Microglia convert aggregated amyloid-ß into neurotoxic forms through the shedding of microvesicles.

Alzheimer's disease (AD) is characterized by extracellular amyloid-ß (Aß) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aß species, rather than insoluble fibrils, are the most toxic forms of Aß. Preventing soluble Aß formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aß species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aß forms trafficked to MVs after Aß internalization into microglia. MV neurotoxicity was neutralized by the Aß-interacting protein PrP and anti-Aß antibodies, which prevented binding to neurons of neurotoxic soluble Aß species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors.

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.

Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice.

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety-one recipients comprised the early cohort, receiving IVUS at weeks 3-6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01-0.77]; p = 0.02) but it did not appear to influence late CAV progression. High-dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time-dependent sequence during CAV development.

From primary progressive aphasia to corticobasal syndrome: two clinical and rCBF functional reports.

We describe two cases, both presenting with a 2-year history of isolated language disorders, one compatible with logopenic variant and the other with non-fluent variant of primary progressive aphasia (PPA). Afterwards, each developed a corticobasal syndrome (CBS) with alien limb phenomenon and a multi-domain cognitive impairment. Regional cerebral perfusion (rCBF) study using 99mTc-ECD single photon emission computed tomography (SPECT) revealed hypoperfusion patterns consistent with these aphasia types and with the presence of limb apraxia. We report two cases of PPA variants associated with CBS and we suggest that SPECT rCBF correlates can be useful in making a differential diagnosis within the PPA spectrum.

Diversity of 16S rRNA genes from bacteria of sugarcane rhizosphere soil

Sugarcane is an important agricultural product of Brazil, with a total production of more than 500 million tons. Knowledge of the bacterial community associated with agricultural crops and the soil status is a decisive step towards understanding how microorganisms influence crop productivity. However, most studies aim to isolate endophytic or rhizosphere bacteria associated with the plant by culture-dependent approaches. Culture-independent approaches allow a more comprehensive view of entire bacterial communities in the environment. In the present study, we have used this approach to assess the bacterial community in the rhizosphere soil of sugarcane at different times and under different nitrogen fertilization conditions. At the high taxonomic level, few differences between samples were observed, with the phylum Proteobacteria (29.6 percent) predominating, followed by Acidobacteria (23.4 percent), Bacteroidetes (12.1 percent), Firmicutes (10.2 percent), and Actinobacteria (5.6 percent). The exception was the Verrucomicrobia phylum whose prevalence in N-fertilized soils was approximately 0.7 percent and increased to 5.2 percent in the non-fertilized soil, suggesting that this group may be an indicator of nitrogen availability in soils. However, at low taxonomic levels a higher diversity was found associated with plants receiving nitrogen fertilizer. Bacillus was the most predominant genus, accounting for 19.7 percent of all genera observed. Classically reported nitrogen-fixing and/or plant growth-promoting bacterial genera, such as Azospirillum, Rhizobium, Mesorhizobium, Bradyrhizobium, and Burkholderia were also found although at a lower prevalence.

Zirconia toughened alumina (ZTA) powders: ultrastructural and histological analysis.

Ceramic materials, as Alumina and Zirconia, has made an improvement in the choice of new biomaterials for the load bearing application in dental and orthopaedic implants. These materials has shown mechanical resistance to high stress related to weight bearing and low debris in time. For this reason they are indicated on young patients implant, with high demanding activities and long life expectance. In literature however the risk of chronic inflammation due to chronic wear debris release and the possibility of carcinogenesis, is still to be definitively investigated. Another point to investigate is the acute reaction of the tissue in case of acute release of powders of these materials. The aim of this study was to investigate the possible local and systemic acute effects of ceramic precursors in form of powders of different size when released into articular joint. Powders of ZTA were implanted in the knee joint of twenty-four New Zealand white adult rabbits, that were sacrificed at 1,3,6, and 12 months. Radiographic, histological and immunoistochemestry analysis were conducted on periprosthetic tissue and peripheral organs, to verifying local host response and systemic toxic effects.

In vivo characterization of Zirconia Toughened Alumina material: a comparative animal study.

