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Biomedical subjects

M Cappello

Publications and source records attributed to M Cappello.

At least 19 recordsLinked to original sources
PubMed2005

Kinematic study of a reconstructed hip in paediatric oncology.

In 1997, a large portion of the femur of a four-year-old child affected by a Ewing's sarcoma was reconstructed with an innovative technique that used a massive bone allograft, in conjunction with a vascularised fibula autograft that was directly articulated within the acetabulum. The aim of the present study was to assess the kinematic behaviour of the reconstructed hip during flexion, once the acute remodelling process observed after the operation had ceased. A few additional CT slices of the hip joint region, in a flexed position, were taken at month 33 of the follow-up. The helical axes relative to the neutral-flexion motor action were estimated: their relative positions, with respect to the anatomical femoral heads, were compared, and the translation of the anatomical head centres was estimated. The angles spanned by the two femurs were almost equal, as were the translations along the respective helical axis. The main difference between the two femurs was the distance between the estimated femoral head centres and the relative helical axes. This resulted in a non-negligible translation of 2.9 mm of the fibula head inside the acetabulum during flexion, significantly higher than the 0.5 mm found for the intact contralateral femur. The results showed that, although the transplanted fibula grew and remodelled during the follow up, the action of the reconstructed hip joint still cannot be described as a ball-and-socket.

Biomechanical Phenomena↗
PubMed2004

Formation of tissue factor-factor VIIa-factor Xa complex promotes cellular signaling and migration of human breast cancer cells.

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor (F)VIIa. Recently, TF has been shown to promote cellular signaling, tumor growth, angiogenesis, and metastasis. In the present study, we examined the pathway by which TF-FVIIa complex induces cellular signaling in human breast cancer cells using the Adr-MCF-7 cell line. This cell line has high endogenous TF expression as measured by flow cytometry and expression of protease-activated receptors 1 and 2 (PAR1 and PAR2) as determined by reverse transcriptase-polymerase chain reaction analysis. Both PAR1 and PAR2 are functionally active as determined by induction of p44/42 mitogen-activated protein kinase (MAPK) phosphorylation using specific agonist peptides. We found that MAPK phosphorylation in this cell line was strongly induced by the combination of FVIIa and factor (F)X, but not by FVIIa alone at a concentration of FVIIa that approaches physiological levels. Induction of MAPK phosphorylation involved the formation of TF-FVIIa-FXa complex and occurred by a pathway that did not require thrombin formation, indicating a critical role for FXa generation. In addition, induction of MAPK phosphorylation was found to be independent of PAR1 activation. We then examined whether TF-FVIIa complex formation could promote tumor cell migration using a modified Boyden chamber chemotaxis assay. The combination of FVIIa and FX, but not FVIIa alone, strongly induced migration of tumor cells by a pathway that probably involves PAR2, but not PAR1 activation. MAPK phosphorylation was found to be required for the induction of cell migration by the combination of FVIIa and FX. These data suggest that TF-FVIIa-mediated signaling in human breast cancer cells occurs most efficiently by formation of the TF-FVIIa-FXa complex. One of the physiological consequences of this signaling pathway is enhanced cell migration that is probably mediated by PAR2, but not PAR1 activation.

Breast Neoplasms↗
PubMed2002

A novel family of anticoagulants from the saliva of Ixodes scapularis.

Using biochemical and molecular approaches, we have identified a 9.8 kDa protein in the saliva of Ixodes scapularis that inhibits the intrinsic pathway of coagulation. The 9.8 kDa anticoagulant protein was purified by reverse-phase HPLC and its N-terminal amino acid sequence determined. The N-terminal sequence showed homology with Salp14, an immuno-dominant antigen present in the saliva of engorging I. scapularis nymphs. Recombinant Salp14 expressed in Escherichia coli prolonged the activated partial thromboplastin time (APTT) of human plasma in a dose-dependent manner and was a specific inhibitor of factor Xa. A cDNA encoding a 9.3 kDa protein, Salp9Pac, was subsequently isolated from an I. scapularis salivary gland cDNA library. Salp9Pac showed 93% identity to the N-terminal sequence of the anticoagulant purified by HPLC. These data indicate that the anticoagulant protein purified by HPLC, Salp9Pac and Salp14 are members of a family of novel coagulation protease inhibitors present in tick saliva. While recombinant Salp9Pac did not show biological activity in the assays tested currently, it is likely to be mechanistically different from its paralogues. This raises the possibility that ticks may enhance their adaptive ability to cope with a wide spectrum of proteases, by transcribing such structurally related anticoagulant proteins with different functions.

