Five-year survival and prognostic factors according to histology in 6101 non-small-cell lung cancer patients.

OBJECTIVE: To estimate five-year survival in non-small-cell lung cancer (NSCLC) patients according to histology and to identify independent prognostic factors by histology. METHODS: Data were obtained during the KBP-2010-CPHG study, which included all new cases of primary lung cancer diagnosed in 2010 in 104 non-academic hospitals. RESULTS: In all, 3199 patients had adenocarcinoma (ADC), 1852 squamous cell carcinoma (SCC), 754 large cell carcinoma (LCC). Five-year survival was 13.3% [12.1%-14.5%] for ADC, 14.3% [12.7%-16.0%] for SCC, 9.6% [7.6%-11.9%] for LCC (P<0.001). Performance status, weight loss prior to diagnosis and tumour stage were consistently significant independent prognostic factors. Age (>70 years; P=0.004), male gender (P<0.001), and smoking (P<0.001) were independent negative prognostic factors for ADC. Epidermal Growth Factor Receptor (EGFR)-mutation tests, performed in 1638 ADC patients, were positive for 186. Five-year survival was 14.7% [10.3%-21%] and 10.9% [9.4%-12.6%] for mutated and wild-type EGFR, respectively (P<0.001). EFGR mutation was an independent positive prognostic factor (HR=0.5 [0.4-0.6], P<0.001); however, the proportional hazards assumption was not fulfilled and hazards were inverted after 35 months. CONCLUSIONS: Five-year survival in patients managed in French non-academic hospitals for primary NSCLC in 2010 remained poor (<15%), whatever the histologic type. The independent negative prognostic factors for five-year survival were: weight, particularly weight loss prior to diagnosis; smoking (active or former) at diagnosis in ADC and LCC and smoking level at diagnosis in smoker patients with SCC. The independent positive prognostic factors were young age and female gender for ADC.

Predictability of the duration of motor blockade induced by unique injection of intrathecal prilocaine - an observational study.

Prilocaine is widely used for spinal anesthesia. Its intermediate effect makes it a valuable choice for one-day surgery. The duration of the motor blockade (DMB) may have an impact on the length of stay. The goal of this study was to establish a correlation between the DMB and different parameters (hyperbaric prilocaine dose, puncture level, surgical position, age, patient weight, and patient height). We prospectively enrolled adult patients scheduled for ambulatory surgery (n = 384). Univariate and multivariate regressions (backward stepwise) were applied. A P value lower than 0.05 was considered significant. We performed first analyzes on the entire population. We achieved same on a subgroup only composed of patients who received 60 mg of hyperbaric prilocaine between L4 and L5 and staying on dorsal position during surgery. The univariate analyses of the entire population demonstrate a significant correlation between DMB and 1) the prilocaine dose (P < 0.001), and 2) the BMI (P = 0.011). On the same population, the multivariate analyses confirm these two independent parameters correlated to the DMB: the patient height (P = 0.03) and the hyperbaric prilocaine dose (P < 0.001). The second analyses performed on the subgroup (n = 65), demonstrate a wide variability in the DBM (mean ± SD): 90.12 ± 30.36 minutes. For this concern, univariate analyses illustrate that only the patient height was significantly correlated to the DMB (P = 0.005). The multivariate analyses confirm that patient height could be considered as an independent parameter of DBM (P = 0.005). Within our entire population, there exists a considerable variation in the duration of the motor block after a unique injection of hyperbaric prilocaine. The prilocaine dose and the patient height were the only independent factors of the extension of the DMB. However, this relation is extremely weak and only allows explaining the variability of the DMB in a minority of the patients. This unknown pharmacological property of hyperbaric prilocaine could restrict its use for day-care surgery.

Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis.

