Ageing successfully with haemophilia: A multidisciplinary programme.

INTRODUCTION: Persons with haemophilia (PWH) born before the middle 1970s have spent a substantial part of their lives without the benefits of replacement therapy, that became available on a relative large scale only during the 1970s. As a consequence, this group of PWH, although still relatively young, suffers from musculoskeletal and functional problems that are typical of old people. METHODS: We report herewith the short-term results of a project based upon a multidisciplinary training programme led by a physiotherapist and an occupational therapist, that was implemented over a period of 12 months in 40 patients with severe or moderate hemophilia A or B born before the middle 1970s and regularly followed-up at a comprehensive haemophilia treatment centre in Italy. The project was aimed to provide information and skills in order to empower the older PWH carrying physical handicaps and functional limitations that had resulted from the inadequate management in their early ages, and to enable them to cope more efficiently with their crippling disease and prevent further disabilities. RESULTS AND CONCLUSIONS: The comparison of the data obtained before and after the 12-month programme found marginal improvements, but the purpose of this programme was indeed to offer a blueprint for the future. In this respect, the level of satisfaction for the programme was very high and we expect that it will be implemented long-term by our older PWH.

Using spatial distribution modeling of commercial species to inform management of small-scale fisheries in a Mediterranean marine protected area.

Marine protected areas (MPAs) make an essential contribution to the spatial management of critical areas, the conservation of coastal species exploited by human activities, and the sustainable use of marine resources. Within MPAs, fishing closure areas are among the most used small-scale fishery management tools, even though their effectiveness largely remains untested or controversial. To reduce the impact of small-scale fisheries on marine resources, a seasonal fishing closure area (SFCA) was established beginning in 2022 in autumn-winter season inside the Capo Caccia-Isola Piana MPA (Sardinia, northwestern Mediterranean Sea). Here, we assessed a posteriori whether the areas of higher habitat suitability for eight species/taxa of relevant ecological value and economic interest to small-scale fisheries were included in the established SFCA, adequately meeting the ecological objectives of the MPA. Thus, landing data (from 2019 to 2023) were used as occurrence records to develop MaxEnt distribution models for the eight target species/taxa. The model outputs allow us to draw important insights about the spatial adequacy of the SFCA established within the MPA aimed to protect the most exploited marine resources. Furthermore, the modeling exercises were useful for understanding the local processes influencing species' habitat selection and to identify essential areas for the target species that could remain unrevealed in larger-scale investigations.

Reproducibility of atopy patch tests with food and inhalant allergens.

Although atopy patch tests (APT) seem a valuable additional tool in the diagnostic work-up for food allergy in children with atopic eczema/dermatitis syndrome, the immunopathology and some technical aspects of testing remain controversial. Few published data are available on the reproducibility of APT with inhalants and only two studies include fresh food allergens. In this study we therefore investigated the reproducibility of duplicate APT (left versus right side of the back) with native and commercially available food (cow s milk, hen s egg, tomato, wheat flour) and with inhalant allergens (Dermatophagoides pteronyssinus and mixed grasses) in a large unselected population of children. We tested a population of 277 Italian school children with three APT allergens: fresh food (cow s milk, hen s egg, tomato and wheat flour), standardised food allergens in petrolatum (the same four foods) and standardised inhalant allergens routinely used for skin prick testing. For the four food allergens (applied in the natural form or as the standardised commercial preparation) from one- to three quarters of the APT gave positive results on one side and negative reactions on the opposite side (Cohen s K coefficient between 0.38, fresh tomato and 0.81, fresh cow s milk). Conversely, APT with inhalant allergens were invariably reproducible (Cohen s K = 1.00). The possible technical and immunologic reasons explaining why reproducibility of APT differed for the two types of allergens await an answer from extensive controlled studies.

Keratinocyte growth factor receptor (KGF-R) in cholesteatoma tissue.

