Costs analysis of cochlear implantation in children.

OBJECTIVES: The study assessed the direct medical costs of the cochlear implantation pathway from the healthcare payer's perspective, in children with bilateral severe to profound hearing loss, from diagnosis to 3 years' follow-up after first implantation. We also compared costs between two populations: congenital and progressive deafness. MATERIAL AND METHODS: A retrospective costs analysis was performed for 56 children who received a cochlear implant in one French pediatric ENT center. The children had severe to profound hearing loss, and were implanted before the age of 10 years. We calculated direct medical costs in 3 phases: diagnosis to pre-implantation assessment, surgical and hospital management of implantation, and 3 years' follow-up. RESULTS: Mean costs were €64,675 (range, €38,709-113,954) per child from diagnosis to 3 years after first implantation. Mean costs in congenital deafness detected on neonatal screening and on progressive deafness were respectively €65,420 and €63,930 (P=0.7). CONCLUSION: The global cost was €64,675 per child from diagnosis to 3 years after first implantation. There was no difference in cost according to congenital versus progressive hearing loss.

[Digital therapeutics: Which barriers for market access?] / Les thérapies digitales : quels freins pour leur prise en charge ?

Integrated to the e-health field, digital therapeutics can be defined as "software, combined or not to a device, in the purpose of prevention, treatment or monitoring of a disease, participating actively in a mechanism of action and based on strong clinical evidence". The aim of this work was to assess the level of digital therapeutics clinical validation and to reflect on their business model. A qualitative study has been conducted and different health actors have been interviewed. The semi-guided interviews made have been analysed through a three-level coding. Twenty-two interviews have been analysed and six categories have been identified. The interlocutors highlighted the leading role of digital therapeutics in the follow-up and prevention, supporting the empowerment of patients. However, the absence of consensus in their definition has led to heterogeneity of definition and a difficulty to limit their scope. Furthermore, the conduct of clinical trials, not really suited for digital therapeutics, forced the editors/manufacturers to search for funding for which availability and continuity are uncertain. By raising the issue of clinical efficacy, demonstration of digital therapeutics, this study has led to new perspectives in assessment and business model. We could see in digital therapeutics a new nature of innovation associated with new organisations of our healthcare system and not necessarily by new therapeutics.

[Health technology assessment of innovative medical devices: Timing and decision at national and local level]. / Accès au marché des dispositifs médicaux innovants : articulation entre évaluations nationales et hospitalières.

INTRODUCTION: The Medical Device Committee (CODIMS) evaluates all innovative medical devices (MD) before their introduction in the hospitals of the Assistance publique-hôpitaux de Paris (AP-HP). At the national level, the Medical Device and Health Technology Evaluation Committee (CNEDiMTS) provides recommendation for MD with respects to reimbursement by the National Health Insurance Fund. The aim of this study is to compare the recommendations of both committees and to analyze their timing on a six-year period. MATERIAL AND METHOD: We selected all innovative MD assessed by the CODIMS between 2013 and 2018. We retrieved all the recommendations for these MD from the CNEDiMTS. We performed quantitative and qualitative analysis of data collected. RESULTS: On 30 innovative MD assessed by both the CODIMS and the CNEDiMTS, 11 (37%) evaluations were performed by the CODIMS before the CNEDiMTS evaluation. They occurred approximately a year before the CNEDiMTS recommendation (an average of 378 days). Among the 25 MD with a recommendation of both committees, the two opinions were consistent in 88 per cent of all cases. DISCUSSION/CONCLUSION: This study highlights that there is a good consistency between the recommendations of both committees. This suggests that the MD evaluations conducted at the hospital level are relevant and timely. Finally, a better coordination between the national and local levels should be promoted for the MD assessment.

[3D printed medical devices and anatomical models: What kind of distribution and which uses in French hospitals?] / Dispositifs médicaux et modèles anatomiques produits par impression 3D : quelle diffusion et quelles utilisations dans les établissements de santé français ?