Amino Acid Sequence↗
PubMed2002

Early viral clearance and sustained response in chronic hepatitis C: a controlled trial of interferon and ribavirin after high-dose interferon induction.

High-dose induction with alpha-interferon induces early viral clearance of hepatitis C and combined with ribavirin enhances sustained response. We assess whether adding ribavirin after viral clearance obtained by alpha-interferon induction increased the rate of viral eradication.Forty-one naïve patients with chronic hepatitis C were randomised to receive, after 4 weeks of 10 mU daily of alpha-interferon (induction), 3 mU daily for 22 weeks and 3 mU thrice weekly for 26 weeks of either interferon alone (monotherapy) or interferon plus 1000-1200 mg daily of ribavirin (combination therapy). At the end of the induction phase, 23 (56%) subjects had cleared HCV-RNA. During therapy, breakthrough was observed in four patients on monotherapy, but never in patients on combination therapy. The rate of clearance of HCV-RNA was different between monotherapy and combination therapy at the end of treatment (40% vs. 76.1%, P=0.02) and at the end of follow-up (5% vs. 57.1%, P=0.001). Twelve of the 23 patients who cleared HCV-RNA during induction, but only one of the 18 still HCV-RNA-positive after 4 weeks of therapy, had a sustained response (52.2% vs. 5.6%, P=0.001). Clearance of HCV-RNA at 1 week had a high positive predictive value for sustained response in combination therapy (PPV=0.75), but not in monotherapy (PPV=0.33). Induction with high daily doses of alpha-interferon obtains suppression of hepatitis C in more than half of patients, but ribavirin is needed to maintain a sustained response. The rate of sustained response is a function of the time to HCV-RNA clearance. In patients not responding to induction therapy addition of ribavirin does not obtain a sustained virological response.

Adolescent↗
PubMed2002

[The thoracic surgery department].

The Department of Thoracic Surgery has been developed since 40 years, and particularly since 23 years at the Hôpital Erasme. The high rate of lung cancers did induce an important activity in surgical oncology, inside multidisciplinary teams. After a first attempt in 1969, lung transplantation is now successful. Infectious diseases, traumas and functional respiratory defects impose heavy daily charge. Research has been developed in lung transplantation, thyroid metabolism, respiratory mechanics and clinical trial in oncology.

Belgium↗
PubMed2001

Mitigation of hookworm disease by immunization with soluble extracts of Ancylostoma ceylanicum.

Hookworms are a leading cause of anemia in developing countries, and a strategy aimed at reducing pathology caused by blood-feeding adult parasites would be a valuable addition to global control efforts. This article describes experiments designed to induce resistance to the major clinical sequelae (weight loss and anemia) of Ancylostoma ceylanicum hookworm infection in Syrian golden hamsters of the outbred LVG strain. Previously infected animals acquired long-lived resistance to weight loss and anemia caused by a secondary hookworm infection. Furthermore, transfer of pooled serum from twice-infected hamsters to animals undergoing a primary infection was associated with partial resistance to growth delay and anemia. Active vaccination of hamsters with soluble adult hookworm antigens emulsified in alum led to partial protection from hookworm-associated pathology in the absence of reductions in adult worm burden. This intriguing result may have important implications for human vaccine development.

Ancylostoma↗
PubMed2001

Ancylostoma caninum anticoagulant peptide-5: immunolocalization and in vitro neutralization of a major hookworm anti-thrombotic.