STUDY QUESTION: Can live birth be accurately predicted following surgical resection of moderate-severe (Stage III-IV) endometriosis? SUMMARY ANSWER: Live births can accurately be predicted with the endometriosis fertility index (EFI), with adnexal function being the most important factor to predict non-assisted reproductive technology (non-ART) fertility or the requirement for ART (www.endometriosisefi.com). WHAT IS KNOWN ALREADY: Fertility prognosis is important to many women with severe endometriosis. Controversy persists regarding optimal post-operative management to achieve pregnancy and the counselling of patients regarding duration of conventional treatments before undergoing ART. The EFI is reported to correlate with expectant management pregnancy rate, although external validation has been performed without specifically addressing fertility in women with moderate and severe endometriosis. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 279 women from September 2001 to June 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We included women undergoing laparoscopic resection of Stage III-IV endometriosis who attempted pregnancy post-operatively. The EFI was calculated based on detailed operative reports and surgical images. Fertility outcomes were obtained by direct patient contact. Kaplan-Meier model, log rank test and Cox regression were used for analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The follow-up rate was 84% with a mean duration of 4.1 years. A total of 147 women (63%) had a live birth following surgery, 94 of them (64%) without ART. The EFI was highly associated with live births (P < 0.001): for women with an EFI of 0-2 the estimated cumulative non-ART live birth rate at five years was 0% and steadily increased up to 91% with an EFI of 9-10, while the proportion of women who attempted ART and had a live birth, steadily increased from 38 to 71% among the same EFI strata (P = 0.1). A low least function score was the most significant predictor of failure (P = 0.003), followed by having had a previous resection (P = 0.019) or incomplete resection (P = 0.028), being older than 40 compared to <35 years of age (P = 0.027), and having leiomyomas (P = 0.037). LIMITATIONS REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Imprecision was higher with low EFI due to smaller sample size in this subgroup. Finally, the EFI is somewhat subjective and could be prone to intra- and inter-observer variations. WIDER IMPLICATIONS OF THE FINDINGS: Women with a high EFI score have excellent fertility prognosis and may be advised to try to become pregnant with timed intercourse compared to women with a low score, for which prompt referral to ART seems more reasonable. Other prognostic factors can be used to guide the management of women with an intermediate EFI score. These data follow women over many years post-resection and represent longitudinal fertility data rarely demonstrated in such a cohort. The location and impact of lesions on the ability of the adnexa to function seems crucial for the fertility prognosis and should be further investigated. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the GRACE Research funds. S.M.-L. is the recipient of a Training Award from the Fonds de Recherche Quebec-Sante. D.A. is the primary author of the Endometriosis Fertility Index. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Integrated production of polyhydroxyalkanoates (PHAs) with municipal wastewater and sludge treatment at pilot scale.

A pilot-scale process was operated over 22 months at the Brussels North Wastewater Treatment Plant (WWTP) in order to evaluate polyhydroxyalkanoate (PHA) production integration with services of municipal wastewater and sludge management. Activated sludge was produced with PHA accumulation potential (PAP) by applying feast-famine selection while treating the readily biodegradable COD from influent wastewater (average removals of 70% COD, 60% CODsol, 24% nitrogen, and 46% phosphorus). The biomass PAP was evaluated to be in excess of 0.4gPHA/gVSS. Batch fermentation of full-scale WWTP sludge at selected temperatures (35, 42 and 55 °C) produced centrate (6-9.4 gCODVFA/L) of consistent VFA composition, with optimal fermentation performance at 42 °C. Centrate was used to accumulate PHA up to 0.39 gPHA/gVSS. The centrate nutrients are a challenge to the accumulation process but producing a biomass with 0.5 gPHA/gVSS is considered to be realistically achievable within the typically available carbon flows at municipal waste management facilities.

