Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients.

BACKGROUND: Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung cancer. Despite the fair sensitivity of SCLC to chemotherapy and radiotherapy, the current standard treatment regimens have modest survival rates and are associated with potential life-threatening adverse events. Therefore, research into new optimised regimens that increase drug efficacy while respecting toxicity constraints is of primary importance. METHODS: A PK/PD model for the combination of cisplatin and etoposide to treat extensive-stage SCLC patients was generated. The model takes into consideration both the efficacy of the drugs and their haematological toxicity. Using optimisation techniques, the model can be used to propose new regimens. RESULTS: Three new regimens with varying timing for combining cisplatin and etoposide have been generated that respect haematological toxicity constraints and achieve better or similar tumour regression. The proposed regimens are: (1) Protocol OP1: etoposide 80 mg m-2 over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m-2 plus cisplatin 80 mg m-2 over 1 h D1, D1-D1 21 days; (2) Protocol OP2: etoposide 80 mg m-2 over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m-2 plus cisplatin 100 mg m-2 over 1 h D1, D1-D1 21 days; and (3) Protocol OP3: etoposide 40 mg m-2 over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m-2 plus cisplatin 50 mg m-2 over 1 h, D1-D1 14 days. CONCLUSIONS: Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients.

Modeling circadian clock-cell cycle interaction effects on cell population growth rates.

The circadian clock and the cell cycle are two tightly coupled oscillators. Recent analytical studies have shown counter-intuitive effects of circadian gating of the cell cycle on growth rates of proliferating cells which cannot be explained by a molecular model or a population model alone. In this work, we present a combined molecular-population model that studies how coupling the circadian clock to the cell cycle, through the protein WEE1, affects a proliferating cell population. We show that the cell cycle can entrain to the circadian clock with different rational period ratios and characterize multiple domains of entrainment. We show that coupling increases the growth rate for autonomous periods of the cell cycle around 24 h and above 48 h. We study the effect of mutation of circadian genes on the growth rate of cells and show that disruption of the circadian clock can lead to abnormal proliferation. Particularly, we show that Cry 1, Cry 2 mutations decrease the growth rate of cells, Per 2 mutation enhances it and Bmal 1 knockout increases it for autonomous periods of the cell cycle less than 21 h and decreases it elsewhere. Combining a molecular model to a population model offers new insight on the influence of the circadian clock on the growth of a cell population. This can help chronotherapy which takes benefits of physiological rhythms to improve anti-cancer efficacy and tolerance to drugs by administering treatments at a specific time of the day.

Impacts of agricultural practices on pyrethroid resistance in Culex pipiens pipiens, an important vector of human diseases, from Tunisia.

Agricultural pesticides may play a profound role in selection of resistance in field populations of mosquito vectors. The aim of the present study was to examine the relationship between agricultural pesticide use and development of resistance to insecticides in Culex pipiens pipiens from Tunisia. Entomological surveys were conducted in three various districts from Tunisia differ in insect control in agriculture and in public health. A reference locality without any chemical activities was used to do different comparisons. Our results revealed that the level of permethrin resistance ranged from 40.9 to 7438. Practically no susceptible populations were found and resistance to permethrin was important, but significantly higher in site submitted to both agricultural and public health applications. However, resistance ratio has been decreased 7000 folds in site not submitted to agricultural pests. These observations expressed an important influence of agricultural applications on permethrin resistance and need an urgent coordination between the integrated vector control program and the Ministry of Agriculture to reduce the development of resistance in populations. The recorded resistance was slightly associated with DDT suggest the involvement of their common mechanism (target site). Synergist's tests indicated that different enzymes played an important role in the detoxification of this insecticide.

[Home non-invasive ventilation for chronic obstructive pulmonary disease]. / Ventilation non invasive à domicile au cours de la broncho-pneumopathie chronique obstructive.

