examined the presence of leptin in the stomach of non-mammalian vertebrates (trout, frog, lizard, and snake). Immunolabeling for leptin was found in the oxyntic-peptic cells of the frog and the two reptilian species studied, but not in the trout. In the trout and the lizard leptin immunoreactivity was also detected in scattered cells presenting the typical features of endocrine cells. In the trout, the frog and the snake, in addition to the epithelium, leptin immunostain was found in elements of the enteric nervous system that were also positive for VIP.     

Combining lisinopril and l-arginine slows disease progression and reduces endothelin-1 in passive Heymann nephritis

BACKGROUND: Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease. METHODS: Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control. RESULTS: Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy. CONCLUSION: Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.     

Effect of simultaneous blockade of AT1 and AT2 receptors on the NFkappaB pathway and renal inflammatory response

BACKGROUND: Angiotensin II (Ang II) is a cytokine that participates in the inflammatory response. The nuclear factor kappa B (NFkappaB) is involved in the regulation of many immune and inflammatory factors. Different works have shown that both angiotensin II receptor type 1 (AT1) and type 2 (AT2) receptors are involved in the NFkappaB pathway; however, some aspects remain mysterious. AT1 antagonists increased plasma Ang II levels that could bind to AT2, so understanding the clinical importance of AT2 stimulation or inhibition is an interesting unresolved point. METHODS: Experiments were done in wild-type (WT) and AT1a receptor knockout mice that received subcutaneous Ang II infusions (1000 ng/kg/min) for 3 days. Specific blockers of AT1 (losartan 10 mg/kg/day) and AT2 (PD123319 30 mg/kg/day) receptors were administered 1 day before and during Ang II infusion. NFkappaB activity was examined by electrophoretic mobility assay and inflammatory (monocyte/macrophage) cell infiltration by immunohistochemistry RESULTS: In WT mice, Ang II infusion caused renal NFkappaB activation that was partially diminished by either AT1 or AT2 antagonists. In AT1 knockout mice, Ang II also activated renal NFkappaB, which was only blocked by the AT2 antagonist. Both Ang II-infused WT and AT1 knockout mice showed inflammatory infiltration in tubulointerstitial areas that were suppressed by the AT2, but not AT1, antagonist. Combined therapy of both AT1 and AT2 antagonists blocked renal NFkappaB activation and inflammatory cell infiltration, both in WT and in AT1 knockout mice. CONCLUSION: Ang II, via AT1 and AT2 stimulation, leads to NFkappaB activation that was only blocked by combined therapy with both antagonists. The participation of AT2 receptors in the recruitment of inflammatory cells underscores the need of future studies that evaluate the clinical usefulness of this strategy.     

Relationship between advanced glycoxidation end products,inflammatory markers/acute-phase reactants,and some autoantibodies in chronic hemodialysis patients

Uremia and dialysis treatment are associated with uncorrected oxidative and carbonyl stress and microinflammation. Elevation of both oxidative/carbonyl stress end products (advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), and advanced lipoperoxidation end products (ALEs), autoantibodies against modified biological structures, and acute-phase reactants (e.g., C-reactive protein [CRP], fibrinogen) seems to take part in the development of various complications, among them accelerated atherosclerosis. These pathogenic mechanisms are supposed to act synergically; nevertheless, oxidative stress shows a closer relationship to inflammation and acute-phase reaction than advanced glycation. Its end product, AOPP, could, thus, represent a biochemical marker of specific importance.     

International variation in histologic grading is large,and persistent feedback does not improve reproducibility

Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.     

