Hypertension and immune activation in antiretroviral therapy naïve people living with human immunodeficiency virus.

BACKGROUND: The pathogenesis of hypertension (HTN) in people living with HIV/AIDS (PLHIV) is complex and remains not fully understood. Chronic immune activation (IA) is postulated to be one of the culprits. This notion is derived from studies in HIV-uninfected populations and/or animals while data on HTN and how it relates to IA in PLHIV remains scarce. We determined the relationship between HTN and IA among antiretroviral therapy (ART) naïve PLHIV. METHODS: We analysed baseline data of 365 out of 430 clinical trial participants whose main aim was to investigate the effect of low-dose aspirin on HIV disease progression in PLHIV starting ART. Soluble CD14 (sCD14), T cells co-expressing CD38 and HLA-DR, and PD-1 were the IA and exhaustion markers, respectively studied and were analysed by flow cytometry. Mann-Whitney U-test was used for comparison of the markers by HTN status. A robust Poisson regression model was used to determine the predictors for HTN. RESULTS: A quarter of the 365 were hypertensive (25.3%, 95% CI 20.9-29.8%), and, had higher median (IQR) body mass index (kg/m2) (23.4 (19.6, 28.0) versus 21.9 (19.3, 25.1)) and lower median (IQR) estimated glomerular filtration rate (mL/min/1.73m2) (101.2 (79.4, 126.9) versus 113.6 (92.7, 138.8)) than normotensive participants (p < 0.05). Participants with HTN had higher median frequencies of all markers of IA and exhaustion but lower sCD14 (p > 0.05). None of these markers significantly predicted the occurrence of HTN. CONCLUSION: Studied markers of IA and exhaustion were higher in PLHIV with HTN than those without but were unpredictive of HTN. Larger multicentre studies with a wider range of markers are needed to confirm the role of IA in HIV-associated HTN.

Hypertension and traditional risk factors for cardiovascular diseases among treatment naïve HIV- infected adults initiating antiretroviral therapy in Urban Tanzania.

BACKGROUND: Cardiovascular diseases (CVDs) have become an important cause of ill health and death among people living with HIV and/or AIDS (PLHIV) in the antiretroviral therapy (ART) era. There is scarce data on the burden of hypertension (HTN) and risk factors for CVDs among PLHIV in developing countries, including Tanzania during the ART era. OBJECTIVE(S): To determine the prevalence of HTN and risk factors for CVDs among ART naïve PLHIV initiating ART. METHODS: We analysed baseline data of 430 clinical trial participants on the effect of low-dose aspirin on HIV disease progression among HIV-infected individuals initiating ART. HTN was the outcome CVD. Traditional risk factors for CVDs studied were age, alcohol consumption, cigarette smoking, individual and family history of CVDs, diabetes mellitus (DM), obesity/overweight, and dyslipidaemia. A generalized linear model (robust Poisson regression) was used to determine the predictors for HTN. RESULTS: The median (IQR) age was 37 (28, 45) years. Females were the majority contributing 64.9% of all participants. The prevalence of HTN was 24.8%. The most prevalent risk factors for CVDs were dyslipidaemia (88.3%), alcohol consumption (49.3%), and overweight or obesity (29.1%). Being overweight or obese predicted the occurrence of HTN, aPR 1.60 (95% CI 1.16-2.21) while WHO HIV clinical stage 3 was protective against HTN, aPR 0.42(95% CI 0.18-0.97). CONCLUSION: The prevalence of HTN and traditional risk factors for CVDs in the treatment naïve PLHIV initiating ART are significant. Identifying these risk factors and managing them at the time of ART initiation may lower future CVDs among PLHIV.

Multiple beneficial effects of 1-year nutritional-behavioral intervention on anthropometric and metabolic parameters in overweight and obese boys.

