High affinity neurotrophin receptors in the human pre-term newborn, infant, and adult cerebellum

The immunohistochemical occurrence of the high affinity neurotrophin (NT) receptors trkA, trkB, and trkC is shown in the pre-term newborn, infant, and adult human post-mortem cerebellum. Immunoreactive neuronal perikarya and processes were observed in all specimens examined, where they appeared unevenly distributed in the cerebellar cortical layers and deep nuclei, and showed regional differences among cerebellar lobules and folia. The trk receptor-antibodies, tested by Western blot on human cerebellum homogenates, revealed multiple immunoreactive bands for trkA and single bands for trkB and trkC. The results obtained show the tissue localization of the trk receptor-like immunoreactivity in the human cerebellum from prenatal to adult age. The analysis for codistribution of the receptors with the relevant ligand and among the receptors in discrete cortical and deep nuclei tissue fields shows a wide variety of conditions, from a good similarity in terms of type and density of labeled structures, to a lack of correspondence, and suggests the possibility of colocalization of trk receptors with the relevant neurotrophin and among them in the cerebellar cortex. These results sustain the concept that the neurotrophin trophic system participates in the development, differentiation, and maintenance of the human cerebellar connectivity and support the possibility of a multifactorial trophic support for the neurotrophins through target-derived and local mechanisms.     

Prognostic relevance of histological grade and its components in node-negative breast cancer patients.

Available results highlight the lack of good level of evidence studies on the pure prognostic value of histological grade. In the present study, the prognostic relevance of histological grade and of its three components, tubule formation, nuclear pleomorphism and mitotic count, was analyzed in a series of 372 patients with node-negative breast cancer treated with locoregional therapy alone until early relapse. Histological grade was determined blindly by two observers and discordance between evaluations was resolved after joint review using a multihead microscope. No relation was observed between histological grade and any of its three components and disease-free survival. Conversely, a significant relation was observed between histological grade and distant metastasis-free survival (at 6 years, 94, 86 and 76% for grades 1, 2 and 3, respectively, P=0.013) as well as overall survival (98, 90 and 86%, P=0.001). A breakdown analysis as a function of the three components showed that neither tubule formation nor nuclear pleomorphism was associated with prognosis, and only mitotic count strongly influenced both distant metastasis-free survival (91, 82 and 74%, P=0.014) and overall survival (97, 87 and 85%, P=0.011). Histological grade suffers from a much higher subjectivity than any other microscopic evaluation of biomarkers as it is the sum of three different morphological features. Within the Italian Network for Quality Assessment of Tumor Biomarkers program we observed that histological grade is an independent prognostic variable, but also that this role is ascribable only to the number of mitotic figures. In conclusion, due to the ever smaller size of diagnosed breast cancers, resulting in less cancer tissue for biofunctional and molecular analysis, mitotic count evaluated under strict quality control conditions seems to be an accurate and feasible prognostic variable.     

Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.

OBJECTIVE: To investigate the association between the use of fluoroquinolone agents and the risk of tendinitis in a large population-based case-control study. METHODS: The study was performed by linking automated health databases from the Region of Lombardia, Italy. Cases were patients aged > or =18 years who had a hospital discharge diagnosis of non-traumatic tendinitis in 2002-3. For each case, up to five controls were randomly selected among those eligible for inclusion in the study. A conditional logistic regression model was used to estimate the odds ratio of tendinitis associated with the current, recent and past use of fluoroquinolones. Odds ratios were adjusted for exposure to other antibacterials and other drugs. RESULTS: 22,194 cases and 104,906 controls met the inclusion criteria. Current use of fluoroquinolones significantly increased the risk of tendon disorders as a whole (odds ratio [OR] = 1.7; 95% CI 1.4, 2.0), tendon rupture (OR = 1.3; 95% CI 1.0, 1.8) and rupture of the Achilles' tendon (OR = 4.1; 95% CI 1.8, 9.6). Concomitant use of corticosteroids and fluoroquinolones increased the risk of both tendon rupture (OR = 3.1; 95% CI 1.5, 6.3) and rupture of the Achilles' tendon (OR = 43.2; 95% CI 5.5, 341.1). DISCUSSION: Evidence that exposure to fluoroquinolones is associated with the sudden occurrence of tendinitis is supported by this large population-based study. We can estimate that a single case of rupture of the Achilles' tendon would occur for every 5958 persons treated with fluoroquinolones (95% CI 2148, 23,085). The corresponding number needed to harm is 979 (95% CI 122, 9172) for patients who concomitantly use corticosteroids and 1638 (95% CI 351, 8843) for those aged >60 years. CONCLUSION: Clinicians should be aware of this adverse effect, and the increased risk for fluoroquinolone-associated tendinitis in elderly patients with corticosteroid use must be considered when these agents are prescribed.     

Neurotrophin-like immunoreactivity in the human pre-term newborn, infant, and adult cerebellum

The immunohistochemical occurrence of the neurotrophin (NT) proteins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) is shown in the pre-term newborn, infant, and adult human post-mortem cerebellum. The NT-like immunoreactive structures were unevenly distributed and showed regional differences among cerebellar lobules and folia. NGF-, NT-4-, and NT-3-positive neuronal perikarya were observed in all specimens examined. At variance with the other neurotrophins, the BDNF antiserum labelled neuronal cell bodies only in newborn life and infancy, as well as extensive nerve fibre systems, whose density increased with age. The NT-antibodies, tested by Western blot on human cerebellum homogenates, revealed immunoreactive bands corresponding to proteins of heterogenous molecular weight. The results obtained provide a first demonstration of the tissue localization of the NTs in the human cerebellum from perinatal to adult age, thus suggesting their involvement in the development, differentiation and maintenance of the cerebellar connectivity. Codistribution of the four NTs or sets of them was observed in cortical and deep nuclei neurons. Multiple trophic roles for NTs, encompassing the classic target-derived and local mechanisms of support, are envisaged as significant in development, differentiation, and maintenance of the human cerebellar connectivity.     

Periodontal disease in adolescents: some clinical and microbiologic correlates of attachment loss

The influence of several clinical and microbiological variables on the site-specific risk of attachment loss was studied in Navajo Indian adolescents aged 14-19. Diagnoses were made at mesio-buccal sites of the four first permanent molars. Case-control analytical methods were used, with A. actinomycetemcomitans, B. gingivalis, and B. intermedius considered the "risk" variables, and with calculus, gingival bleeding, age, and gender treated as possible confounders. The presence of B. intermedius significantly increased the likelihood that attachment loss would be diagnosed at a site (odds ratio = 2.86). However, this association was confounded by calculus and gingival bleeding; when either or both were present, the effect of B. intermedius was markedly weaker. Step-wise multiple logistic regression analyses showed that, of the variables considered, the combination of calculus, gingival bleeding, and B. intermedius gave the most parsimonious explanation of the presence of attachment loss. The chance that attachment loss would be diagnosed was increased five times when calculus was present, 16.5 times in the presence of both calculus and gingival bleeding, and 37 times when these variables plus B. intermedius were observed at a particular site.