CONCLUSION: Distribution of the receptor for epidermal growth factor (EGF-R) and of the receptor for the keratinocyte growth factor (KGF-R) in cholesteatoma was found to differ in analogy with other epithelial tissues and accordingly to epidermal differentiation and intensity of paracrine stimulation. Moreover, both EGF-R and KGF-R expression was increased, suggesting a fair correlation with aggressiveness and recurrence rate of this pathology. OBJECTIVES: To obtain information on the biological behaviour of cholesteatoma by assessing the expression and localization of EGF-R and KGF-R and correlating their tissue distribution with that of cytokeratins as a marker of differentiation. MATERIALS AND METHODS: Cholesteatoma tissue was taken during tympanoplasty surgery and processed for indirect immunofluorescence. Murine monoclonal antibodies were tested for the different growth factor receptors and pancytokeratins analysed. Fluorescence intensity signal was measured on randomly captured digital images, using FISH 2000/HI software, with a pseudocolours generation module. RESULTS: EGF-R was mostly expressed at the level of keratinocytes of the basal layer, while KGF-R signal was mainly distributed on the spinous and granular suprabasal layers that were also highly positive for cytokeratins. Significant correlation between the immunofluorescence signals was found for KGF-R and cytokeratins only, demonstrating that KGF-R expression is increased in more differentiated areas of the cholesteatoma tissue, while EGF-R is associated with proliferative and migratory portions of the lesion.

Double localization of a unilateral sporadic vestibular schwannoma.

Vestibular schwannoma may present as a sporadic or genetically-based multi-localized benign neoplasm of the internal auditory canal and/or cerebello-pontine angle region. Multiple localization is generally regarded as genetic in origin and often affects the stato-acoustic bundle on both sides. A case of double vestibular schwannoma localized on the same stato-acoustic bundle is presented. After removal, slight histological differences were found between the two separate masses. From these findings, the possibility of a unilateral multiple localization of a vestibular schwannoma is considered plausible within the range of clinical presentation, with negative genetic features. Whether these individual masses might have an autonomous origin or a different growth pattern remains to be fully elucidated.

Ultrastructural ciliary findings in nasal obstructive diseases.

Specific ultrastructural findings have widely been described in case of obstructive nasal diseases due to congenital defects. Ciliary impairment has in particular been observed as the main pathological feature in these conditions. In this study, nasal mucosal samples from different pathologies have been collected via the "brushing" technique and analysed by transmission electron microscopy. TEM analysis was focused on specific features, such as the numerical array of peripheral and central doublets of the cilium axoneme, including eventual microtubular disarrangement; partial or total loss of inner and/or outer dynein arms; defects of radial spokes and nexin links; disorientation of the ciliary axis in closely adjacent cilia, calculating the angle between the line crossing the central microtubular core and the horizontal ciliary axis and compound cilia (CC). Statistical comparison was carried out between study and control groups. A significant incidence of organic ciliary defects was found not only in patients with inflammatory processes, but mostly in those supposed to have a long-lasting nasal respiratory disease due to mechanical stenosis in relation to septum deviation and turbinate hypertrophy. Prevalence and percentage of compound cilia were instead more related to inflammatory conditions. The "brushing" technique can be considered an easy and reliable method for the assessment of the condition of the nasal mucosa. According to the findings derived from this study, mechanical nasal obstruction seems to cause major alterations on the nasal ciliary arrangement, thus determining a functional impairment on the whole nasal function.

Conformationally constrained congeners of 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones active on the cardiovascular system: conformational studies by molecular mechanics calculations and 1H NMR spectroscopy.

Unsubstituted phenylpyridazinones 1a and 2a and their tricyclic analogues indenopyridazinone 3a, benzocinnolinone 4a, and benzocycloheptapyridazinone 5a were submitted to conformational analysis with Allinger's MM2(85) program in order to better define the relationship between the cardiovascular properties of some derivatives and their preferred conformations. Structures 1-4, giving rise to highly active compounds, were found to exist in a conformation showing a near-planar arrangement of the phenyl and the pyridazinone ring. On the contrary, 5, whose derivatives were inactive, shows two significantly populated conformations both markedly deviated from planarity. 1H NMR analysis of the tricyclic systems 3-5 was in full agreement with the molecular mechanics calculations.