PURPOSE: Childhood obesity is on the rise worldwide increasing the risk for metabolic, cardiovascular and liver diseases in children. Eating habits and lifestyle changes are currently the standard of care for treating pediatric obesity. Our study aimed to determine the impact of a dietary intervention based on the Mediterranean Diet (MD) and the Health Eating Plate, on anthropometric and metabolic parameters in obese and overweight boys. METHODS: We studied 126 overweight/obese boys with anthropometric measurements, blood biochemistry and nutrient intakes evaluation by means of Food Frequency Questionnaire (FFQ) at baseline, at 6 and 12 months after a nutritional-behavioral intervention. RESULTS: We observed a significant reduction in energy, macronutrients and micronutrients intakes. BMI-SDS significantly decreased after 1 year with the proportion of obese boys decreasing by 33% and of overweight boys by 41%, while also all fat mass measures decreased both in obese and overweight individuals. In obese boys, ALT decreased significantly after 1-year nutritional intervention and these changes correlated with BMI-SDS reduction. Insulin-resistance and secretion indexes correlated with fat mass and BMI-SDS. In obese boys, significant changes were observed at 6 months for insulin concentrations, 1/HOMA-IR and QUICKI. With regard to the lipid profile, significant decreases were observed for total and LDL cholesterol in obese boys. CONCLUSION: Metabolic and anthropometric risk factors in overweight and obese boys can be improved by a nutritional-behavioral intervention of 1-year duration.

PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia.

The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

Long-term clinical outcome of dental implants: A retrospective clinical study with a minimum follow-up between 9.5 and 17.7 years.

The aim of this retrospective case series was to evaluate the clinical and radiographic outcomes of the patients that underwent implant surgery in all indication classes, with a follow-up of at least 9 years. 121 healthy patients in need for oral rehabilitation with dental implants were included in this study. 196 implants (160 conical, 73 cylindric design implants) were inserted. The implant survival rate was the primary outcome. Intra- and postoperative complications were additional criteria for success. The mean follow-up of the patients was 12.29 years (SD 1.39). Mean age of the study population was 51.0 years (SD 12.7). The mean bone loss around implants after at least 9 years of loading was measured as 2.0 mm (SD 0.73 mm). Intra-operative complications were seen in 5 patients. Post-operative complications included: 5 mucositis,1 dehiscence, 2 screw loosening, 1 infection at site and 1 nonintegrated implant. Two implants were lost in two patients. The overall implant survival rate was 99.1%. As a conclusion, oral rehabilitation with dental implant-supported prostheses can be accepted as a safe procedure with relevantly high survival rates of oral implants and successful aesthetic and functional outcomes.

Anti-oxidant and anti-inflammatory effect of polar extracts obtained from waste product of wine making.

A lot of diseases are characterized by an increased inflammatory response with an exacerbated production of free radicals. The anti-inflammatory effect of different compounds with antioxidant capacity, as polyphenols present in grape is well known. Therefore, the objective is to evaluate the anti-oxidant and anti-inflammatory activity of waste product of wine production.Six different non-toxic-marc-polar extracts from Malbec and Syrah grape varieties were obtained, their total phenol and flavonoid content were evaluated, and their antioxidant and anti-inflammatory activity were determined.High content of total phenols and flavonoids were found mainly in extracts obtained from Syrah (80.51 ± 16.63 g equivalent to gallic acid/100 g and 25.47 ± 3.33 g equivalent to quercetin/100 g). In addition, they had a high antioxidant effect (above 88.5% of ABTS inhibition by Syrah extracts). Finally, all extracts decreased the nitric oxide (NO) production, but this was more accented when extract from Syrah obtained by infusion was used, which decreased NO levels to baseline (4.46 µM).Taking together, our results show the potential pharmaceutical use of waste product of wine making to prevent or to treat diseases which inflammatory response is exacerbated.

Therapeutic effects of CPAP on cognitive impairments associated with OSA.