INTRODUCTION: The benefits of long-term non-invasive ventilation (NIV) in the management of chronic obstructive pulmonary disease (COPD) patients remain controversial. AIM: To analyze the characteristics of COPD patients under home NIV and to evaluate its impact among this population. METHODS: We carried out a retrospective study between January 2002 and April 2016 of COPD patients under long-term NIV at "la Rabta" and the Military Hospital. RESULTS: There were 27 patients with an average age of 64 and a sex ratio (M/F) of 0.92. Active smoking was reported in 96.3%. A persistent hypercapnia following an acute exacerbation of COPD with failure to wean the NIV was the main indication of long-term NIV. We noted a reduction in hospital admissions in the first year of 60% and in intensive care of 83.3% (P<10-3). There was no non-significant decrease of PaCO2 (4.5mmHg). There was no modification in FEV 1 and in FVC (P>0.05). The survival rate was 96.3% at 1 year, 83.3% at 2 years and a median survival of 24 months. CONCLUSIONS: Our study suggests that home NIV contributes to the stabilization of some COPD patients by reducing the hospitalizations rates for exacerbation. More prospective studies are needed to better assess the impact of NIV on survival and quality of life and to better define the COPD patients who require NIV.

Characterization of resistance to pirimiphos-methyl (an organophosphate insecticide) in Culex pipiens pipiens (Diptera: Culicidae) from Northern and Southern Tunisia.

Despite the public health importance of Culex pipiens pipiens, their resistance to pirimiphos-methyl insecticides has not been explored enough. Late third and early fourth larvae of Culex pipiens pipiens were collected from three localities between 2003 and 2005 in Northern and Southern Tunisia. All bioassays were carried out using pirimiphosmethyl and propoxur insecticides. Populations of Culex pipiens pipiens were susceptible, moderate and resistant to pirimiphos-methyl insecticide. Resistance to this compound ranged from 2.62 in sample # 2 to 19.9 in sample # 1. The moderate resistance (5.25) was recorded in sample # 3. Synergist's tests showed that the resistance to pirimiphos-methyl was not affected by detoxification enzymes. However, biochemical assays showed the involvement of both metabolic (esterases) and target site (insensitive acetylcholinesterase) resistance mechanisms. The highest frequencies of the resistant phenotypes ([RS] and [RR]) (<0.74) were detected in the most resistant samples (#1). Four esterases enzymes including C1 encoded by the Est-1 locus and three esterases encoded by the Ester super locus: A2-B2, A4-B4 (or A5-B5, which has the same electrophoretic mobility) and B12 were detected. The highest (0.61) and the lowest (0.22) frequencies of these esterases were recorded in samples # 1 (Sidi Hcine) and # 2 (El Fahs) which recorded the highest and the lowest level of resistance, respectively. Monitoring of insecticide resistance should be evaluated regularly for management of vector control.

Multiple resistance mechanisms associated with low pirimifos-methyl resistance in Culex pipiens pipiens in three populations of Tunisia.

The aim of this study was to evaluate the resistance status of Culex pipiens pipiens to pirimiphos-methyl insecticide. Three field populations of mosquitoes were collected from Tunisia and analyzed in laboratory. The samples studied showed low level of resistance not exceeding 5-folds. The low resistance recorded is particularly interesting, because it leaves a range of tools useable by vector control services. Both metabolic and target-site resistance mechanisms were identified. Different esterases of high activity including A2-B2, A4-B4 (and/or A5-B5) and B12 were observed in studied field samples using starch electrophoresis although opposite results were found using synergists tests on samples # 1 and 3. The polymorphism of AChE1 (Acetylcholinesterase) was analyzed and three phenotypes were detected: susceptible (ACHE1S, phenotype [SS]), resistant (ACHE1R, phenotype [RR]), and heterozygous (phenotype [RS]) of ACHE1. The resistance of Culex pipiens pipiens to pirimiphos-methyl remains low although the occurrences of multiple resistance mechanisms are able to confer high resistance levels to organophosphate insecticides. Therefore, continuous monitoring of resistance is fundamental for rational use of insecticides and mosquito control programs.

[Pneumocystis pneumonia in 3 non HIV patients]. / Pneumocystose pulmonaire chez les patients non VIH: à propos de trois cas.

We report 3 cases of pneumocystis pneumonia (PCP) in 2 female and 1 male patients (mean age=50 years) free of human immunodeficiency virus (HIV) infection. One female patient presented with breast neoplasm the other with Wegener's granulomatosis, the male patient with lymphoma. All patients were taking immunosuppressive treatment at the time of infection. Persistent cough, dyspnea, and severe hypoxemia were the most characteristic clinical signs. All patients presented with lymphopenia (average CD4-cell count=275/mm3), two with hypoalbuminemia, and one with renal failure. In all cases, the microscopic analysis of bronchoalveolar lavage was used to establish the diagnosis. All patients were treated with trimethoprim and sulfamethoxazole and a tapering dose of corticosteroids. Outcome was favorable for 1 patient, 1 was transferred to the intensive care unit for acute respiratory failure, and 1 died.