External auditory canal cholesteatoma: clinical and imaging spectrum

BACKGROUND AND PURPOSE: Cholesteatoma is an inflammatory lesion of the temporal bone that uncommonly involves the external auditory canal (EAC). In this large case series, we aimed to define its imaging features and to determine the characteristics most important to its clinical management. METHODS: Thirteen cases of EAC cholesteatoma (EACC) were retrospectively reviewed. Clinical data were reviewed for the history, presentation, and physical examination findings. High-resolution temporal bone CT scans were examined for a soft-tissue mass in the EAC, erosion of adjacent bone, and bone fragments in the mass. The middle ear cavity, mastoid, facial nerve canal, and tegmen tympani were evaluated for involvement. RESULTS: Patients presented with otorrhea, otalgia, or hearing loss. Eight cases were spontaneous, and five were postsurgical or post-traumatic. CT imaging in all 13 cases showed a soft-tissue mass with adjacent bone erosion. Intramural bone fragments were identified in seven cases. This mass most often arose inferiorly (n = 8) or posteriorly (n = 8), but it was circumferential in two cases. We noted middle ear extension (n = 5), mastoid involvement (n = 4), facial canal erosion (n = 2), and tegmen tympani dehiscence (n = 1). CONCLUSION: Temporal bone CT shows EACC as a soft-tissue mass within the EAC, with adjacent bone erosion. Bone fragments may be present within the mass. The cholesteatoma may extend into the mastoid or middle ear, or it may involve the facial nerve canal or tegmen tympani. Recognition of this entity and its possible extension is important because it may influence clinical management.     

Rapid progression of midventricular obstruction in adults with double-chambered right ventricle

OBJECTIVE: The purpose of this study was to determine the rate of progression of midventricular obstruction in adolescents and adults with double-chambered right ventricle. METHODS: Clinical and echocardiographic findings in 45 patients (mean age 26 +/- 6 years, range 15-44) diagnosed with double-chambered right ventricle were retrospectively analyzed. Twenty patients underwent surgical repair before the age of 15 years. The relationship between Doppler midventricular pressure gradient and patient age was analyzed in 25 patients without previous repair. Sequential change in midventricular obstruction was determined for patients with 2 or more Doppler echocardiographic examinations performed within at least a 2-year interval. RESULTS: Right midventricular pressure gradient in nonrepaired patients was 70 +/- 38 mm Hg (range 25-150). A significant relationship between midventricular obstruction and patient age (r = 0.64, P <.001) was found. Midventricular pressure gradient at initial evaluation was 32 +/- 27 mm Hg in 16 patients < 25 years and 73 +/- 45 mm Hg in 9 patients >/= 25 years (P <.03). After the initial study, 5 patients underwent surgical repair and 13 patients without repair were followed up for a period of 6.1 +/- 2.7 years (range 2-9), in which midventricular pressure gradient increased from 32 +/- 26 mm Hg to 67 +/- 35 mm Hg (P <.001). The slope of the change in midventricular pressure gradient was 6.2 +/- 3 mm Hg per year of follow-up. Seven more patients underwent surgical repair during follow-up due to progression of the obstruction. There was no mortality nor residual midventricular obstruction in surgically repaired patients. CONCLUSIONS: Mild right midventricular obstruction shows a fast rate of progression in adolescents and young adults. Thus, close clinical and echocardiographic follow-up is advised, and surgical repair should be considered if significant progression of obstruction is detected.     

Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro

Mechanisms of antibiotic resistance of bacteria include efflux pumps which extrude the antibiotic prior to reaching its target. Phenothiazines inhibit the activity of some efflux pumps thereby altering the susceptibility of bacteria. This study demonstrated that chlorpromazine and thioridazine reduce the susceptibility of methicillin-resistant strains (MRSA) but not that of methicillin-susceptible Staphylococcus aureus (MSSA) strains to oxacillin (MIC of oxacillin reduced from >500 to 10 mg/l). Reserpine, an inhibitor of antibiotic efflux pumps also reduced the resistance of MRSA strains to oxacillin suggesting the presence of an efflux pump that contributes to antibiotic resistance of MRSA strains.     

Heterogeneity in regional notification patterns and its impact on aggregate national case notification data: the example of measles in Italy

Background

A monthly time series of measles case notifications exists for Italy from 1949 onwards, although its usefulness is seriously undermined by extensive under-reporting which varies strikingly between regions, giving rise to the possibility of significant distortions in epidemic patterns seen in aggregated national data.

Results

A corrected national time series is calculated using an algorithm based upon the approximate equality between births and measles cases; under-reporting estimates are presented for each Italian region, and poor levels of reporting in Southern Italy are confirmed.

Conclusion

Although an order of magnitude larger, despite great heterogeneity between regions in under-reporting and in epidemic patterns, the shape of the corrected national time series remains close to that of the aggregated uncorrected data. This suggests such aggregate data may be quite robust to great heterogeneity in reporting and epidemic patterns at the regional level. The corrected data set maintains an epidemic pattern distinct from that of England and Wales.