Obstructive sleep apnea (OSA) is the most common type of sleep apnea and caused by upper airway obstructions. Clinically, patients with OSA characteristically experience intermittent nocturnal hypoxemia and impaired sleep quality. Cognitive impairments are commonly seen in patients with an OSA diagnosis. A literature search on OSA, cognitive impairments and CPAP was performed with various electronic databases including Medline, EMBASE and Google Scholar. The chosen evidence was limited to human subject studies only, and reports on either central sleep apnea or non-classified sleep apnea were excluded. Available evidence has been systemically reviewed to ascertain what types of cognitive impairments are related to OSA as well as the pathological connections. In addition, effectiveness of continuous positive airway pressure (CPAP) was analyzed as a standard therapy for improving cognitive performance in patients with OSA. The review contributed in: (1) delineating OSA as a risk factor of cognitive impairments; (2) enumerating cognitive impairments seen in patients with OSA; (3) substantiating the relation between OSA and cognitive impairments from the pathological perspective of AD biomarkers; and (4) revealing duration of CPAP is crucial for its therapeutic effects on improving cognitive performance in patients with OSA.

Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.

BACKGROUND: Many unclassified variants (UV) of BRCA1 or BRCA2 may have an effect on pre-mRNA splicing. Patient blood samples suitable for RNA extraction are not always available for testing UVs at the RNA level. METHODS: Analyses of RNA from patient peripheral blood were performed, using a one-step reverse transcriptase-PCR (RT-PCR) protocol, and were compared with an ex vivo splicing assay based on PCR-amplified patient DNA inserted into a splicing reporter minigene. Using both methods 20 variants found in 17 patients were examined. RESULTS: Data from patient RNA and from the minigene assay were fully concordant, but the ex vivo splicing assay, which is monoallelic, clarified several ambiguities in the patient RNA data. Two intronic variants induced strong splicing defects: BRCA1 c.4987-5T-->A (IVS16-5T-->A) induced exon 17 skipping and BRCA2 c.316+5G-->C (IVS3+5G-->C) induced complete skipping of exon 3. Of the exonic variants, BRCA2 c.7805G-->C (p.Arg2602Thr), at the last base of exon 16, induced both exon skipping and activation of a cryptic exonic donor site, and BRCA2 c.8023A-->G (p.Ile2675Val) generated a strong donor site within exon 18. These four variants were thus classified as pathogenic, because of the total absence of a normal transcript from the corresponding allele. Variant BRCA2 c.9501+3A-->T (IVS25+3A-->T) induced incomplete skipping of exon 25, suggesting a mutation with incomplete penetrance, and BRCA2 c.8257_8259del (p.Leu2753del) modified the alternative splicing of exons 17 and 18. CONCLUSIONS: We show that functional analysis using a splicing reporter minigene is sensitive and specific, and should be used for initial screening of potential splicing defects, especially when patient RNA is not readily available.

Fruit and vegetable residues flours with different granulometry range as raw material for pectin-enriched biodegradable film preparation.

The aim of this study was to develop biodegradable films using fruit and vegetable residue (FVR) flour with different granulometry range and pectin levels. The FVR flour was divided in three fractions, according to their granulometric distribution: A (425-500 µm), B (212-300 µm) and C (<150 µm). FVR presented heterogeneous particle size distribution and fibrous structure showing granular compounds adhered to the surface. The fiber contents decreased according to granulometry, whereas the protein content increased. The films obtained from FVR were malleable, homogeneous, yellowish, and presented high solubility (90%). The granulometry reduction and the pectin addition have significantly improved the viscosity and the yellow color of the film solutions (FS). There was decrease of solubility (50%) and improvement of the mechanical properties of the pectin-based films: decrease of elongation (16-30%) and increase of tensile strength (2.88 ±â€¯0.79 MPa). The sorption isotherms of the pectin-FVR films evidenced the lower availability of polar groups able to work as water-sorption sites. Therefore, different residue fractions could have different applications depending on their particle size and composition, either as source of dietary fibers (the thickest fractions) or as raw material for film production.

Comparison of a quantitative PCR method with FISH for the assessment of the four aneuploidies commonly evaluated in CLL patients.