3D printing plays an increasingly important role in the medical sector and particularly in surgery. Nowadays, numerous manufacturers benefit from this technology to produce their medical devices and some hospitals have also purchased 3D printers. In this context, the aim of the present study was to study the distribution and the use of 3D printing in French hospitals in order to its main features in surgery. By conducting a national survey, we targeted hospitals equipped with 3D printers and those using external providers to benefit from this technology. Forty-seven hospitals were identified as using 3D printing including eight equipped with in-house 3D printers. This work gives us a first picture of 3D printing for hospital use in France and it raises questions about hospital pharmacists' involvement in 3D printed medical device production.

[Introduction of Health technology assessment at hospital]. / Mise en place de l'évaluation des technologies de santé en milieu hospitalier.

INTRODUCTION: The Medical Devices Committee (CODIMS) of the Assistance publique-Hôpitaux de Paris (AP-HP) is responsible for deciding whether innovative and costly sterile medical devices (SMD) should be adopted for the AP-HP network and for issuing recommendations on their proper use. The aim of this study was to qualify retrospectively the level of evidence of clinical studies used for the device evaluations by the CODIMS in 2012 and 2013 and to analyze the relationship between levels of evidence and decisions. MATERIAL AND METHOD: Executive summaries written in 2012 and 2013 about studied SMD was analyzed and the level of evidence of clinical studies used was qualified in high/low levels of evidence according to the scale of Sackett et al. Then, levels of evidence were correlated to decisions published by the CODIMS. RESULTS: Sixty-one files of SMD (72.1% of implantable MD) have been evaluated (225 clinical studies). Among them, only 28% of clinical studies had a high level of evidence (and 28.6% of MD at-risk) and 18% did not have any clinical studies. The CODIMS delivered an unfavourable opinion for 16 SMD: only 28 clinicals studies were available for evaluation. Among these, only 6 studies had a high level of evidence. DISCUSSION ET CONCLUSION: The amount and level of evidence of clinical studies is naturally correlated to admittance of SMD. These findings suggest that the clinical evidence used to demonstrate safety and efficacy for high-risk medical devices is based on clinical studies with poor quality data, making more difficult the evaluation of SMD in hospital. The development of a multi-criteria tool to help decision-making would improve the process of SMD evaluation by the CODIMS.

Roflumilast inhibits leukocyte-platelet interactions and prevents the prothrombotic functions of polymorphonuclear leukocytes and monocytes.

UNLABELLED: ESSENTIALS: Thrombosis is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase type-4 (PDE4) inhibitor approved for treatment of severe COPD. PDE4 blockade by roflumilast inhibits prothrombotic functions of neutrophils and monocytes. PDE4 inhibitors may reduce thrombotic risk in COPD as well as in other vascular diseases. BACKGROUND: Roflumilast, an oral selective phosphodiesterase type 4 inhibitor, is approved for the treatment of severe chronic obstructive pulmonary disease (COPD). A recent meta-analysis of trials on COPD revealed that treatment with roflumilast was associated with a significant reduction in the rate of major cardiovascular events. The mechanisms of this effect remain unknown. OBJECTIVES: We tested the hypothesis that roflumilast N-oxide (RNO), the active metabolite of roflumilast, curbs the molecular mechanisms required for leukocyte-platelet (PLT) interactions and prevents the prothrombotic functions of polymorphonuclear leukocytes (PMNs) and monocytes (MNs). METHODS: Using well-characterized in vitro models, we analysed the effects of RNO on: (i) PMN adhesiveness; (ii) the release of neutrophil extracellular traps (NETs); and (iii) tissue factor expression in MNs. Key biochemical events underlying the inhibitory effects of RNO were defined. RESULTS AND CONCLUSIONS: In PMNs, RNO prevented phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt on Ser473, and Src family kinase (SFK)-mediated Pyk2 phosphorylation on Tyr579-580, while inducing protein kinase A-mediated phosphorylation of C-terminal Src kinase, the major negative regulator of SFKs. Modulation of these signaling pathways by RNO resulted in a significant impairment of PMN adhesion to activated PLTs or human umbilical vein endothelial cells, mainly mediated by inhibition of the adhesive function of Mac-1. Moreover RNO curbed SFK/PI3K-mediated NET release by PMNs adherent on fibrinogen-coated surfaces. In MNs interacting with activated PLTs, RNO curbed PI3K-mediated expression of tissue factor. The efficacy of RNO was significantly potentiated by formoterol, a long acting ß-adrenergic receptor agonist. This study reveals novel antithrombotic activities by which roflumilast may exert protective effects against cardiovascular comorbodities in COPD.