[Sclerosing hemangioma of the lung: a rare lesion with a difficult diagnosis]. / L'hémangiome sclérosant du poumon: une lésion rare et de diagnostic difficile.

Sclerosing hemangioma of the lung is a rare lesion described for the first time in 1956 by Liebow. We report a case in a 45 year-old woman who was admitted for exploration of chronic cough. The chest x-ray revealed a round opacity, well delimited in the left pulmonary parenchyma. Surgical resection enabled the histopathological diagnosis of sclerosing hemangioma. We review progress in our knowledge of the histogenesis and diagnosis of this tumor. Immunohistochemistry has been highly contributory although numerous points remain controversial.

[Mediastinal neuroblastoma: Unusual localization with late revelation]. / Neuroblastome médiastinal : localisation inhabituelle à révélation tardive.

Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system. It represents the most common malignant extracerebral solid tumor, and the first solid tumor in children aged less than one year. Neuroblastoma is rare in adults. We report the case of a 21-year-old male patient. Diagnosis of neuroblastoma was confirmed by percutanous CT scanner biopsy. Radiological assessment of the extension concluded to a stage IV NB with multifocal bone disease. The patient received chemotherapy based on cisplatin-etoposide (6 cycles) and a mediastinal radiotherapy. The evolution was marked by the progression of bone metastasis and the emergence of a tissular process sheathing the left optic nerve and the terminal portion of the internal carotid artery. Second line chemotherapy was indicated. A thoracic localization of NB is rare. Treatment is not codified and the prognosis is variable.

[Alveolar haemorrhage following a cannabis water pipe]. / Hémorragie alvéolaire suite à un bang de cannabis.

Respiratory toxicity of cannabis is well-known today particularly with the new consumption patterns. We report the case of a 25-year-old man admitted for haemoptysis, with unfavourable outcome and acute respiratory failure. Various explorations concluded to acute respiratory distress syndrome secondary to diffuse alveolar haemorrhage. Etiological assessment was initially negative. Outcome was favourable during hospitalization, authorizing the discharge of our patient. Two days later, alveolar haemorrhage recur, with positive toxicological tests for cannabis and the patient admits smoking cannabis by plastic "bang". We illustrate, through this case, the severity of respiratory complications caused by new methods of using cannabis, particularly with plastic 'bang', hence the need to insist of the importance of supported withdrawal and to inform young people how these techniques are serious.ssss.

Changes in thyroid hormone and thyrotrophin in the serum and thyroid glands of developing genetically obese male and female Zucker rats.

In a first experiment, serum thyroxine (T4), 3,5,3'-triiodothyronine (T3) and thyrotrophin (TSH) concentrations as well as thyroid gland T4 and T3 contents were measured in developing lean and obese Zucker male and female rats of 4-16 weeks of age. The rats were bred in our laboratory and always treated in sex-matched pairs of one lean and one obese rat from the same litter. Serum T4 was not different in any phenotype/sex group at 4 weeks. In male rats, it became progressively lower (27 and 37% at 12 and 16 weeks respectively) in obese than in lean rats. In females, similar levels of serum T4 were maintained in both obese and lean developing rats. Serum T3 was similar in obese and lean male 4-week-old rats whereas it was lower (28%) in obese than in lean females. It became progressively lower (39 and 49% at 12 and 16 weeks respectively) in obese than in lean developing male rats. In females, lower levels of serum T3 were maintained (25 and 43% at 12 and 16 weeks respectively) in obese than in lean rats. Serum TSH was not different in any phenotype/sex group at 4 weeks. It rose in both obese and lean male rats with age, but became progressively lower (33 and 23% at 12 and 16 weeks respectively) in obese compared with lean rats. In females, similar levels of serum TSH were maintained in both obese and lean developing rats. Thyroid gland weight was not different in any phenotype/sex group at 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of prolonged fasting on thyroid hormone modulation of lipolysis in isolated epididymal adipocytes of Wistar rats.