Partial depletion of the proinflammatory monocyte population is neuroprotective in the myenteric plexus but not in the basal ganglia in a MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) patients often suffer from gastrointestinal (GI) impairments that are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric nervous system. Growing evidence suggests that inflammation originating from the gut may have a major impact in both the initiation and progression of PD. Here, we investigated the role of the innate immune response in neurodegeneration occurring in central nervous system (CNS) and enteric nervous system (ENS) in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism in both humans and animal models. We found a strong immune response in the gut of mice treated with MPTP, as demonstrated by the prominent presence of macrophages derived from CD115(+) CD11b(+) Ly6C(Hi) monocytes, known as M1 monocytes, and increased production of IL-1ß and IL-6. Partial depletion of proinflammatory M1 monocytes through intravenous injections of clodronate-encapsulated liposome protects against MPTP-induced reduction of tyrosine hydroxylase (TH) expression in the ENS. In contrast, loss of striatal TH expression in the CNS after MPTP intoxication occurs regardless of partial monocyte depletion. Examination of brain tissue revealed that microglial activation, comprising the majority of the immune response in the CNS after MPTP injections is unaffected by M1 depletion. In vitro experiments revealed that MPTP and MPP(+) act directly on monocytes to elicit a proinflammatory response that is, in part, dependent on the MyD88/NF-κB signaling pathway resulting in nitrite and proinflammatory cytokine production. Taken together, our results demonstrate a critical role for proinflammatory M1 monocytes/macrophages in DAergic alterations occurring in the GI, but not in the brain, in the MPTP model of PD.

[Pemetrexed-induced scleroderma-like changes in the lower legs]. / Sclérose cutanée des deux membres inférieurs sous pemetrexed.

BACKGROUND: Pemetrexed (Alimta(®)) is a new-generation antifolate used to treat malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). We report two cases of a new toxicity induced by pemetrexed: scleroderma-like induration of the lower extremities. PATIENTS AND METHODS: The first case concerned a 66-year-old man diagnosed with pulmonary adenocarcinoma metastatic from the outset and in whom maintenance treatment comprised pemetrexed after first-line therapy comprising six courses of cisplatin-pemetrexed. After the fourth cycle of pemetrexed, he presented an erythematous oedema of the left leg, which was subsequently bilateral. Clinically, there was painful cellulitis associated with areas of bruising. The lesions had an appearance of erysipeloid-like infection, and there was no fever. The second case concerned a 70-year-old woman diagnosed with metastatic NSCLC. From the first course of pemetrexed, given as maintenance therapy, she presented erythematous oedema of both legs, without fever. After the second course, we observed the recurrence of the lesions consisting of erythemato-violaceous plaques on both legs, with severe bilateral indurated and painful oedema, associated with major functional disability. A diagnosis of bilateral erysipelas was made, and antibiotic treatment with cloxacillin was given. In both cases, pemetrexed was discontinued and the local outcome was very slowly favourable, with persistence of scleroderma. DISCUSSION: This cutaneous adverse effect is unrecognized, resulting in delayed diagnosis. It is often initially confused with bilateral erysipelas, despite absence of fever. According to some studies, the severity of the cutaneous toxicity may be connected with patients' folate status. Thus folate and vitamin B12 supplementation combined with dexamethasone could decrease the incidence of this side effect. There was no recurrence and no worsening with taxanes, chemotherapy agents known to induce scleroderma. We feel that this cutaneous toxicity must be recognised on account of its potential severity.

Wavelet-based clustering for mixed-effects functional models in high dimension.

We propose a method for high-dimensional curve clustering in the presence of interindividual variability. Curve clustering has longly been studied especially using splines to account for functional random effects. However, splines are not appropriate when dealing with high-dimensional data and can not be used to model irregular curves such as peak-like data. Our method is based on a wavelet decomposition of the signal for both fixed and random effects. We propose an efficient dimension reduction step based on wavelet thresholding adapted to multiple curves and using an appropriate structure for the random effect variance, we ensure that both fixed and random effects lie in the same functional space even when dealing with irregular functions that belong to Besov spaces. In the wavelet domain our model resumes to a linear mixed-effects model that can be used for a model-based clustering algorithm and for which we develop an EM-algorithm for maximum likelihood estimation. The properties of the overall procedure are validated by an extensive simulation study. Then, we illustrate our method on mass spectrometry data and we propose an original application of functional data analysis on microarray comparative genomic hybridization (CGH) data. Our procedure is available through the R package curvclust which is the first publicly available package that performs curve clustering with random effects in the high dimensional framework (available on the CRAN).

Evidence of genotoxicity related to high PAH content of sediments in the upper part of the Seine estuary (Normandy, France).

In order to characterize the genotoxicity in the Seine estuary and Seine bay, chemical and toxicological analyses were performed on 17 sediments collected in June 2001 and June 2003. Many potent mutagenic and/or carcinogenic compounds - including polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and metals - were detected. Those compounds were found to be at relatively high concentrations in the upper part of the Seine estuary but were barely detectable at sites outside the plume from the Seine. The levels of pollution did not vary significantly between the two sampling periods, except that PAH concentrations in sediments collected at Oissel and Le Havre showed a marked increase in June 2003. The toxicity of organic extracts from sediments was evaluated by both embryotoxicity and in vitro genotoxicity (SOS Chromotest) assays. Organic extracts from sediments taken from the Seine estuary appeared significantly more embryotoxic than those from the Seine bay. In addition, the sediment extracts from the upper part of the Seine estuary exhibited higher genotoxicity than those from the lower part, and no genotoxicity was reported for sediments from the Seine bay. The genotoxic activity was detected only after adding an S9 microsomal fraction, suggesting the preponderant involvement of pro-genotoxic organic compounds. In addition, SOS Chromotest responses obtained with purified organic fractions revealed that PAH and, to a lesser extent, unknown polar organic compounds were probably responsible for this genotoxicity. Altogether, these results suggest that sediments from the upper Seine estuary are genotoxic and embryotoxic, and therefore, could be potentially hazardous for species living or feeding in the area.

Effective dimension reduction methods for tumor classification using gene expression data.

MOTIVATION: One particular application of microarray data, is to uncover the molecular variation among cancers. One feature of microarray studies is the fact that the number n of samples collected is relatively small compared to the number p of genes per sample which are usually in the thousands. In statistical terms this very large number of predictors compared to a small number of samples or observations makes the classification problem difficult. An efficient way to solve this problem is by using dimension reduction statistical techniques in conjunction with nonparametric discriminant procedures. RESULTS: We view the classification problem as a regression problem with few observations and many predictor variables. We use an adaptive dimension reduction method for generalized semi-parametric regression models that allows us to solve the 'curse of dimensionality problem' arising in the context of expression data. The predictive performance of the resulting classification rule is illustrated on two well know data sets in the microarray literature: the leukemia data that is known to contain classes that are easy 'separable' and the colon data set.

Analysis of chicken mucosal immune response to Eimeria tenella and Eimeria maxima infection by quantitative reverse transcription-PCR.

The recent cloning of chicken genes coding for interleukins, chemokines, and other proteins involved in immune regulation and inflammation allowed us to analyze their expression during infection with Eimeria. The expression levels of different genes in jejunal and cecal RNA extracts isolated from uninfected chickens and chickens infected with Eimeria maxima or E. tenella were measured using a precise quantitative reverse transcription-PCR technique. Seven days after E. tenella infection, expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) mRNA was increased 80-fold. Among the chemokines analyzed, the CC chemokines K203 (200-fold) and macrophage inflammatory factor 1beta (MIP-1beta) (80-fold) were strongly upregulated in the infected ceca, but the CXC chemokines IL-8 and K60 were not. However, the CXC chemokines were expressed at very high levels in uninfected cecal extracts. The levels of gamma interferon (IFN-gamma) (300-fold), inducible nitric oxide synthase (iNOS) (200-fold), and myelomonocytic growth factor (MGF) (50-fold) were also highly upregulated during infection with E. tenella, whereas cyclooxygenase 2 showed a more modest (13-fold) increase. The genes upregulated during E. tenella infection were generally also upregulated during E. maxima infection but at a lower magnitude except for those encoding MIP-1beta and MGF. For these two cytokines, no significant change in expression levels was observed after E. maxima infection. CD3+ intraepithelial lymphocytes may participate in the IFN-gamma upregulation observed after infection, since both recruitment and upregulation of the IFN-gamma mRNA level were observed in the infected jejunal mucosa. Moreover, in the chicken macrophage cell line HD-11, CC chemokines, MGF, IL-1beta, and iNOS were inducible by IFN-gamma, suggesting that macrophages may be one of the cell populations involved in the upregulation of these cytokines observed in vivo during infection with Eimeria.

