Statistical mechanics of Hamiltonian adaptive resolution simulations.

The Adaptive Resolution Scheme (AdResS) is a hybrid scheme that allows to treat a molecular system with different levels of resolution depending on the location of the molecules. The construction of a Hamiltonian based on the this idea (H-AdResS) allows one to formulate the usual tools of ensembles and statistical mechanics. We present a number of exact and approximate results that provide a statistical mechanics foundation for this simulation method. We also present simulation results that illustrate the theory.

Value of autologous bone marrow transplantation in follicular lymphoma: a France Autogreffe retrospective study of 42 patients.

The value of high-dose chemotherapy with hematologic stem cell rescue has not been established in the treatment of low-grade non-Hodgkin's lymphoma. We report the results of a retrospective 'France Autogreffe' study of 42 patients grafted in first partial remission (n = 13) or chemosensitive relapse (n = 29) for follicular lymphoma before January 1990. The median age was 38 years (range 26-61 years). Preparative therapy was chemotherapy alone in 22 patients and total body irradiation (TBI)-containing regimens in 20 patients. Thirty-seven patients received hematopoietic marrow stem cells. Bone marrow purging was performed in 15 patients. Five patients received peripheral blood stem cells. Three patients died of bone marrow transplantation toxicity and two others died in complete remission 10 months after autologous bone marrow transplantation. With a median follow-up of 43 months, relapse-free survival is 60%, event-free survival 58% and overall survival 83%. To date no prognostic factors have been shown.

Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters.

Doxorubicin was given by short i.v. infusion (dose range 25-72 mg/m2) to 18 patients who underwent three to seven successive courses of chemotherapy (total, 57 courses). Plasma levels of doxorubicin and its major metabolite doxorubicinol were determined by high-performance liquid chromatography over a 48-h period after the infusion. Pharmacokinetic parameters for the parent drug and its metabolite were calculated for each course of treatment. The results show considerable inter- and intraindividual variations for most parameters. The coefficients of variation (CV) ranged from 37% to 93% (inter-individual) and from 6% to 59% (intra-individual). Nevertheless, we observed a good stability over successive courses for terminal half-life in six patients (CV, 6%-25%) and for clearance and AUC in four subjects (CV, 10%-22%). The ratio of the AUCs for doxorubicinol: doxorubicin averaged 0.514. The pharmacokinetic pattern of doxorubicinol was biphasic in plasma of the majority of patients. We propose a model for curve-fitting of these metabolite plasma concentrations that is based on two successive releases of the compound in the plasma compartment, separated by a lag time.

Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva.

The pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28-72 mg/m2 DOX (nine courses). Plasma and parotid saliva were collected over a 48-h period, and DOX and DOXol were quantified by high-performance liquid chromatography with fluorescence detection. As reported previously, a wide range of plasma levels were found among our patients. It appears that in addition to being quickly cleared from the plasma, both DOX and DOXol are excreted in detectable amounts in parotid saliva, a route of elimination that has been given little attention, if any. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to drug and may play a role in causing stomatitis in patients receiving DOX by the i.v. route. Since huge interindividual and pronounced intraindividual differences were found in S/P ratios that mostly were not systematically related to the plasma drug concentration, the concentration in parotid saliva was not useful in predicting the level of free DOX and DOXol in plasma. For the parent drug and its metabolite, the S/P ratios increased significantly with time during the 48-h period after dosing.

Bayesian estimation of doxorubicin pharmacokinetic parameters.

Doxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m2) to 28 patients for 2-7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A3/V1 and t1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were -0.0315 x 10(-4) l-1 for A3/V1, 0.0839 h for t1/2 elimination, and -0.22 ng/ml for c(48 h). The precision of the prediction of these three parameters (0.304 x 10(-5) l-1, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42 x 10(-4) l-1, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.

Inaugural intra-atrial neoplastic thrombosis in stage II Hodgkin's disease.

We report the first case of intra-atrial neoplastic thrombosis discovered in the initial stage of Hodgkin's disease. Considering the course of the case and the recurrence after 18 months we emphasize the necessity of screening cardiac cavities by CT Scan with a bolus, and of treating such a case as an initial stage IV Hodgkin's disease.

Long-term and preventive effects of sublingual allergen-specific immunotherapy: a retrospective, multicentric study.

There is now an increasing body of evidence to support the practice of allergen-specific sublingual-swallow immunotherapy (SLIT) in the treatment of IgE-mediated respiratory allergies. Recent studies on traditional injection therapy have pointed out that this form of treatment is not only capable to decrease actual allergic symptoms, but may also have long-term clinical and preventive effects and may influence atopy natural history. In the year 2000, our group published a retrospective, multicenter study showing the efficacy and safety of SLIT in a survey of 302 patients. We now carried out a second study on the same patients, with the aim of investigating long-term and preventive effects of SLIT. Beside the well-known safety and efficacy of this treatment (80.8% of patients reported clinical benefits), SLIT proved also to elicit long term clinical effects: over a mean follow-up of 11.6 months after the end of treatment, 80.8% of patients still maintained the previously achieved benefits. During the follow-up period, only 1% of non-asthma patients reported an onset of respiratory symptoms, and only 9.6% of patients undergoing new skin tests showed new sensitizations. All the clinical benefits were strongly linked to the length of treatment: patients with long-lasting benefits were treated for a mean length of 29.1 months, while patients showing a return to pre-SLIT condition were treated for a mean 13.3 months. SLIT can obtain long-term and preventive effects so far attributed to injection immunotherapy.

Nanofriction behavior of cluster-assembled carbon films.

We have characterized the frictional properties of nanostructured carbon films grown by supersonic cluster beam deposition via an atomic force-friction force microscope (AFM-FFM). The experimental data are discussed on the basis of a modified Amonton's law for friction, stating a linear dependence of friction on load plus an adhesive offset accounting for a finite friction force in the limit of null total applied load. Molecular dynamics simulations of the interaction of the AFM tip with the nanostructured carbon confirm the validity of the friction model used for this system. Experimental results show that the friction coefficient is not influenced by the nanostructure of the films nor by the relative humidity. On the other hand the adhesion coefficient depends on these parameters.

[Therapeutic failures in early stages of Hodgkin's disease : causes and prevention (author's transl)]. / Les formes précoces de la maladie de Hodgkin : analyse des causes d'échecs, attitudes thérapeutiques.

A retrospective study of 65 patients with Hodgkin's disease (clinical stage I: 11 cases; stage II: 54 cases) included an analysis of the causes of therapy failure. Twenty-five of the 65 patients had been treated by regional irradiation (thoracic mantle or inverted Y field) restricted to only one side of the diaphragm; 27 patients had received the same irradiation followed by chemotherapy (MOPP). The subjects were irradiated on both sides of the diaphragm; 3 of these had received the same radiotherapy followed by chemotherapy (MOPP). Relapses in the irradiated fields were rare. Relapses in the areas bordering the irradiated fields were definitely the result of faulty delivery. Better evaluation of the precise extent of the disease, particularly by laparotomy, would lead to improved initial treatment (radio- or chemotherapy). The availability of improved irradiation techniques and a better choice of indications, particularly concerning the timing for chemotherapy, should result in maximal reduction of therapeutic failures in the early stages of Hodgkin's disease.

[Cardiotoxicity of anthracyclines]. / Cardiotoxicité des anthracyclines.

The only factor limiting the use of anthracyclines (very powerful antimitotic antibiotics) is their cardiotoxicity. The cardiac involvement is irreversible, dose-dependent and may be detected at an early stage by non-invasive (echocardiography, myocardial scintigraphy) or invasive investigations (endomyocardial biopsy). The mechanism of cardiac toxicity involves the oxidative metabolism of the cardiac myocyte and liberation of oxygen free radicals and is different from the antitumoral effect. Protocols of administration over 6 to 24 hours have enabled the use of higher total doses and the reduction of cardiotoxicity without affecting the therapeutic efficacy. The use of "antioxidants" such as ICRF 187 has given promising results in myocardial protection. The strategy of surveillance (screening) of cardiotoxicity, of the mode of administration of the anthracyclines, results from the essential coordination of the efforts of the chemotherapist, taking into account the pathology, the sensitivity of the tumor to anthracyclines therapy, enabling personalization of the prescription and the abandon of the concept of maximal dosage.

[Hereditary protein S deficiency responsible for digestive vascular thrombosis]. / Déficit constitutionnel en protéine S à l'origine de thrombose vasculaire digestive.

Protein S is a physiological inhibitor of coagulation. It intervenes as co-factor of activated protein C and increases the inactivation of factors V and VIII induced by the latter. Patients with protein S deficiency are exposed to recurrent venous and arterial thrombosis. Most of these thromboses affect the lower limbs, but other regions, and notably the digestive tract, may be involved. Deficiencies in physiological inhibitors of coagulation, and in particular protein S, seem to be a new entity in the vascular pathology of the gastrointestinal system. All young patients with thromboembolic accidents affecting the digestive tract should be investigated for protein S deficiency. If such deficiency is found, then all members of the patients' family must also be investigated. Long-term treatment with antivitamin K drugs prevents recurrences of these thromboembolic accidents.

[Bullous pemphigoid treated by plasma exchange. Open study in 10 patients]. / Pemphigoïdes bulleuses traitées par échanges plasmatiques. Etude ouverte chez 10 malades.