Anti-tumor-promoting effects of glycoglycerolipid analogues on two-stage mouse skin carcinogenesis.

Four glycoglycerolipid analogues, 1-O-hexanoyl-2-O-beta-D-glucopyranosyl-sn-glycerol (1), 1-O-hexanoyl-2-O-beta-D-galactopyranosyl-sn-glycerol (2), 2-O-(6-O-hexanoyl-beta-D-galactopyranosyl)-sn-glycerol (3) and 2-O-(6-O-hexanoyl-alpha-D-galactopyranosyl)-sn-glycerol (4), potent in vitro inhibitors of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation, were submitted to an in vivo two-stage mouse skin carcinogenesis test, using dimethylbenz[a]anthracene (DMBA) and TPA. The study was extended to two deacylated galactosylglycerol structures, 1-O-beta-D-galactopyranosyl-sn-glycerol (5) and 3-O-beta-D-galactopyranosyl-sn-glycerol (6). All the tested compounds exhibited remarkable anti-tumor-promoting effects on mouse skin tumor promotion, the 1-hexanoate 2 being the most active among the glycoglycerolipids until now studied.

Inhibitory effects of monoacylated 2-O-beta-galactosylglycerols on Epstein-Barr virus activation: the significant role of the hexanoyl chain.

Three series of monoacyl-2-O-beta-D-galactosylglycerols bearing an acyl chain of varying length, from C4 to C10, were studied due to their antitumor promoting effects on the activation of the Epstein-Barr virus early antigen (EBV-EA), such activation being induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). This study indicates that it is more the length of the acyl chain that is important for the activity, six carbon atoms resulting in maximum effect, rather than the position of the ester function and the nature of the sugar (galactose or glucose).

Inhibitory effects of fatty acid monoesters of 2-O-beta-D-glucosylglycerol on Epstein-Barr virus activation.

In a screening for cancer chemopreventing agents several glycosylglycerols were found to be active. In order to optimize the anti-tumor activity of this class of compounds, a series of 1-O-acyl-2-O-beta-D-glucopyranosyl-sn-glycerols differing in the acyl chain length, which varied from C4 to C18, were examined for their in vitro anti-tumor promoting effects on Epstein-Barr virus early antigen (EBV-BA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the compounds tested, the monohexanoyl derivative was the most active and, noteworthy, the most potent compound of the glycosylglycerol series hitherto known.

Photoproduction of straight phi(1020) mesons on the proton at large momentum transfer

The cross section for straight phi meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the straight phi.

Mediterranean clone of penicillin-susceptible, multidrug-resistant serotype 6B Streptococcus pneumoniae in Greece, Italy and Israel.

In 1996, 19 isolates of serotype 6B Streptococcus pneumoniae with a unique resistance pattern were found in carriers attending daycare centres in Patras, Southwestern Greece. These isolates were penicillin susceptible but resistant to chloramphenicol, tetracycline, erythromycin, clindamycin and trimethoprim-sulphamethoxazole. Subsequently, isolates with the same characteristics were found in 23 additional carriers in central and southern Greece in 1997-98 as well as in 19 carriers in central Italy in 1997, and in seven carriers in southern Israel in 1998. Carriers were all children under 6 years of age, attending daycare centres or outpatient hospital visits. The relatedness of the isolates was determined on representative isolates from the three countries by pulsed-field gel electrophoresis of SmaI digests of chromosomal DNA. Most Greek isolates were identical to each other, while isolates from Italy and Israel showed one to three band differences, with all isolates being closely related to each other as well as to the isolates from Greece. We have therefore documented the presence of this unique clone of S. pneumoniae in these three countries and have named this the 'Mediterranean' clone. While isolates appear to have a common origin, their source and direction of spread are unknown. However, isolates from Italy showed the most diversity, suggesting that this clone had been present in that country for a longer period than it had been in Greece.

Glycoglycerolipid analogues active as anti-tumor-promoters: the influence of the anomeric configuration.