Cryptosporidium parvum-specific mucosal immune response in C57BL/6 neonatal and gamma interferon-deficient mice: role of tumor necrosis factor alpha in protection.

Both neonatal and C57BL/6 gamma interferon (IFN-gamma) knockout (C57BL/6-GKO) mice are susceptible to Cryptosporidium parvum, but the course of infection is different. Neonatal mice are able to clear the parasite within 3 weeks, whereas C57BL/6-GKO mice, depending on age, die rapidly or remain chronically infected. The mechanism by which IFN-gamma leads to a protective immunity is yet poorly understood. In order to investigate the effect of IFN-gamma on other cytokines expressed in the intestinal mucosa during C. parvum infection, we studied cytokine mRNA expression in the neonates and GKO (neonatal and adult) mice by quantitative reverse transcription-PCR (RT-PCR) at 4 and 9 days after infection. IFN-gamma mRNA levels were quickly and strongly up-regulated in the mucosa of neonatal mice. In GKO mice, the Th1-type response was dramatically altered during the infection, whereas the mRNA expression levels of the Th2-type cytokines interleukin 4 (IL-4) and IL-10 were increased in both mouse models. In the absence of IFN-gamma, the adult knockout mice up-regulated the mRNA levels of inflammatory cytokines, such as IL-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor, in the mucosa, but not tumor necrosis factor alpha (TNF-alpha), whereas all these cytokines were up-regulated in the infected neonatal mice. Further experiments indicated that injections of TNF-alpha into GKO adult mice significantly reduced oocyst shedding. The results of the present study indicate that the resolution of infection is dependent on the expression of Th1-type cytokines in the mucosa of C57BL/6 mice and that TNF-alpha may participate in the control of parasite development.

Gastrointestinal injuries during gynaecological laparoscopy.

A retrospective case review study was carried out on gastrointestinal injuries which occur during gynaecological laparoscopy. Fifty-six patients with 62 gastrointestinal injuries were identified. One-third of the complications (32.2%) occurred during the installation phase for laparoscopy. Four of the six complications attributed to electrosurgery were secondary to the use of monopolar coagulation. Diagnosis of these gastrointestinal injuries was made during surgery in only 20 patients (35.7%). The mean time before diagnosis was 4.0 +/- 5.4 (range 0-23) days. Treatment of these complications was performed by laparoscopic surgery in 16.1% of cases. Prevention relies on the surgeon's experience, strict observance of the safety rules, perfect familiarity with the physical properties of the instruments used, systematic use of bowel preparation for patients presenting a risk of bowel complications, systematic supervision of the route taken by the trocars, meticulous inspection on completion of surgery of all areas where bowel adhesiolysis has been used and, in case of any doubt, tests for leakage involving the rectosigmoid. For patients with a risk of bowel complications, the creation of a pneumoperitoneum and performing a mini laparoscopy in the left hypochondrium can be the judicious option.

Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain.

The aim of this study was to investigate the influence of the acute-phase response and the proinflammatory cytokines on the transcription of the genes encoding the limiting enzymes for the production of prostaglandins, cyclooxygenase (COX)-1 and COX-2, in the rat brain. The bacterial endotoxin lipopolysaccharide (intravenous and intraperitoneal) and turpentine (intramuscular) were used as different models of inflammation in adult male rats. Animals were also killed at various times after intravenous administration of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6, and mRNAs encoding COX-1 and COX-2 were assayed by in situ hybridization histochemistry. A profound transcriptional activation of the gene encoding COX-2 was detected over blood vessels of the entire brain microvasculature, choroid plexus, and leptomeninges of lipopolysaccharide-challenged rats. Injection of the endotoxin intravenously also increased COX-2 gene expression within parvocellular division of the hypothalamic paraventricular nucleus. It is interesting that intramuscular turpentine injection stimulated transcription of COX-2 along endothelium of brain capillaries, and the signal of this transcript paralleled the inflammation of the left hind limb. A robust COX-2 mRNA signal was detected rapidly in the brain microvessels of interleukin-1beta-injected rats, whereas tumor necrosis factor-alpha administration caused a modest but significant induction of this transcript. In contrast, intravenous injection of interleukin-6 did not alter genetic expression of COX-2, and none of the above described models affected the synthesis of COX-1 gene in the rat brain. These results indicate that specific cell populations, in particular vascular- and/or perivascular-associated cells, are responsible for the central production of prostaglandins during systemic inflammation, and circulating interleukin-1beta is likely to be a potent mediator of this response.