Ten patients with bullous pemphigoid underwent low volume plasma exchange (1/3 to 1/2 of the plasmatic mass) 3 times a week for 2 to 6 weeks followed, in some of them, by maintenance corticosteroid therapy. Eight patients benefited from this treatment. Complete control of the disease was obtained with PE alone in 3: low-dose corticosteroids were sufficient to procure remission in 2, and dosage could be reduced in 3 patients who previously required high doses of corticosteroids. No serious side-effects were recorded. The best results were observed in patients who had been ill for less than 3 months. Thus, low volume plasma exchanges make it possible to obtain clinical improvement while avoiding the rebound phenomena sometimes observed after high volume plasma exchanges. Circulating immune complexes and pemphigoid antibodies usually decreased under treatment, but there was no close correlation between these changes and therapeutic effectiveness.

Transurethral incision of prostate (TUIP) and retrograde ejaculation.

OBJECTIVE: Men of any age with bladder outlet obstruction and without measurable enlargement of the prostate constitute ideal candidates for TUIP. Effectiveness of any technique with respect to flow rate improvement is firmly established, indifferently whether unilateral or bilateral. But there is a wide variation in the reported incidence of retrograde ejaculation with unilateral and bilateral incision. MATERIAL AND METHODS: The retrospective analysis of our 45/57 available patients treated with this technique, between January 1993 and March 1995, does not show a major incidence of this complication for the bilateral incision, with an overall incidence of 6.6% (3/45 patients). CONCLUSIONS: Although ejaculation may be preserved, it cannot be guaranteed.

[Cutaneous lesions in POEMS syndrome. Apropos of 3 case reports and a review of the literature]. / Les signes cutanés du syndrome POEMS. A propos de 3 observations et revue de la littérature.

We present three new cases of POEMS syndrome with the most common cutaneous signs of this entity. The syndrome is a multivisceral complex, mostly described in Japanese patients, which includes polyneuropathy, organomegaly, endocrine disorders, monoclonal gammopathy and skin changes. The latter are constant but sometimes reduced to one type of lesion. The most frequent are hyperpigmentation sparing the mucosae, hypertrichosis, scleroderma-like skin thickening and capillary angiomas. The other signs are much less common, as shown in table I. Histological findings are seldom reported and usually have little specificity. None of these abnormalities is pathognomonic, but their predominance at the extremities may be suggestive and leads to a search for other elements of the syndrome, notably gammopathy. The main differential diagnostic problem is with scleroderma, sometimes circumscribed and often systemic. Some cases are very ambiguous. The relationship between the two diseases would suggest the existence of one or several common pathogenic factors. The overall physiopathology of POEMS syndrome is obscure. The role of endocrine disorders in the genesis of the cutaneous signs is subject to discussion: hyperoestrogenism may explain some of these signs, but hypertrichosis is incompatible with the frequent finding of low androgen secretion. The role of one or several "toxic" substances secreted by plasmocytes is highly hypothetical. In some cases, the skin abnormalities have regressed after treatment of gammopathy, and in rare patients the recurrence of gammopathy was followed by that of skin lesions. In a few cases, a "paraneoplastic" character may be suspected.

[The role of surgery in primary gastric non-Hodgkin's malignant lymphoma]. / Place de la chirurgie dans les lymphomes malins non Hodgkiniens gastriques primitifs (L.M.G.P.).

A total of 15 cases of primary gastric non-Hodgkin's malignant lymphoma (PGML) seen between 1974 and 1985 were reviewed, and data obtained combined with reports in the literature, to define the place of surgery in this affection becoming the monopoly of chemotherapists. The indication for surgery is indisputable when the diagnosis is in doubt, and justified for ulcerated and preperforating forms and in extirpable tumoral forms of loco malignancy. It should be avoided in high grade PGML unless the operation does not delay chemotherapy. Total gastrectomy should not be performed by principle but by necessity. Abdominal exploration should include lymph node and liver biopsies. An effective total care of these patients requires close cooperation between medical and surgical teams.

Proton Wires via One-Dimensional Water Chains Adsorbed on Metallic Steps.

The process of proton transfer is here analyzed for one-dimensional water chains adsorbed on metallic steps. When the water chain contains a hydronium and a hydroxyl ion, two different mechanisms are possible, depending on the metal substrate. On coinage metals (Ag, Au), recombination is observed through a spontaneous Grotthuss mechanism. On more reactive surfaces (Pd and Pt), the hydronium ion is unstable and releases a proton that adsorbs onto the metal, leaving the negatively charged OH(-) unbalanced. In this case, the negative charge can be transferred along the wire with very low activation barriers.