Four chromosomal defects associated with outcome are commonly evaluated by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia (CLL), namely deletions of the 13q13-q14, 11q22 and 17p13 regions and trisomy 12. In this study, we compared a quantitative PCR method--quantitative multiplex PCR of short fluorescent fragment (QMPSF)--with FISH for the detection of these acquired aneuploidies in a series of 110 patients with Binet stage A CLL. Genes located in the deleted or gained regions were selected as target genes and amplified using a method based on the simultaneous amplification of short fluorescent genomic fragments under quantitative conditions. A chromosomal imbalance involving one or several of the four loci was detected by either method in 72 patients (65%). A chromosome 13 deletion was present in 61 patients (54%), a 11q22 deletion in nine (8%), a trisomy 12 in nine and a 17p deletion in one. FISH and QMPSF results were identical for 103 out of 110 patients and discrepancies could be explained in most cases. This study demonstrates that a quantitative multiplex PCR represents a cost-effective method that could replace FISH in CLL patients. However, although QMPSF is perfectly adapted to the detection of primary defects, care should be taken when searching for clonal evolutions present in a small proportion of tumor cells.

Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch.

Neutrophil elastase has been implicated as a factor that impairs local host defenses in chronic Pseudomonas aeruginosa (Pa) lung infection in cystic fibrosis (CF). We recently showed that this enzyme cleaves the C3b receptor, CR1, from neutrophils (PMN) in the lungs of infected CF patients. The C3bi receptor on these cells, CR3, is resistant to elastase. We now show that purified neutrophil elastase markedly impairs complement-mediated PMN-Pa interactions including phagocytosis of opsonized Pa, stimulation by opsonized Pa of PMN superoxide production, and killing of opsonized Pa by PMN. When PMN and opsonized Pa were treated separately with elastase, additive levels of inhibition were observed in each of the above assays. The effects on the bacteria were due to cleavage of the bound C3bi from the surface of opsonized Pa by neutrophil elastase. C3bi was also cleaved by pseudomonas elastase, or bronchoalveolar lavage fluid from CF patients with chronic Pa lung infection. Inhibitors of neutrophil elastase eliminated C3bi cleavage by BAL fluid, while inhibitors of pseudomonas elastase had no effect. Blocking CR1 and CR3 on PMN with specific monoclonal antibodies reduced phagocytosis of opsonized Pa to an extent similar to that caused by elastase cleavage of CR1 on PMN and C3bi on Pa. We conclude that neutrophil elastase in the lungs of chronically infected CF patients cleaves C3bi from opsonized Pa as well as CR1 from PMN, creating an "opsonin-receptor mismatch" that severely impairs complement-mediated phagocytic host defenses against these bacteria.

Surface expression of Fc gamma receptor III (CD16) on chemoattractant-stimulated neutrophils is determined by both surface shedding and translocation from intracellular storage compartments.

Stimulation of neutrophils (PMN) with chemoattractants markedly increases surface expression of several membrane proteins, including the complement receptors, CR1 and CR3, by translocation from intracellular storage compartments to the cell surface. When we stimulated freshly-isolated PMN with FMLP, we observed little net change in surface Fc gamma receptor (R) III expression. However, if elastase was first used to cleave most (85-90%) of the Fc gamma R III from the PMN surface, subsequent treatment with FMLP induced a rapid renewal of surface Fc gamma R III, achieving levels of approximately 70% of that originally present on the cell surface after 15 min, suggesting translocation of intracellular receptors. This was confirmed by demonstrating concomitant depletion of greater than 80% of the intracellular Fc gamma R III. Studies of density gradient fractions of N2-cavitated PMN indicated at least two distinct intracellular membrane fractions that contain Fc gamma R III. Shedding of Fc gamma R III induced by FMLP was about half-maximal by 15 min and nearly complete by 60 min. Stoichiometric assessment of FMLP-induced changes in PMN surface and intracellular Fc gamma R III showed a marked depletion in intracellular Fc gamma R III, little net change in surface Fc gamma R III, and a large overall loss of total cell Fc gamma R III that could be attributed to shedding. We conclude that stimulation by chemoattractants causes a rapid translocation of intracellular Fc gamma R III to the PMN surface that is roughly balanced by the concomitant FMLP-induced shedding of this receptor.

Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis.

Activation of human neutrophils (PMN) is accompanied by rapid upregulation of CR1, the C3b receptor, and CR3, the iC3b receptor, which also serves as the PMN's major adherence protein. This is necessary for migration and phagocytosis, but the extent of expression of these proteins on PMN at inflammatory sites has not been determined. We used monoclonal antibodies and flow cytometry to assess CR1 and CR3 expression on PMN in bronchoalveolar lavage (BAL) fluid of cystic fibrosis (CF) patients chronically infected with pseudomonas and in sterile joint fluid of arthritis patients. Resting peripheral blood PMN from these patients and normals expressed similar low levels of CR1 and CR3, and the patients' PMN increased CR1 and CR3 expression normally when stimulated in vitro. CR3 expression on CF BAL PMN was 90 +/- 12% of that on the same patient's blood cells stimulated in vitro with FMLP. In contrast, CR1 expression on BAL PMN was only 27 +/- 8% of that on stimulated blood cells. Similar results were obtained for joint PMN. This pattern could be reproduced in vitro by treating FMLP-stimulated blood cells with BAL supernatants or with pseudomonas or PMN elastase. The serine protease inhibitors, PMSF and alpha 1-antitrypsin prevented the lavage supernatant from reducing CR1 expression, while metalloprotease inhibitors had no effect. Treatment of PMN with elastase in vitro decrease their ability to kill opsonized Pseudomonas aeruginosa. These results suggest that PMN at inflammatory sites have maximally upregulated expression of their complement receptors, but that CR1 is then cleaved by proteolysis in situ. Although not related to the basic defect in CF, this may interfere with efficient phagocytosis and contribute to the CF patient's inability to eradicate chronic lung infection.

Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function.

The last exon of the C1-1NH gene was screened for point mutations in 36 unrelated hereditary angioedema patients. Mutations were found in eight patients, predicting changes in the short COOH-terminal region which anchors the reactive site loop on its COOH-terminal side. The effects of each of these mutations were examined in transiently transfected Cos-7 cells. Complete intracellular retention or degradation was observed with substitutions in the COOH-terminal strands 4B or 5B: Leu459-->Pro, Leu459-->Arg, and Pro467-->Arg were all blocked at early stages of intracellular transport, but differences in the immunofluorescence patterns indicated that a significant fraction of the Leu459-->Pro and of the Pro467-->Arg proteins reached a compartment distinct from the endoplasmic reticulum. In line with previous findings with alpha 1-antitrypsin, chain termination within strand 5B resulted in rapid degradation. Mutant Val451-->Met, in strand 1C, and mutant Pro476-->Ser, replacing the invariant proline near the COOH terminus, yielded reduced secretion, but these extracellular proteins were unable to bind the target protease C1s. Presence of low levels of both dysfunctional proteins in patient plasmas defies the conventional classification of C1 inhibitor deficiencies as type I or type II. These data point to a key role of certain residues in the conserved COOH-terminal region of serpins in determining the protein foldings compatible with transport and proper exposure of the reactive site loop.

Abnormalities of polymorphonuclear leukocyte function associated with a heritable deficiency of high molecular weight surface glycoproteins (GP138): common relationship to diminished cell adherence.