The development of a new chromia-doped Zirconia Toughened Alumina (ZTA) material was previously reported as displaying mechanical properties suitable for implants with load bearing applications, such as orthopaedic and dental implants. This type of biomaterial is expected to be in contact with living tissues for a long period of time and its long-term toxicity must be carefully evaluated. In this study the suitability of this ZTA material as a candidate biomaterial for orthopaedic implants and dental devices was further investigated in vivo in comparison to alumina and zirconia, which are currently used in orthopaedic and dental surgery. Cylinders of the materials were implanted in vivo in white rabbits, and local and systemic tissue reactions were analyzed at different time intervals after surgery. Radiologic examinations displayed the absence of radiolucence around cylinders and no signs of implant loosening up to twelve months. No tumours developed in the animals either locally (at the site of implantation), or systemically in the peripheral organs. The results obtained suggest that this new ZTA material does not display any long term pathogenic effect in vivo. These findings extend our previous observations on the biocompatibility and the absence of any long-term carcinogenic effect in vitro of this material which displays interesting properties for biomedical applications. In conclusion, we report the in vivo characterization of a new chromia-doped ZTA material and confirm its suitability as a candidate biomaterial for orthopaedic implants and dental devices since it does not give any local nor systemic toxicity even after a long period of time after implantation.

Langerhans cell histiocytosis: bilateral temporal bone involvement in an adult with diabetes insipidus.

OBJECTIVE: To present a clinical case of an adult affected by Langerhans cell histiocytosis with bilateral, non-simultaneous, involvement of the temporal bone, associated with diabetes insipidus and to review the literature. METHODOLOGY: A rare case of bilateral temporal bone involvement of Langerhans cell histiocytosis in a 42-year-old woman affected by diabetes insipidus is reported. We present patient's clinical history supported by radiologic, histopathologic and audiologic findings. RESULTS: The patient was submitted to a series of otologic surgical procedures due to the progression of the disease. Ossicular chain was always preserved, so that conservative surgery (canal wall-up technique) was performed, permitting the achievement of good hearing results, bilaterally. CONCLUSIONS: Temporal bone involvement of Langerhans cell histiocytosis may lead to a progressive chronic disease. However, the ossicular chain can remain uninvolved, making a conservative surgical treatment possible. Careful follow-up is essential for detecting new lesions and serial CT scans are mandatory.

Development of a new zirconia-toughened alumina: promising mechanical properties and absence of in vitro carcinogenicity.

High purity alumina as well as zirconia ceramics have been widely used as orthopaedic implant biomaterials and dental devices displaying optimal, but sometimes exclusive, mechanical properties. In order to combine the advantages of alumina and zirconia ceramic materials different types of composites have been developed in which either zirconia is dispersed in an alumina matrix or vice versa. Orthopaedic and dental implant biomaterials are expected to be in contact with living tissues for a long period of time and their long term toxicity must be carefully evaluated. In this study we report the development of a high performance chromia-doped zirconia toughened alumina (ZTA) material which displays promising mechanical properties in terms of hardness, strength and fracture toughness that make it suitable for prosthesis even for small joints. The long-term biocompatibility of this material was also evaluated, mainly in terms of DNA damage, mutagenicity and cancerogenetic potential in mammalian cells. The results obtained suggest that this new ZTA material does not display any longterm carcinogenic effect and it is suitable for biomedical applications from a cancerogenetic point of view. In conclusion, we report the development of a new chromia-doped ZTA material with interesting properties, both from a mechanical and a biocompatibility point of view which warrant further studies on its suitability as a candidate biomaterial for orthopaedic implants and dental devices.

Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.

The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult-onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline.

Emergency stenting to treat neurological complications occurring after carotid endarterectomy.