Hookworm infection is a major cause of gastrointestinal blood loss and iron deficiency anemia in the developing world. Recently two major anticoagulant serine protease inhibitors have been identified and cloned from adult Ancylostoma caninum hookworms. One of these, A. caninum anticoagulant peptide 5 (AcAP5), is a potent and specific inhibitor of human coagulation factor Xa. A polyclonal IgG has been purified from rabbits immunized with recombinant AcAP5 using affinity chromatography. Using immunohistochemistry, the polyclonal alpha-rAcAP5 IgG localized to the cephalic or amphidial glands, confirming previous biochemical studies that had identified this secretory gland as the primary source of anticoagulant activity in the adult worm. This polyclonal IgG also neutralized the inhibitory activity of recombinant and native AcAP using a single stage chromogenic assay of coagulation factor Xa activity. In addition, the polyclonal IgG also neutralized the anticoagulant activity of native and recombinant AcAP5 as measured by the activated partial thromboplastin time clotting assay. Importantly, this neutralizing activity is species specific, as the polyclonal IgG failed to neutralize the anticoagulant activity of A. ceylanicum. Taken together, these data suggest that the hookworm anticoagulant AcAP5 represents a viable target for future immunization strategies aimed at inhibiting the ability of the adult hookworm to feed on blood in vivo.

Ancylostoma↗
PubMed2001

Effects of lung volume reduction surgery for emphysema on diaphragm dimensions and configuration.

Part of the functional benefit provided by lung volume reduction surgery (LVRS) may be related to improvement in respiratory muscle function resulting from changes in diaphragm dimension and configuration. To study these changes, we obtained 3D reconstructions of the muscle using spiral computed tomography in 11 patients with severe emphysema before and 3 mo after surgery, and in 11 normal subjects matched for sex, age, height, and weight. Bilateral LVRS was performed by thoracoscopy in eight patients and by sternotomy in three patients. Acquisitions were made in the supine posture at relaxed FRC, midinspiratory capacity, and TLC. On average, LVRS produced a 51 +/- 11% increase in FEV(1) and a 30 +/- 4% decrease in FRC. The total surface area of the diaphragm (A(di)) and of the zone of apposition (A(ap)) at FRC increased by 17 +/- 4% and 43 +/- 8%, respectively, but the surface area of the dome did not change. Compared with the values recorded in the normal subjects, postoperative values of A(di) and A(ap) at FRC were reduced by 11% (p < 0.05) and 24% (p < 0.005), respectively. The curvature of the dome increased at TLC in the left sagittal plane, but was otherwise unaffected by the procedure. We conclude that LVRS substantially increases A(di) and A(ap), but does not significantly improve diaphragm configuration at FRC.

Anthropometry↗
PubMed2000

A broad spectrum Kunitz type serine protease inhibitor secreted by the hookworm Ancylostoma ceylanicum.

Although blood-feeding hookworms infect over a billion people worldwide, little is known about the molecular mechanisms through which these parasitic nematodes cause gastrointestinal hemorrhage and iron deficiency anemia. A cDNA corresponding to a secreted Kunitz type serine protease inhibitor has been cloned from adult Ancylostoma ceylanicum hookworm RNA. The translated sequence of the A. ceylanicum Kunitz type inhibitor 1 (AceKI-1) cDNA predicts a 16-amino acid secretory signal sequence, followed by a 68-amino acid mature protein with a molecular mass of 7889 daltons. Recombinant protein (rAceKI-1) was purified from induced lysates of Escherichia coli transformed with the rAceKI-1/pET 28a plasmid, and in vitro studies demonstrate that rAceKI-1 is a tight binding inhibitor of the serine proteases chymotrypsin, pancreatic elastase, neutrophil elastase, and trypsin. AceKI-1 inhibitory activity is present in soluble protein extracts and excretory/secretory products of adult hookworms but not the infective third stage larvae. The native AceKI-1 inhibitor has been purified to homogeneity from soluble extracts of adult A. ceylanicum using size exclusion and reverse-phase high pressure liquid chromatography. As a potent inhibitor of mammalian intestinal proteases, AceKI-1 may play a role in parasite survival and the pathogenesis of hookworm anemia.

Amino Acid Sequence↗
PubMed2000

Lung metastases from melanoma: when is surgical treatment warranted?