[Hospital-based health technology assessment in France: how to proceed to evaluate innovative medical devices?]. / Évaluation des technologies de santé en milieu hospitalier : quelle organisation pour évaluer et acquérir des dispositifs médicaux innovants ?

Innovative medical devices offer solutions to medical problems and greatly improve patients' outcomes. Like National Health Technology Assessment (HTA) agencies, hospitals face numerous requests for innovative and costly medical devices. To help local decision-makers, different approaches of hospital-based HTA (HB-HTA) have been adopted worldwide. The objective of the present paper is to explore HB-HTA models for adopting innovative medical devices in France and elsewhere. Four different models have been conceptualized: "ambassador" model, "mini-HTA" model, "HTA unit" model and "internal committee". Apparently, "HTA unit" and "internal committee" (or a mixture of both models) are the prevailing HB-HTA models in France. Nevertheless, some weaknesses of these models have been pointed out in previous works. Only few examples involving hospital pharmacists have been found abroad, except in France and in Italy. Finally, the harmonization of the assessment of innovative medical devices in France needs a better understanding of HB-HTA practices.

[Computerized prescription for medical devices: examples, interest and limits]. / Vers la prescription informatisée des dispositifs médicaux : exemples d'application, intérêts et limites.

INTRODUCTION: Related to the good practice contract implemented in hospitals, the prescription dedicated to medical devices, such as pharmaceuticals, could promote safety and good practice. MATERIAL AND METHOD: We attempted to implement a computerized prescription for medical devices. In order to illustrate the method, two examples were selected: the Negative Pressure Wound Therapy (NPWT) and the Drug Eluting Stents (DES). RESULTS: In partnership with the medical teams was elaborated a computerized protocol which included all the needed items for the good use of NPWT. For DES, a pre-existing questionnaire was used. We updated it in order to integrate new items such as the prescriber's name, the patient's name, the characteristics of the wound, the DES references and the indications. DISCUSSION AND CONCLUSION: Computerized prescriptions for high-risk and expensive medical devices seem to be an interesting approach to guarantee the patient care safety and to reduce the budget impacts. In order to monitor the indications funded as fee-for-service medical devices, a prescription will emerge as a gold standard in the future in France. Eventually, this study highlights a new activity of clinical pharmacy for hospital pharmacists dealing with medical devices.

Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value?

WHAT IS KNOWN AND OBJECTIVE: In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL. METHODS: Relapsed patients and subjects in EFS were compared for MTX serum concentrations 24, 36, 48 and 72 h after the start of 24 h infusion. Clearance (Cl), area under the curve (AUC) and volume of distribution (V(d) ) of the drug were estimated by the NONMEM computer program and also compared between both groups. RESULTS AND DISCUSSION: Among 69 children included, 54 (78·3%) were still in EFS, whereas 15 (21·7%) relapsed. The difference between relapsed and EFS patients for the pharmacokinetic parameters studied was not significant. On the contrary, the cohort studied was representative and known prognostic factors for relapse in ALL were significantly associated with relapse. WHAT IS NEW AND CONCLUSION: Serum concentrations and pharmacokinetic parameters of MTX are not associated with outcome in ALL. Prognoses based on single-drug pharmacokinetic estimates within a complex multiple-agent protocol appear to be unreliable. However, therapeutic drug monitoring of high-dose methotrexate remains a useful tool for early detection of impaired elimination and for avoiding systemic toxicity.

Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma.

Patients with moderate persistent asthma (n = 523; mean FEV1 77.4%) not fully controlled with inhaled corticosteroids (ICS; 400-1000 microg/day) were randomized to receive either once-daily budesonide/formoterol (160/4.5 microg, two inhalations); or twice-daily budesonide/formoterol (160/4.5 microg, one inhalation); or budesonide (400 microg) once-daily for 12 weeks. Once-daily dosing was administered in the evening and twice-daily dosing was administered in the morning and evening. All patients received twice-daily budesonide (200 microg) during a 2-week run-in. Compared with budesonide alone, change in mean morning and evening peak expiratory flow was greater in the once-daily budesonide/formoterol group (27 and 171 min(-1), respectively; P < 0.001) and twice-daily budesonide/formoterol group (23 and 24 l min(-1), respectively; P < 0.001). Night awakenings, symptom-free days, reliever-use-free days and asthma-control days were all improved during once-daily budesonide/formoterol therapy vs. budesonide (P < or = 0.05). Similar improvements were also seen with twice-daily budesonide/formoterol (P < or = 0.05). The risk of a mild exacerbation was reduced after once- and twice-daily budesonide/formoterol vs. budesonide (38% and 35%, respectively; P < 0.002). All treatments were well tolerated. Budesonide/formoterol, once- or twice-daily, in a single inhaler improved asthma symptoms and exacerbations compared with budesonide. In the majority of patients with moderate persistent asthma requiring ICS and long-acting beta-agonists, once-daily formoterol/budesonide provided sustained efficacy over 24 h, similar to twice-daily dosing.

Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin.

Adhesion of polymorphonuclear leukocytes (PMNLs) to activated platelets requires a P-selectin-triggered, tyrosine kinase-dependent adhesiveness of Mac-1 and is accompanied by tyrosine phosphorylation of a 110-kd protein (P-110) in PMNLs. Inhibitors of SRC tyrosine kinases were found to inhibit PMNL adhesion to activated platelets or to P-selectin expressing Chinese hamster ovary (CHO-P) cells and the tyrosine phosphorylation of P-110. Adhesion of PMNLs to activated platelets or to CHO-P cells stimulated activity of LYN and HCK. Monoclonal antibody blockade of P-selectin or beta2-integrins reduced the activation of both kinases. In PMNLs either adherent to platelets or aggregated by P-selectin-IgG chimera, Mac-1 was rapidly redistributed to the Triton X-100-insoluble cytoskeletal fraction, and large clusters of Mac-1 colocalized with patches of F-actin at the sites of cell-cell contact. In PMNLs stimulated by P-selectin-IgG chimera, SRC kinase inhibition impaired Mac-1 clustering, F-actin accumulation, and CD18 redistribution to the cytoskeleton. Disruption of the actin filament network by cytochalasin D prevented PMNL-platelet adhesion and P-selectin-induced PMNL aggregation and impaired the clustering of Mac-1. In agreement with the requirement for the beta2-integrin in the functional up-regulation of LYN and HCK, integrin blockade by monoclonal antibodies resulted in a complete inhibition of P-selectin-induced Mac-1 clustering and F-actin accumulation. Taken together, the results indicate that, after an initial P-selectin-triggered beta2-integrin interaction with the ligand, SRC kinases are activated and allow the remodeling of cytoskeleton-integrin linkages and integrin clustering that finally strengthen cell-cell adhesion. This model highlights a new role for SRC kinases in a regulatory loop by which the Mac-1 promotes its own adhesive function.

Polymorphonuclear leukocyte apoptosis is inhibited by platelet-released mediators, role of TGFbeta-1.