OBJECTIVES: The purpose of this study was to assess the efficacy of emergency stent implantation for the treatment of perioperative stroke after carotid endarterectomy (CEA). BACKGROUND: Carotid endarterectomy has been proven safe and effective in reducing the risk of stroke in symptomatic and asymptomatic patients with >60% carotid artery stenosis. However, perioperative stroke has been reported in 1.5% to 9% of CEA cases. The management of such a complication is challenging. Recently, percutaneous transluminal carotid angioplasty with stent deployment has emerged as a valuable and alternative strategy for the treatment of carotid artery disease. METHODS: Between April 1998 and February 2000, 18 of the 995 patients (1.8%) who had CEA in our institution experienced perioperative major or minor neurological complications. Of these, 13 patients underwent emergency carotid angiogram and eventual stent implantation, whereas the remaining five had surgery re-exploration. RESULTS: Carotid angiogram was performed within 20+/-10 min and revealed vessel flow-limiting dissection (five cases) or thrombosis (eight cases). Percutaneous transluminal carotid angioplasty with direct stenting (self-expandable stent) was performed in all 13 cases. Angiographic success was 100%. Complete remission of neurological symptoms occurred in 11 of the 13 patients treated by stent implantation and in one of the five patients treated by surgical re-exploration (p = 0.024). CONCLUSIONS: Stent implantation seems to be a safe and effective strategy in the treatment of perioperative stroke complicating CEA, especially when carotid dissection represents the main anatomic problem.

HTLV-II down-regulates HIV-1 replication in IL-2-stimulated primary PBMC of coinfected individuals through expression of MIP-1alpha.

The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF-alpha were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta were also determined in IL-2-stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8(+) T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4(+) T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1alpha. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines. (Blood. 2000;95:2760-2769)

Kikuchi's disease: an uncommon cause of fever of unknown origin.

Kikuchi's disease or histiocytic necrotizing lymphadenitis is an uncommon clinical condition that causes diagnostic difficulties because of its lack of specific signs, symptoms and serological markers. Diagnosis is based on histopathological findings, but overlapping of the histological features requires a differential diagnosis among histiocytic necrotizing lymphadenitis and a number of infectious, autoimmune and lymphoproliferative lymphadenopathies. We report a case of Kikuchi's disease in a 19-year-old woman presenting with generalized lymphadenopathy and persistent fever.

Analysis of a failed alumina THR ball head.

The favourable properties, on which is based the successful history of the use of alumina in orthopaedic surgery, are due to the tough control made by manufacturers on the whole process from raw materials purity to the quality controls. The minimum requirements of a medical grade alumina are stated from 1981 in ISO 6474 standard. Nevertheless, due to the voluntary character of standards, and lack of national and international laws, it was possible in the past to introduce into the market materials with characteristics not in compliance with the standard ISO 6474. A THR implanted on a fifty years old patient was revised three years after implantation, due to the failure of the alumina ball head. To understand the causes of such an early failure, the fragments of the retrieved ball head were submitted to a series of non destructive and destructive controls. The results show that the poor quality of the design and manufacture of the implant was the origin of the failure.

Second-line chemotherapy in human immunodeficiency virus-related non-Hodgkin's lymphoma: evidence of activity of a combination of etoposide, mitoxantrone, and prednimustine in relapsed patients.

BACKGROUND: There is very little experience reported in the literature on the treatment of patients with relapsed or resistant human immunodeficiency virus-related non-Hodgkin's lymphoma (HIV-NHL). We performed a prospective study to evaluate the feasibility and activity of a second-line chemotherapy regimen consisting of etoposide, mitoxantrone, and prednimustine (VMP) in this setting. METHODS: Twenty-one patients were consecutively treated. Thirteen patients were resistant to primary chemotherapy and 8 patients had relapsed after their first complete remission (CR). Etoposide and prednimustine were both given orally at doses of 80 mg/m2 daily for 5 days, and mitoxantrone was given intravenously at a dose of 10 mg/m2 on Day 1; the cycles were repeated every 3 weeks. RESULTS: Nineteen of 21 patients were evaluable for response. The median number of cycles administered was 2 (range, 1-5). A CR occurred in 5 of 19 patients (26%; exact 95% confidence interval; 9-51%). Four of these CRs were observed in the 7 evaluable relapsed patients. Of 45 cycles evaluable for toxicity, severe neutropenia (< 500/microL) occurred in 19 (42%) cycles and severe thrombocytopenia (< 25,000/microL) in 6 (13%) cycles. One toxic death occurred due to sepsis during neutropenia. The overall median survival was 2 months (range, < 1-13 months); the median survival time for the 5 patients with CR (13 months; range, 6-13 months) was statistically significantly longer than that observed in patients without CR (2 months; range, < 1-7 months). CONCLUSIONS: Although the overall prognosis of patients with resistant or relapsed HIV-NHL is very poor, palliative therapy with VMP can be effective and relatively safe in the latter group. Prolonged survival has been observed in some patients who had relapsed after initial chemotherapy.

Rhodococcus equi infection in HIV-positive subjects: a retrospective analysis of 24 cases.

Rhodococcus equi causes a rare infection in immunocompromised hosts. We describe 24 cases of infection in patients with AIDS-related complex (ARC)/acquired immunodeficiency syndrome (AIDS). Pneumonia was always the first manifestation of R. equi infection, but extrapulmonary involvement was also observed. The main sources of bacteria were sputum, bronchial washings and blood. The strains isolated were mainly susceptible to erythromycin, vancomycin, teicoplanin, rifampicin, imipenem and aminoglycosides. Initial treatment should involve an intravenously administered antibiotic combination therapy including imipenem or vancomycin or teicoplanin, followed by orally administered maintenance combination therapy. Drug combinations should be investigated for serum bactericidal activity in vitro. Surgery does not increase survival time and should only be performed in cases that do not respond to antibiotic treatment. Presumptive risks of infection (contact with horses or farm dust, or cohabiting with people affected by R. equi infection) were present in more than 50% of patients. This finding, and the frequency of bacteria in the sputum, are not sufficient proof of transmission between humans, but do suggest the need for respiratory isolation of patients affected by R. equi pneumonia.

Prognostic value of adenosine deaminase compared to other markers for progression to acquired immunodeficiency syndrome among intravenous drug users.

This study was designed to determine the prognostic value of erythrocyte adenosine deaminase (ADA) as a possible indicator of progression to AIDS, and compare this with other known cellular and serological markers. At the end of a 3-year study, a cohort of 114 human immunodeficiency virus-1 (HIV-1) seropositive intravenous drug users (IVDUs) from the five different Center for Disease Control (CDC) groups was examined in order to estimate the prognostic relevance with respect to the progression to acquired immunodeficiency syndrome (AIDS) of each of the following markers at baseline value: number and percentage of CD4+ T cells, number of CD8+ T cells, CD4+/CD8+ ratio, IgA and beta 2 microglobulin and ADA levels, and the presence of HIV antigens. Moreover, 57 IVDUs belonging to II and III CDC groups were analyzed in a follow-up study at 6-month intervals, in order to evaluate and compare the behavior of each marker over time. The prognostic significance of each marker was assessed by computing the survival distribution and the Cox analysis in a multivariate model providing the set of markers with greatest predictive value. The levels of ADA and the CD4+/CD8+ ratio showed a linear association with disease staging, whereas beta 2 microglobulin and CD4+/CD8+ ratio were the best predictors for AIDS progression. A highly significant increase in ADA and beta 2 microglobulin was observed during follow-up. The results obtained among HIV-positive IVDUs clearly indicate that the erythrocyte ADA may be considered a reliable marker of the development of HIV infection from the intermediate stages of the disease onwards.(ABSTRACT TRUNCATED AT 250 WORDS)

Octreotide versus terlypressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding.

Sixty patients with endoscopically confirmed active variceal bleeding entered a randomized controlled clinical trial aimed at comparing the efficacy of octreotide vs. terlypressin in the control of acute variceal hemorrhage (period I, 24 h) and in the prevention of early rebleeding (period II, 6 days). Of the sixty 30 received octreotide (period I, 100 micrograms bolus followed by continuous intravenous infusion at 25 micrograms/h; period II, 100 micrograms t.i.d. subcutaneously), and 30 received terlypressin (period I, 2 mg intravenous bolus every 4 h; period II, 2nd day, 2 mg every 6 h; from 3th to 7th days, 1 mg every 6 h). Control of bleeding was achieved in 23 (76.6%) patients receiving octreotide and in 16 (53%) treated with terlypressin (NS); none of these patients suffered rebleeding during treatment. No significant difference in mortality was observed between the two groups during the hospitalization period. Complications due to therapy were lower with octreotide than with terlypressin (P < 0.01). Under the same effectiveness conditions the cost/benefit ratio must be taken into account.