Male Wistar rats, 3 weeks old, were thyroidectomized surgically, kept for 1 month at 25 degrees C and then fasted for 3 days, with or without daily intraperitoneal injection of 3,5,3'-triiodo-L-thyronine (4.6 nmol T3/100 g body weight). Age-matched fed euthyroid rats were used as controls. All the experiments were carried out using isolated epididymal adipocytes. Basal lipolysis was higher during fasting in euthyroid or T3-treated adipocytes than in hypothyroid adipocytes. Adipocytes of fed hypothyroid rats were quite unresponsive to theophylline alone or combined with adrenaline or isoproterenol, whereas lipolysis was stimulated by these drugs in euthyroid or T3-treated adipocytes. Such a stimulated lipolysis was increased partially by fasting in hypothyroid adipocytes and was restored to a euthyroid level in T3-treated adipocytes. Lipolysis was more stimulated by adenosine deaminase in fasted euthyroid adipocytes than in fed ones. Hypothyroid and T3-treated adipocytes were unresponsive to adenosine deaminase except in fasted T3-treated rats. In these adipocytes, lipolysis was activated by the combination of adenosine deaminase plus theophylline. Finally, lipolysis was inhibited strongly in hypothyroidism while it was activated weakly by fasting. Lipolysis was inhibited slightly in fasted hypothyroid rats and thyroid hormone restored lipolysis. The findings are discussed in terms of the dual regulation of lipolysis by fasting and thyroid hormones.

Influence of prolonged fasting and thyroid hormone on the alpha 2-adrenergic response in isolated epididymal adipocytes of Wistar rats.

Fasting and thyroid hormone have been reported to modulate the beta-adrenergic pathway of lipolysis in rat, but their effects on the alpha 2-adrenergic response are not well known. The purpose of the present study was to investigate this point. Male Wistar rats, 3 weeks old, were thyroidectomized surgically, kept for 1 month at 25 degrees C and then fasted or not fasted for 3 days with or without daily intraperitoneal injection of 3,5,3'-tri-iodo-L-thyronine (T3; 4.6 nmol/100 g body weight). Age-matched, sham-operated, fed and fasted euthyroid rats were used as controls. The experiments were carried out using isolated epididymal adipocytes. The alpha 2-adrenergic agonist UK 14304 (UK) inhibited the stimulated lipolysis more in fed than in fasted euthyroid rats whereas it had no effect in hypothyroid or T3-treated hypothyroid rats. The alpha 2-adrenergic antagonist idazoxan reversed the antilipolytic effect of UK more in fasted than in fed euthyroid rats. The alpha 2-adrenergic antagonist RX 821002 (RX) did so, but at lower concentrations than those of idazoxan. Idazoxan slightly increased the glycerol release in hypothyroid and especially T3-treated hypothyroid rats. RX had practically no effect on the production of glycerol in these animals. The findings suggest that (a) fasting and probably hypothyroidism decrease the alpha 2-adrenergic response in adipocytes from rats, (b) T3 treatment of hypothyroid rats has no effect on the alpha 2 response, and (c) thyroid hormone does not directly modulate the alpha 2-adrenergic response in rat adipocytes.

Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers.

The pharmacokinetics/tolerability of lanreotide Autogel have been evaluated. Healthy volunteers (n = 24) first received immediate-release lanreotide as a single subcutaneous (s.c.) injection. After two days, 40 or 60 mg lanreotide Autogel was injected subcutaneously. Blood was sampled at various intervals for 56 days. Systemic/local adverse events and changes in biological profile/vital signs were recorded. Lanreotide Autogel produced a prolonged-release pharmacokinetic profile: mean area under the serum concentration-time curve from time 0 to infinity (AUC) was 53.73 +/- 8.99 and 79.48 +/- 13.06 ng mL(-1) day for 40 and 60 mg, respectively, mean peak serum concentration (C(max)) was 4.38 +/- 2.91 and 5.71 +/- 3.52 ng mL(-1), respectively, median time to reach C (minimum-maximum) was 0.50 (0.083-18.0) and 0.38 (0.083-9.01) days, respectively, mean apparent elimination half-life was 21.63 +/- 9.42 and 22.01 +/- 9.87 days, respectively, and relative bioavailability was 0.93 +/- 0.12 and 0.82 +/- 0.15, respectively. Thus, lanreotide Autogel exhibited linear pharmacokinetics for the doses studied. Pharmacokinetic profiles were similar in both genders, apart from statistically significant differences in C(max) and C(max)/AUC. The Autogel formulation of lanreotide was well tolerated, with systemic adverse events being mild/moderate. Erythema and a painless subcutaneous induration were the most common local adverse events. Lanreotide Autogel provided a prolonged dosing interval and good tolerability for treating acromegaly and carcinoid syndrome.

Mesophilic biogas production from fruit and vegetable waste in a tubular digester.