The in vitro anti-tumor promoting effect of monohexanoates of 2-O-alpha-D-gluco- and galactopyranosyl-sn-glycerol on the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation was evaluated and compared to the potencies of the corresponding beta-anomers. The results show that the inversion of the anomeric configuration from beta to alpha does not seem to significantly influence the activity, which is present, as for the beta-anomers, even at 1x10 mol ratio without any cytotoxicity.

Diesters of glycosylglycerols active in cancer chemoprevention.

Enzymatic transesterification, mediated by Pseudomonas cepacia lipase (lipase PS), led to the pure 1,6'-diacylderivatives of 2-O-beta-D-glucosyl-sn-glycerol and 2-O-beta-D-galactosyl-sn-glycerol, the acyl chains being derived from short-medium length fatty acids. A study of the in vitro inhibitory effects of these diacylderivatives on Epstein-Barr virus early antigen activation induced by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate revealed that maximum activity was reached for the hexanoyl chain and that the introduction of a second acyl chain did not significantly modify the inhibitory potential referring to the corresponding 1- or 6'-monoesters.

MPTP-induced increase in c-Fos- and c-Jun-like immunoreactivity in the monkey cerebellum.

The transcription factors c-Fos and c-Jun have been described to be overexpressed following many pathological stimuli, but whether they are required for neurodegeneration or neuroprotection is still open. In the present report, we analyzed the role of c-Fos and c-Jun proteins in Purkinje cell degeneration caused by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in the monkey cerebellum, and determined the neuroprotective effect of the antioxidant drug a-dihydroergocryptine (DHEC), whose prior and simultaneous administration reduced the MPTP-induced neuronal loss in the substantia nigra. Immunocytochemistry for c-Fos- and c-Jun-like proteins showed persistent increased staining in Purkinje cells of MPTP-treated monkeys. The staining was greatly reduced in animals receiving DHEC. Similar results were observed in white matter glial cells after immunoreaction for c-Fos. The results suggest that, at least as far as the cerebellum is concerned, the increase in c-Fos and c-Jun expression correlate with cell damage, rather than with preservation.

Early rehabilitation of facial nerve deficit after acoustic neuroma surgery.

OBJECTIVE: To determine whether an early physical rehabilitative program could improve and/or accelerate recovery from a postoperative deficit of facial nerve (FN) function. MATERIAL AND METHODS: A retrospective study of the charts of patients who presented a postoperative FN deficit after surgery for acoustic neuroma (AN) was carried out. Twenty-nine patients were enrolled and divided into 2 groups: 18 who underwent early physical rehabilitation and 11 who did not undergo rehabilitation. All the AN patients underwent translabyrinthine removal and were classified preoperatively according to the House-Brackmann staging system. Physical rehabilitation was performed according to Kabat (i.e. neuromuscular facilitation). FN function was assessed postoperatively and classified according to the House-Brackmann grading system. RESULTS: In Grade IV and V patients, early rehabilitation allowed a faster and better recovery with respect to AN patients for whom rehabilitation was not carried out. CONCLUSION: Early physical rehabilitation has proved to be effective as a helpful tool for recovery from FN deficit and it is therefore advisable to use it soon after surgery, especially for FN deficits worse than Grade IV.

Delayed loss of residual hearing in Clarion cochlear implant users.

Hearing threshold has been measured in a group of patients following cochlear implantation with a Clarion device for the last eight years. The patients had received either a pre-curved carrier or the Hi-Focus I plus Electrode Positioner System (EPS). The assessment was carried out within the first post-operative week as well as at a later stage, between six and 87 months, post-operatively. Residual hearing thresholds were still measurable early after surgery in 24.5 per cent of the patients, without differences between the two different Clarion models. However, the number of subjects with measurable hearing dropped to 16.3 per cent as observed when hearing was measured at a later stage, with an equal distribution between the two groups of patients. From this study it has been possible to observe that only a limited number of patients maintain residual hearing after Clarion cochlear implantation, and that this tends to decrease further over time. Nevertheless, the performance of these patients for speech tests did not appear to be affected by deterioration of the pure-tone auditory threshold.

Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status.

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naïve, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory.