The haptoglobin beta subunit sequesters HMGB1 toxicity in sterile and infectious inflammation.

BACKGROUND: Extra-corpuscular haemoglobin is an endogenous factor enhancing inflammatory tissue damage, a process counteracted by the haemoglobin-binding plasma protein haptoglobin composed of alpha and beta subunits connected by disulfide bridges. Recent studies established that haptoglobin also binds and sequesters another pro-inflammatory mediator, HMGB1, via triggering CD163 receptor-mediated anti-inflammatory responses involving heme oxygenase-1 expression and IL-10 release. The molecular mechanism underlying haptoglobin-HMGB1 interaction remains poorly elucidated. METHODS: Haptoglobin ß subunits were tested for HMGB1-binding properties, as well as efficacy in animal models of sterile liver injury (induced by intraperitoneal acetaminophen administration) or infectious peritonitis (induced by cecal ligation and puncture, CLP, surgery) using wild-type (C57BL/6) or haptoglobin gene-deficient mice. RESULTS: Structural-functional analysis demonstrated that the haptoglobin ß subunit recapitulates the HMGB1-binding properties of full-length haptoglobin. Similar to HMGB1-haptoglobin complexes, the HMGB1-haptoglobin ß complexes also elicited anti-inflammatory effects via CD163-mediated IL-10 release and heme oxygenase-1 expression. Treatment with haptoglobin ß protein conferred significant protection in mouse models of polymicrobial sepsis as well as acetaminophen-induced liver injury, two HMGB1-dependent inflammatory conditions. CONCLUSIONS: Haptoglobin ß protein offers a novel therapeutic approach to fight against various inflammatory diseases caused by excessive HMGB1 release.

[Mobile phone use while driving in Fiorentine area: results of the new survey]. / Utilizzo del telefono cellulare alla guida nel territorio fiorentino: i risultati della nuova indagine.

Despite the growing evidence that the use of hand-held mobile phone while driving increases the risk of motor vehicle crashes and the banning by law, in many countries, of this kind of use, this behaviour is more and more spreading. Following a survey we have conducted in 2004, in 2005 we have realized in florentine area a monthly monitoring about this incorrect use of phoning while driving. Overall, 15001 vehicles were observed, and the prevalence of mobile phone use while driving was 2.6%, higher if compared with that referred to the previous year (1.8%). The association between mobile, hand-held, phone use and the considered variables (the same of the 2004 study) is always statistically significant and the conditions with the highest probability of meeting a phoning driver are showed by regression analysis. Intervention for reducing the spread of this behaviour is needed, especially if we consider the recent technological innovations introduced in the new models of mobile phones, which offer new distractions for drivers, the uncertainty of the absence of risk in using hand-free phone and the scarcely proved long-term effectiveness of legislation banning this use.

Two-year follow-up results of copper bromide laser treatment of striae.

OBJECTIVE: The aim of our study was to follow-up 15 patients with stretch marks treated positively with the CuBr laser (577-511 nm) in 1998-99 and followed-up for 2 years. MATERIALS AND METHODS: The patients were Italian women, young to middle age (average 30 years old), with skin coloration classified as Fitzpatrick II-III. Biopsies were taken on some patients before the treatment and 1 month after the first treatment. Double-blind histological, histochemical and photographic evaluation was performed. Results obtained as well as to the contradictory effects reported elsewhere in the literature were compared. RESULTS: On average, the results were positive and there were some pathogenic considerations that justified the use of laser.

Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland.

The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.

The role of Otx and Otp genes in brain development.

Over the last ten years, many genes involved in the induction, specification and regionalization of the brain have been identified and characterized at the functional level through a series of animal models. Among these genes, both Otx1 and Otx2, two murine homologues of the Drosophila orthodenticle (otd) gene which encode transcription factors, play a pivotal role in the morphogenesis of the rostral brain. Classical knock-out studies have revealed that Otx2 is fundamental for the early specification and subsequent maintenance of the anterior neural plate, whereas Otx1 is mainly necessary for both normal corticogenesis and sense organ development. A minimal threshold of both gene products is required for correct patterning of the fore-midbrain and positioning of the isthmic organizer. A third gene, Orthopedia (Otp) is a key element of the genetic pathway controlling development of the neuroendocrine hypothalamus. This review deals with a comprehensive analysis of the Otx1, Otx2 and Otp functions, and with the possible evolutionary implications suggested by the models in which the Otx genes are reciprocally replaced or substituted by the Drosophila homologue, otd.

Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene.

Development of the neuroendocrine hypothalamus is characterized by a precise series of morphogenetic milestones culminating in terminal differentiation of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed in neurons giving rise to the paraventricular (PVN), supraoptic (SON), anterior periventricular (aPV), and arcuate (ARN) nuclei throughout their development. Homozygous Otp(-/-) mice die soon after birth and display progressive impairment of crucial neuroendocrine developmental events such as reduced cell proliferation, abnormal cell migration, and failure in terminal differentiation of the parvocellular and magnocellular neurons of the aPV, PVN, SON, and ARN. Moreover, our data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differentiation of the PVN, SON, and aPV, act in parallel and are both required to maintain Brn2 expression which, in turn, is required for neuronal cell lineages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropin-releasing hormone (CRH).

Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5.

The Dlx5 gene encodes a Distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of the mouse embryo. In later developmental stages, it appears in the branchial arches, the otic and olfactory placodes and their derivatives, in restricted brain regions, in all extending appendages and in all developing bones. We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E. coli lacZ gene. Heterozygous mice appear normal. Beta-galactosidase activity in Dlx5+/- embryos and newborn animals reproduces the known pattern of expression of the gene. Homozygous mutants die shortly after birth with a swollen abdomen. They present a complex phenotype characterised by craniofacial abnormalities affecting derivatives of the first four branchial arches, severe malformations of the vestibular organ, a delayed ossification of the roof of the skull and abnormal osteogenesis. No obvious defect was observed in the patterning of limbs and other appendages. The defects observed in Dlx5-/- mutant animals suggest multiple and independent roles of this gene in the patterning of the branchial arches, in the morphogenesis of the vestibular organ and in osteoblast differentiation.

Otx1 and Otx2 activities are required for the normal development of the mouse inner ear.

The Otx1 and Otx2 genes are two murine orthologues of the Orthodenticle (Otd) gene in Drosophila. In the developing mouse embryo, both Otx genes are expressed in the rostral head region and in certain sense organs such as the inner ear. Previous studies have shown that mice lacking Otx1 display abnormal patterning of the brain, whereas embryos lacking Otx2 develop without heads. In this study, we examined, at different developmental stages, the inner ears of mice lacking both Otx1 and Otx2 genes. In wild-type inner ears, Otx1, but not Otx2, was expressed in the lateral canal and ampulla, as well as part of the utricle. Ventral to the mid-level of the presumptive utricle, Otx1 and Otx2 were co-expressed, in regions such as the saccule and cochlea. Paint-filled membranous labyrinths of Otx1-/- mutants showed an absence of the lateral semicircular canal, lateral ampulla, utriculosaccular duct and cochleosaccular duct, and a poorly defined hook (the proximal part) of the cochlea. Defects in the shape of the saccule and cochlea were variable in Otx1-/- mice and were much more severe in an Otx1-/-;Otx2(+/)- background. Histological and in situ hybridization experiments of both Otx1-/- and Otx1-/-;Otx2(+/)- mutants revealed that the lateral crista was absent. In addition, the maculae of the utricle and saccule were partially fused. In mutant mice in which both copies of the Otx1 gene were replaced with a human Otx2 cDNA (hOtx2(1)/ hOtx2(1)), most of the defects associated with Otx1-/- mutants were rescued. However, within the inner ear, hOtx2 expression failed to rescue the lateral canal and ampulla phenotypes, and only variable rescues were observed in regions where both Otx1 and Otx2 are normally expressed. These results suggest that both Otx genes play important and differing roles in the morphogenesis of the mouse inner ear and the development of its sensory organs.

Laser therapy for fibromyositic rheumatisms.

BACKGROUND AND OBJECTIVES: The objectives of this study is to treat the cases of fibromyositic rheumatisms untreatable with other therapies. The authors chose defocalized laser beams because some experimental studies had showed their analgesic and anti-phlogistic effects on experimental phlogosis. Since 1980 non-surgical laser effects were often noncomparable because of the lack of common treatment protocols. This summarizes fifteen years of clinical observations as to the purpose of identifying some indications on laser treatment of defined pathologies included in fibromyositic rheumatism. STUDY DESIGN/MATERIALS AND METHODS: 846 patients with different types of fibromyositic rheumatisms were submitted to defocalized laser therapy from 1980 to 1995. Criteria for selection included age, sex, and pathological pictures. Control groups were used to compare results with those of traditional methods. Diodes and CO2 lasers were employed, to exploit the photothermic and photochemical effects of the laser radiations to the fullest extent. RESULTS: On the whole, results were positive in comparison with other methods both as regards recovery time and persistence of results. Results were evaluated on the basis of subjective (such as local pain) and objective (hypomotility, phlogosis) criteria. CONCLUSIONS: Results obtained (approximately 2/3 of the patients benefited from the treatment) indicate that there are greater advantages in use of laser over other presently available methods. Standardalization of treatment protocols deserves further studies.

[Effects of guaiacolic ester of acetylsalicylic acid on spirometric and plethysmographic parameters in subjects with chronic obstructive bronchopneumopathy]. / Effetti dell'estere guaiacolico dell'acido acetilsalicilico su alcuni parametri spirometrici e pletismografici in soggetti affetti da broncopneumopatia cronica ostruttiva.

The effects of oral administration of guaiacolic ester of acetyl salicilic acid in 24 patients with chronic obstructive lung disease have been evaluated. 1.5 g of this drug were given daily into 3 administrations improving both objective and subjective symptomatology in 19 of the 24 patients after 1 or 3 weeks of treatment. Moreover, a statistically significant improvement of FEV 1" (p less than 0.001), Raw (p less than 0.005) and FEV 1"/VC (p less than 0.01) was observed. The remaining 5 patients discontinued the treatment failing the improvement of the subjective symptomatology.

[Serial evaluation by effort test of the effects of coronary artery bypass on effort angina (author's transl)]. / Valutazione seriata mediante prove da sforzo degli effetti della chirurgia coronarica sul'angina stabile da sforzo.

To evaluate the duration of favourable effects of coronary artery bypass (CAB) on exercise-induced angina (A), 58 patients: 13 with single 21 with double and 24 with triple vessel disease, were studied. All patients underwent CAB for stable angina on effort. Patients underwent exercise testing (ET) before surgery at one, two and three years. Heart rate peak (HR), HR x systolic blood pressure peak (DP), work load (W), exercise-induced ST segment depression (ST) and incidence of A were evaluated; the results of ET before surgery were compared with those found after CAB. Our findings show that HR, DP, W and ST were significantly improved by surgery for at least 3 years. The lowest incidence of A was found at one year ET (20.6%), while it increased at two years (27,5%) and three years ET (37.9%). Most patients with A had angiographic evidence of left ventricular abnormal wall motion and ec-graphic signs of previous myocardial infarction. Our data indicate that serial exercise testing can objectively monitor the results of CAB. Most patients show an improved exercise tolerance for up to 3 years after CAB. Some patients, with more extensive CAD, showed a progressive deterioration of the clinical pattern and a decrease of the exercise tolerance.

[Changes in plasma renin activity induced by acute administration of nifedipine in hypertensive patients (author's transl)]. / Modificazioni dell'attività reninica plasmatica indotte dalla somministrazione acute di nifedipina in pazienti ipertesi.

In the present study we assessed plasma renin activity (PRA) variations induced by Ca++ antagonist antihypertensive drug Nifedipine in 8 normoreninaemic or hyporeninaemic hypertensive patients. On two successive days three venous blood samples were sampled, two in clinostatic position and the last one 120 min later in orthostatic position; on the second day 20 mg of nifedipine were administered sublingually. Nifedipine increases significantly PRA after orthostatic position compared with starting conditions (p < 0.01) and compared with the values recorded without the drug at the same times (p < 0.01). Both systolic and diastolic blood pressure decreased 15 and 120 min after nifedipine administration while heart rate increased at the same times. Acute nifedipine administration augments PRA in hypertensive subjects; explanatory hypoteses are proposed.