Surgical treatment of lung metastases from melanoma is highly controversial as the expected outcome is much poorer than for other primary tumours and a reliable system for selecting patients is lacking. This study evaluated the long-term results of lung metastasectomy for melanoma, with the aim of defining a subset of patients with better prognosis. By reviewing the data of the International Registry of Lung Metastases (IRLM), we identified 328 patients who underwent lung metastasectomy for melanoma in the period 1945-1995. Survival was calculated by Kaplan-Meier estimate, using log-rank test and Cox regression model for statistical analysis. After complete pulmonary metastasectomy (282 patients) the 5- and 10-year survival was 22% and 16%, respectively. In this group of patients, a time to pulmonary metastases (TPM) shorter than 36 months or the presence of multiple metastases were independent unfavourable prognostic factors. There were no long-term survivors after incomplete resection (46 patients, P< 0.01). Using the IRLM grouping system, patients without risk factors (TPM > 36 months and single lesion) experienced the best survival (29% at 5 years), followed by those with one risk factor only (20% at 5 years). On the other hand, those with two risk factors or incomplete resection showed a significantly poorer survival (7% and 0% at 5 years). Surgery plays an important role in carefully selected cases of pulmonary metastatic melanoma. The prognostic grouping system proposed by the International Registry of Lung Metastases provides a simple and effective method for improving the selection of surgical candidates.

Adolescent↗
PubMed2000

Interaction between left and right intercostal muscles in airway pressure generation.

The interactions between the different rib cage inspiratory muscles in the generation of pleural pressure remain largely unknown. In the present study, we have assessed in dogs the interactions between the parasternal intercostals and the interosseous intercostals situated on the right and left sides of the sternum. For each set of muscles, the changes in airway opening pressure (DeltaPao) obtained during separate right and left activation were added, and the calculated values (predicted DeltaPao) were then compared with the DeltaPao values obtained during symmetric, bilateral activation (measured DeltaPao). When the parasternal intercostals in one or two interspaces were activated, the measured DeltaPao was commonly greater than the predicted value. The difference, however, was only 10%. When the interosseous intercostals were activated, the measured DeltaPao was nearly equal to the predicted value. These observations strengthen our previous conclusion that the pressure changes produced by the rib cage inspiratory muscles are essentially additive. As a corollary, the rib cage can be considered as a linear elastic structure over a wide range of distortion.

Animals↗
PubMed1999

The hookworm platelet inhibitor: functional blockade of integrins GPIIb/IIIa (alphaIIbbeta3) and GPIa/IIa (alpha2beta1) inhibits platelet aggregation and adhesion in vitro.

Hookworms, aggressive, blood-feeding, intestinal nematodes, are currently a leading cause of iron deficiency anemia in the developing world. An inhibitor of platelet aggregation and adhesion has been partially purified and characterized from soluble protein extracts of adult Ancylostoma caninum hookworms. This protein, named the hookworm platelet inhibitor, has an estimated molecular mass of 15 kDa as determined by size-exclusion chromatography. In addition to blocking platelet aggregation in response to a variety of agonists, the partially purified inhibitor also prevents adhesion of resting platelets to immobilized fibrinogen and collagen. Inhibitory monoclonal antibodies were used to identify specific blockade of cell surface integrins GPIIb/IIIa (alphaIIbbeta3) and GPIa/IIa (alpha2beta1), the platelet receptors for fibrinogen and collagen, respectively. This broad-spectrum anti-platelet activity is also present in excretory and secretory products of adult worms, suggesting a biologic role for the hookworm platelet inhibitor in vivo.

Ancylostoma↗
PubMed1999

Penetration of meropenem in lung, bronchial mucosa, and pleural tissues.

Lung, bronchial mucosa, and pleural tissue samples were obtained from 14 patients undergoing lung surgery 1 to 5 h after administration of 1 g of meropenem. The mean (range) peak concentrations of meropenem were 3.9 (0.2 to 8.2), 6.6 (3.0 to 13.3), and 2.8 (0.6 to 7.8) mg/kg of tissue, respectively, exceeding the MICs at which 90% of isolates are inhibited for most respiratory pathogens.

Adult↗
PubMed1999

Determinants of rib motion in flail chest.

We have previously developed a canine model of isolated flail chest to assess the effects of this condition on the mechanics of breathing, and these studies have led to the conclusion that the respiratory displacement of the fractured ribs is primarily determined by the fall in pleural pressure (Delta Ppl) and the action of the parasternal intercostal muscles. The present studies were designed to test the validity of this conclusion. A flail was induced in six supine anesthetized animals by fracturing both dorsally and ventrally the second to fifth ribs on the right side of the chest, after which the phrenic nerve roots were bilaterally sectioned in the neck. Sectioning the phrenic nerves caused a 34% decrease in Delta Ppl, associated with a 39% increase in parasternal intercostal inspiratory EMG activity (p < 0.05), and resulted in a marked reduction in the inspiratory inward displacement of the ribs. In three animals, the inward rib displacement was even reversed into a small outward displacement. When the airway was then occluded at end-expiration to increase Delta Ppl during the subsequent inspiration, all animals again showed a clear-cut inward rib displacement. These observations therefore confirm that in dogs with flail chest, the inspiratory displacement of the fractured ribs is set by the balance between the force related to pleural pressure and that generated by the parasternal intercostals. These observations also point to the critical importance of the pattern of inspiratory muscle activation in determining the magnitude of rib cage paradox in such patients.

Animals↗
PubMed1998

Tsetse thrombin inhibitor: bloodmeal-induced expression of an anticoagulant in salivary glands and gut tissue of Glossina morsitans morsitans.

The tsetse thrombin inhibitor, a potent and specific low molecular mass (3,530 Da) anticoagulant peptide, was purified previously from salivary gland extracts of Glossina morsitans morsitans (Diptera: Glossinidae). A 303-bp coding sequence corresponding to the inhibitor has now been isolated from a tsetse salivary gland cDNA library by using degenerate oligonucleotide probes. The full-length cDNA contains a 26-bp untranslated segment at its 5' end, followed by a 63-bp sequence corresponding to a putative secretory signal peptide. A 96-bp segment codes for the mature tsetse thrombin inhibitor, whose predicted molecular weight matches that of the purified native protein. Based on its lack of homology to any previously described family of molecules, the tsetse thrombin inhibitor appears to represent a unique class of naturally occurring protease inhibitors. Recombinant tsetse thrombin inhibitor expressed in Escherichia coli and the chemically synthesized peptide are both substantially less active than the purified native protein, suggesting that posttranslational modification(s) may be necessary for optimal inhibitory activity. The tsetse thrombin inhibitor gene, which is present as a single copy in the tsetse genome, is expressed at high levels in salivary glands and midguts of adult tsetse flies, suggesting a possible role for the anticoagulant in both feeding and processing of the bloodmeal.

Amino Acid Sequence↗
PubMed1998

Interrupted expiratory flow on automatically constructed flow-volume curves may determine the presence of intrinsic positive end-expiratory pressure during one-lung ventilation.

UNLABELLED: We studied patients undergoing elective pulmonary surgery to establish whether observing interrupted expiratory flow (IEF) on the flow-volume curves constructed by the Ultima SV respiratory monitor is a reliable way to identify patients with dynamic pulmonary hyperinflation and intrinsic positive end-expiratory pressure (PEEPi). Patients' tracheas were intubated with a double-lumen endotracheal tube and ventilated with a Siemens 900C constant flow ventilator. In 30 patients, PEEPi was determined by the end-expiratory occlusion (EEO) method during the periods of two-lung and one-lung ventilation in the lateral position. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of the IEF method were calculated. From the 122 measurement pairs, PEEPi was identified with the EEO method in 65 occasions. The mean level of PEEPi was 4.4 cm H2O. During one-lung ventilation, the level of PEEPi and the number of true-positive findings was significantly higher (PEEPi = 4.7 cm H2O and 32 episodes) than during two-lung ventilation (2.9 cm H2O and 19 episodes). When the level of PEEPi was higher than 5 cm H2O, the predictive value of IEF was 100%. The overall sensitivity of the IEF method was 0.78, its specificity was 0.91, and its predictive value was 0.92. In conclusion, examination of the flow-volume curves displayed on the respiratory monitor may identify patients with dynamic hyperinflation and PEEPi during anesthesia for thoracic surgery. IMPLICATIONS: To identify patients with intrinsic positive end-expiratory pressure during anesthesia without the need to interrupt mechanical ventilation, the flow-volume curves of an online respiratory monitor may be examined. The presence of an interrupted expiratory flow may suggest the presence of intrinsic positive end-expiratory pressure with a reasonable accuracy.

Adult↗