A semi-continuously mixed mesophilic tubular anaerobic digester was tested for the conversion of fruit and vegetable waste (FVW) into biogas. The effect of hydraulic retention time (HRT) and the feed concentration on the extent of the degradation of the waste was examined. Varying the HRT between 12 and 20 days had no effect on the fermentation stability and pH remained between 6.8 and 7.6, but an inhibition of methanogenic bacteria was observed at HRT below 12 days. The overall performance of the reactor was depressed by changing the feed concentration from 8% to 10% TS (dry weight). By applying a feed concentration of 6% and HRT of 20 days in the tubular digester, 75% conversion efficiency of FVW into biogas with a methane content of 64% was achieved.

[Pleural amyloidosis: thoracoscopic diagnosis and physiopathological approach]. / Amylose pleurale. Diagnostic thoracoscopique et approche physiopathologique.

The authors report a case of pleural amyloidosis presenting as a generalised primary amyloidosis with immunological disturbance, in which the diagnosis was made at thoracoscopy. Bronchopulmonary disease during the course of generalised amyloidosis is frequent, but there are only thirteen cases of histologically proven pleural amyloidosis which have been reported in the literature. Using pleuroscopy the histology obtained enables a pathophysiological approach to this disease, taking account of the cells and enzymes found in the pleura, the inflammatory reactions suggests a local production at the pleura level and this would explain the exudative character of some effusions, although a transudate is most often described and is directly linked to congestive cardiac failure. The deposit of fibrin by occluding the stomas of Wang, explains the failure of the absorptive properties of the pleura and also the recurrent nature of these effusions. The pleural disease is without doubt, under-estimated in generalised amyloidosis and the character of the effusions variable. Most often there are transudates secondary to congestive cardiac failure, although exudates occur as a result of local inflammatory phenomena. Amyloidosis should be remembered as a possible cause of exudative pleurisy.

[Thoracic computed tomography data and cytology of the bronchoalveolar lavage fluid in an adult case of Niemann-Pick disease. The physiognomy of the disease in Tunisia]. / Manifestation tomodensitométrique thoracique et cytologie du liquide de lavage broncho-alvéolaire dans un cas adulte de maladie de Nieman-Pick. Physionomie de la maladie en Tunisie.

From a personal observation of a case of the chronic type-B form Niemann-Pick's disease in a 23 year old adult, the authors decided to review all the Tunisian published cases. They bring to light, in a review of the literature, the pulmonary disorder that occurs during this disease and discuss the contribution of computed tomography and the value of broncho-alveolar lavage as a method of diagnosis and prognosis in this disorder.

[Aorticopulmonary paraganglioma. A case report]. / Paragangliome aortico-pulmonaire. A propos d'un cas.

Paraganglioma is a tumor which develops from the paraganglion system, generally in the adrenal medulla (90%). Thoracic localisations are exceptional and arise essentially for the aortic and subaortic bodies, leading, in this case, to an anterior and posterior localisation. We report a case of non-chromaffin non-secreting aorticopulmonary paraganglioma, discovered fortuitously in a 64-year-old man.

[Multiple bilateral pulmonary nodules revealing a congenital cystic adenomatoid malformation]. / Lâcher de ballon révélateur d'une malformation adénomatoïde kystique congénitale du poumon.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare congenital developmental abnormality, representing about 25% of all congenital lung lesions. It is very rare that presentation is delayed until adulthood. We report a case of 63-year-old woman without notable pathological antecedents in whom a systematic chest X-ray revealed multiple bilateral pulmonary nodules. The patient was asymptomatic and her physical examination was normal. CT scan showed bilateral liquid rounded thin-walled densities of various size, with a homogeneous non calcified content. The diagnosis was based on radiological findings and surgery. The result of histopathological examination obtained by thoracic surgery confirmed CCAM without malignancy. The postoperative follow up showed an excellent recovery.

[Unusual lung localization of histiocytic sarcoma]. / Localisation pulmonaire inhabituelle d'un sarcome histiocytaire.

Histiocytic sarcoma, proliferation araising from immunoregulatory effector system cells, is a very rare and recently recognised tumor. Diagnosis is based on immunohistochemistry and molecular genetic techniques, which allow to distinguish histiocytic sarcoma from lymphocytic proliferation, such as non-Hodgkin's. We report this rare case of multivisceral histiocytic sarcoma revealed by lung localization and for which the evolution was fatal.