Platelets regulate several polymorphonuclear leukocyte (PMN) functions. We have found that thrombin-stimulated platelets potently inhibited PMN apoptosis. Cell-free supernatant from increasing concentrations of stimulated platelets inhibited PMN apoptosis in a dose-dependent manner, with an effect similar to that of corresponding concentrations of platelets. At the plateau, platelet supernatant inhibited PMN apoptosis by 54.6 +/- 6.8%, the anti-apoptotic activity being higher than that of GM-CSF and comparable to that of LPS. Neither IL-1ra nor a combination of anti-IL1alpha + betamAb affected the activity of platelet supernatant. In contrast a mAb recognizing the active form of TGF-beta1 significantly decreased this activity. Moreover, exogenous TGF-beta1 inhibited PMN apoptosis in a dose-dependent manner. The active form of this cytokine was indeed present in the supernatant of stimulated platelets at a concentration able to elicit an anti-apoptotic effect. The p38 MAPK inhibitor SB203580 prevented the anti-apoptotic effect of TGF-beta1 in a dose-dependent manner. Interestingly, it also prevented the anti-apoptotic effect of IL-1alpha, but not that of GM-CSF, LPS and dexamethasone. In conclusion, we report for the first time that PMN apoptosis is potently inhibited by platelet-released mediators, that TGF-beta1 mediates an important part of this effect, and that p38 MAPK is involved in the TGF-beta1 signaling leading to its anti-apoptotic effect. These results provide novel evidence to support the central role of platelets in inflammation.

Nutritional antioxidants as antidegenerative agents.

In this study, primary cultures of cerebellar granule neurons were prepared from eight-day-old Wistar rats, and maintained in an appropriate medium containing a high (25 mM) concentration of KCl. All experiments were performed with fully differentiated neurons (eight days). To induce apoptosis, culture medium was replaced with a serum-free medium (containing 5 mM KCl) eight days after plating. In another series of experiments, apoptosis was induced by application of glutamate (50 microM) to the cell cultures. Apoptosis was measured by flow cytometry, the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end-labeling) method, and by the classical method of DNA fragmentation. Since there is evidence that an increased formation of reactive oxygen species (ROS) is involved in the apoptosis induced by both low K(+) concentrations and glutamate, a series of natural antioxidants and a red wine lyophilized extract (which is rich in antioxidant compounds) were tested in our experimental model. It was found that ascorbic acid (30 microM) and a red wine lyophilized extract (5 microgram/ml) were capable of blocking the apoptotic process. Addition of the following natural antioxidants did not have any protective effect on apoptosis induced by low K(+) concentrations: trans- and cis-resveratrol (5-200 microM), alpha-tocopherol (100-200 microM), reduced glutathione (100-400 microM), 3-hydroxytirosol (25-100 microM), epicatechin (25-100 microM), or quercetin (25-50 miroM). It is concluded that only a limited number of natural antioxidants are provided with antiapoptotic activity in cultured cerebellar granule neurons. This effect is probably exerted by reducing ROS formation, and by blocking caspase-3 activity.

Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule.

Polymorphonuclear leukocyte (PMN) adhesion to activated platelets is important for the recruitment of PMN at sites of vascular damage and thrombus formation. We have recently shown that binding of activated platelets to PMN in mixed cell suspensions under shear involves P-selectin and the activated beta2-integrin CD11b/CD18. Integrin activation required signaling mechanisms that were sensitive to tyrosine kinase inhibitors.1 Here we show that mixing activated, paraformaldehyde (PFA)-fixed platelets with PMNs under shear conditions leads to rapid and fully reversible tyrosine phosphorylation of a prominent protein of 110 kD (P approximately 110). Phosphorylation was both Ca2+ and Mg2+ dependent and was blocked by antibodies against P-selectin or CD11b/CD18, suggesting that both adhesion molecules need to engage with their respective ligands to trigger phosphorylation of P approximately 110. The inhibition of P approximately 110 phosphorylation by tyrosine kinase inhibitors correlates with the inhibition of platelet/PMN aggregation. Similar effects were observed when platelets were substituted by P-selectin-transfected Chinese hamster ovary (CHO-P) cells or when PMN were stimulated with P-selectin-IgG fusion protein. CHO-P/PMN mixed-cell aggregation and P-selectin-IgG-triggered PMN/PMN aggregation as well as P approximately 110 phosphorylation were all blocked by antibodies against P-selectin or CD18. In each case PMN adhesion was sensitive to the tyrosine kinase inhibitor genistein. The antibody PL-1 against P-selectin glycoprotein ligand-1 (PSGL-1) blocked platelet/PMN aggregation, indicating that PSGL-1 was the major tethering ligand for P-selectin in this experimental system. Moreover, engagement of PSGL-1 with a nonadhesion blocking antibody triggered beta2-integrin-dependent genistein-sensitive aggregation as well as tyrosine phosphorylation in PMN. This study shows that binding of P-selectin to PSGL-1 triggers tyrosine kinase-dependent mechanisms that lead to CD11b/CD18 activation in PMN. The availability of the beta2-integrin to engage with its ligands on the neighboring cells is necessary for the tyrosine phosphorylation of P approximately 110.

Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18.

Adhesion between platelets and polymorphonuclear leukocytes (PMN) is a key event in thrombosis and inflammation. Double color fluorescence-activated cell sorter (FACS) analysis was used to determine the extent and kinetics of adhesion of thrombin-activated platelets to resting or activated PMN when mixed cell populations were incubated in dynamic conditions. Activated platelets bound very rapidly to PMN. Mixed cell conjugates reached a maximum at 1 minute and were reversible within 10 minutes. Platelet/PMN adhesion required both Ca2+ and Mg2+ and was markedly increased by the presence of Mn2+. The latter made mixed cell conjugates stable up to 10 minutes. Adhesion of platelets required metabolic activity of PMN and was abolished by tyrosine kinase inhibitors. Furthermore, adhesion of platelets to PMN resulted in binding of a monoclonal antibody (MoAb 24) known as beta 2 integrins "activation reporter." When PMN were activated by exogenous stimuli, the adhesion of platelets was markedly increased: fMLP induced a rapid and transient effect, while PMA resulted in a slower, but stable, increase in mixed conjugates formation. The hypothesis that activated PMN beta 2 integrins are able to bind a counter-receptor on platelets was directly demonstrated by the increase of mixed cell conjugates following PMN treatment with KIM127 and KIM185, two anti-CD18 antibodies able to induce the active conformation of beta 2 integrins. Consistently, two other anti-CD18, as well as an anti-CD11b inhibitory antibody abolished platelet/PMN adhesion. PMN beta 2 integrin activation was not the only mechanism for activated platelet/PMN adhesion to occur: indeed, this phenomenon could also be inhibited by two anti-P-selectin antibodies. Resting platelets did not adhere to resting PMN, but markedly adhered to fMLP- or PMA-activated PMN. Resting platelet/fMLP-activated PMN adhesion was abolished by anti-CD18 antibodies, but not by anti-P-selectin antibodies. In conclusion, activated platelet/PMN interaction can be modeled as an adhesion cascade involving a P-selectin-dependent recognition step and a functional signal. The latter proceeds through tyrosine kinase activation and enables a beta 2 integrin-dependent adhesion to a not yet identified counter-receptor constitutively expressed on platelet surface.

Subarachnoid hemorrhage after aneurysm surgery.

The surgical treatment of intracranial aneurysms by clipping is recognized as effective and definitive. However some cases that suffered a new subarachnoid hemorrhage (SAH) some time after they were submitted to aneurysm clipping have raised doubts about the concept of "cure" after this treatment. Eleven patients previously submitted to aneurysm clipping who presented a new SAH were analyzed. The time elapsed from surgery to SAH varied from 3 to 10 years. After SAH four patients had a poor outcome. The new episode of SAH occurred due to intrinsic factors of the cerebral vasculature: 1. a weak point of the vessel wall near the previous aneurysm, 2. a weak point of another vessel far from the previous aneurysm, 3. a previous infundibular dilation of the posterior communicating artery; and due to technical problems: 1. aneurysm not identified during the previous treatment, 2. aneurysm deliberately left untreated, 3. persistence of the aneurysm due to inappropriate surgery, 4. persistency of part of the aneurysm neck after clipping and 5. slipping of the clip from the neck of the aneurysm. The measures to prevent new SAH after surgery start with adequate preoperative angiographic studies, a careful inspection of the position of the clip and emptying of the aneurysm. Early angiography studies may reveal a persistent neck and later ones may reveal newly developed aneurysms. In conclusion, SAH after aneurysm clipping is a late and severe phenomenon and the concept of "cure" after this surgery should be interpreted with caution.

Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes.

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.

Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis.

In PMN/platelet suspensions stimulated by fMLP giant mixed aggregates are formed and TxB2 and LTC4 are synthesized as the result of the cooperation in the arachidonic acid (AA) metabolism during cell/cell contact. PMN-derived cathepsin G induced the expression of P-selectin on platelet surface. GE12, an antibody against P-selectin, significantly reduced mixed cell aggregates. GE12 did not affect platelet aggregation induced by PMN-derived supernatants, indicating that the inhibitory effect of GE12 on mixed cell aggregation depends on inhibition of PMN/platelet adhesion. GE12 significantly reduced TxB2 and LTC4 production in PMN/platelet mixed cell suspensions stimulated by fMLP. As previously reported, synthesis of 3H-TxB2 in 3H-AA-labeled PMN/unlabeled platelets indicates that platelets utilize 3H-AA from PMN. 3H-LTC4 production in unlabeled PMN/3H-AA-labeled platelets indicates that bidirectional routes are utilized in this system for LTC4 synthesis. GE12 significantly reduced 3H-TxB2 and 3H-LTC4 synthesis. These results show that cathepsin G released by activated PMN induces the expression of P-selectin on platelet membrane: this adhesive glycoprotein modulates cell-cell contact and transcellular metabolism of AA.

Cysticercosis of the central nervous system. I. Surgical treatment of cerebral cysticercosis: a 23 years experience in the Hospital das Clínicas of Ribeirão Preto Medical School.

Cysticercosis is the most frequent parasitosis of the nervous system and nowadays it is widespread through the world. Despite the development of anticysticercal drugs (praziquantel and albendazole), their efficacy is more marked in cases with parenchymal active cysts and they do not prevent complications such as hydrocephalus. Thus, many patients with neurocysticercosis require surgical intervention, generally of palliative nature, but that may occasionally produce a cure. The clinical outcome of 180 patients with cerebral cysticercosis who underwent surgical treatment form 1970 to 1993 was analyzed. Surgical treatment was performed to control increased ICP in 177 patients and due to local compression of cranial nerves or brainstem in five. Some patients had more than one surgical procedure, totalizing 287 interventions. Increased intracranial pressure (ICP) was caused by hydrocephalus in 91%, by intracranial mass lesion (tumoral form) in 6.2% and by pseudotumor cerebri (pseudotumoral form) in 2.8% of the case. Based on the pathophysiological mechanisms of intracranial hypertension identified through conventional CT-scan, ventriculography, cysternotomography, ventriculotomography and MRI, different surgical approaches were indicated. Patients with tumoral form were submitted to direct approach and cyst removal and generally they had benefits from this procedure. Patients with pseudotumoral form whose clinical treatment failure underwent decompressive craniectomies and had a poor outcome (40% of good results). Direct removal of ventricular/cisternal cysts and/or ventriculoatrial/peritoneal shunting (VA/VPS) was performed in patients with hydrocephalus. Removal of free ventricular cysts in patients who had no ependimitis/arachnoiditis generally allowed a good outcome. Patients with adherent cysts and inflammatory process needed a VA/VPS posteriorly and the outcome was not so good. One hundred thirty-two patients were submitted to VA/VPS (109 as the first procedure and 23 after another surgical treatment). The VA/VPS was effective to control increased ICP, despite many complications observed mainly during the two first postoperative years. After this period the surviving patients generally had a better outcome. The patients submitted to cyst removal due to local compression of cranial nerves/brainstem generally had good results. Based on the experience acquired with the management of these patients we present our recent policy for the treatment of patients with neurocisticercosis.