Investigations of polymorphonuclear leukocyte (PMN) function were performed in a 5-yr-old white female with delayed umbilical cord separation, impaired pus formation, and a severe defect of PMN chemotaxis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated an almost total deficiency of a high molecular weight glycoprotein(s) (GP138) in the granule and membrane fractions of the patient's cells, and NaB3H4-galactose oxidase labeling demonstrated the absence of a major glycoprotein complex on the surface of her PMNs. Monoclonal antibodies (MAb) were employed in flow cytometry experiments to demonstrate that two previously characterized glycoproteins (Mo1 and LFA1) were undetectable on the surface of the patient's PMNs and monocytes. Immunoprecipitation of 125I-labeled patient cells with subunit specific MAbs confirmed that the alpha-subunits of Mo1 (155 kD) and LFA1 (177 kD) and their common beta-subunit (94 kD) were totally deficient. Functional analyses of patient PMNs demonstrated severe impairment of adherence- and adhesion-dependent cell functions including spreading, aggregation, orientation in chemotactic gradients, antibody-dependent cellular cytotoxicity, and phagocytosis of particles (Oil-Red-0-paraffin, zymosan) selectively opsonized with C3-derived ligands. Patient PMNs demonstrated a normal capacity to rosette with IgG or C3b-coated sheep erythrocytes, but rosette formation with C3bi-coated erythrocytes was profoundly diminished. Adhesion-independent functions including shape change, N-formyl-methionyl-leucyl-3H-phenylalanine binding, and O-2 generation or secretion elicited by soluble stimuli were normal. Membrane fluidity, surface charge, and microtubule assembly were also normal. These findings provide new evidence that critical PMN surface glycoproteins are required to facilitate multiple adhesion-dependent cellular functions of the inflammatory response.

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

Ex vivo HR-MAS Magnetic Resonance Spectroscopy of human gastric adenocarcinomas: a comparison with healthy gastric mucosa.

The present study reports the characteristics of the biochemical profile of human gastric adenocarcinoma in comparison with that of healthy gastric mucosa, using ex vivo HR-MAS Magnetic Resonance Spectroscopy. Healthy human mucosa is mainly characterized by the presence of small metabolites (more than 50 identified) and macromolecules, whereas the adenocarcinoma spectra are dominated by the presence of signals due to triglycerides, whose content on the contrary is very low in healthy gastric mucosa. The use of spin-echo experiments enable us to detect some metabolites in the unhealthy tissues and to determine their variation with respect to the healthy ones. We have observed that the Cho:ChoCC ratio changes from 20:80 in the healthy tissues to 80:20 in the neoplastic gastric mucosa.

Ex vivo HR-MAS MRS of human meningiomas: a comparison with in vivo 1H MR spectra.

We report on the magnetic resonance spectroscopy (MRS) characterisation of different human meningiomas. Three histological subtypes of meningiomas (meningothelial, fibrous and oncocytic) were analysed both through in vivo and ex vivo MRS experiments. The ex vivo high-resolution magic angle spinning (HR-MAS) investigations, permitting an accurate description of the metabolic profile, are very helpful for the assignment of the resonances in vivo of human meningiomas and for the validation of the quantification procedure of in vivo MR spectra. By using one- and two-dimensional experiments, we were able to identify several metabolites in different histological subtypes of meningiomas. Our spectroscopic data confirmed the presence of the typical metabolites of these benign neoplasms and, at the same time, that meningomas with different morphological characteristics have different metabolic profiles, particularly regarding macromolecules and lipids. The ex vivo spectra allowed a better understanding and interpretation of the in vivo MR spectra, showing that the HR-MAS MRS technique could be a complementary method to strongly support the in vivo MR spectroscopy and increase its clinical potentiality.

Complement genes C1r and C1s feature an intronless serine protease domain closely related to haptoglobin.

The exon-intron structure of the human complement C1s gene displays a striking similarity with that of the gene encoding haptoglobin, a peculiar transport protein distantly related to the serine proteases. While the protease regions of the serine zymogens are typically encoded by multiple exons, the protease domains of C1s and of its genetically linked and functionally interacting homolog C1r are encoded as intronless domains, not unlike a region of haptoglobin, which in fact is devoid of proteolytic activity. The close similarity of the C1s gene with haptoglobin includes the precise conservation of exon-intron junctions and it extends to upstream exons encoding the short repeats typical of several complement components, but found also in other functionally unrelated proteins. Additional evidence of the common ancestry of C1r, C1s and haptoglobin is the presence, within the protease domain, of a set of sequence markers that distinguish these three proteins from all known serine proteases. The finding of vertebrate serine protease genes with an uninterrupted protease-encoding exon supports the definition of a novel evolutionary branch of this gene family and rules out the hypothesis that regards this unusual exon as an irrelevant byproduct of the extravagant functional divergence of haptoglobin.