Major vascular injuries during gynecologic laparoscopy.

BACKGROUND: This study was undertaken to report our experience with major vascular injuries in gynecologic laparoscopy in order to specify the circumstances under which they occurred, the means of diagnosis, the risk factors, and the means for prevention. STUDY DESIGN: Retrospective case review study. RESULTS: Seventeen patients with 21 major vascular injuries were identified. The average age of the patients was 33.8 +/- 11.6 years, and the mean body index mass was 21.6 +/- 3.08 kg/m2. Three of four of the accidents occurred during the set-up phase of laparoscopy (13 cases; 76.5%), and in 4 cases (23.5%) the accident occurred during the laparoscopic surgery procedure. Eleven (84.6%) of the complications occurring during the set-up phase were secondary to insertion of the umbilical trocar and 2 (15.4%) to insertion of the needle used to create the pneumoperitoneum (P-needle). Half (6 cases; 54.5%) of the major vascular injuries secondary to insertion of the umbilical trocar were observed when reusable trocars were used. In every case, the diagnosis was made during the operation. Two patients died, and two others presented a serious complication (phlebitis; acute ischemia requiring reoperation). CONCLUSIONS: Major vascular injuries are rare but serious complications of laparoscopic surgery. Prevention of these accidents relies on the surgeon's experience and scrupulous respect of the safety rules. In the vast majority of cases, it is necessary to convert to laparotomy immediately, calling in a vascular surgeon.

Influence of interleukin-6 on neural activity and transcription of the gene encoding corticotrophin-releasing factor in the rat brain: an effect depending upon the route of administration.

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by various lymphoid and neural cells. In addition to its classic role during immune and inflammatory responses, IL-6 acts on the central nervous system to elicit changes, such as activation of the hypothalamic-pituitary-adrenal (HPA) axis. This study investigated the effects of systemic and central injection of IL-6 on neural activity and transcription of the corticotrophin-releasing factor (CRF) gene in the brain of conscious rats. The animals were killed 1 and 3 h after a single infusion of IL-6 into the right jugular vein (0.83 or 3.0 microg) or the right lateral ventricle (0.2 microg) and their brains cut from the olfactory bulb to the end of the medulla in 30-microm coronal sections. Messenger RNA encoding the protein Fos, a marker of neural activity, and the neuropeptide CRF were localized by in situ hybridization histochemistry using 35S-labelled exonic and intronic riboprobes. The results show that systemic injection of IL-6 induced specific transcription of c-fos gene in most of the sensorial circumventricular organs, including the organum vasculosum lamina terminalis, subfornical organ, median eminence, and area postrema, as well as in the central nucleus of the amygdala and bed nucleus of the stria terminalis. On the other hand, central injection of IL-6 increased cellular level of c-fos mRNA in the ependymal layer and the walls of the ventricles, meninges, nucleus of the solitary tract, and circumventricular organs. These effects were rapid and transient, since the signals for c-fos mRNA were detected 1 h after both treatments and vanished 3 h afterwards. Moreover, the CRF gene was not activated by either systemic or central administration of IL-6 in the paraventricular nucleus of the hypothalamus. Taken together, these results suggest that circumventricular organs hold a privileged position in mediating the central effects of systemic IL-6 and that centrally injected IL-6 can strongly activate cells of the ventricular system and surrounding structures. Although this differential circuitry may explain distinct origin-dependent functions of IL-6, this cytokine seems insufficient, in itself, to induce transcription of the gene encoding neuroendocrine CRF, the neuropeptide responsible for control of the HPA axis.

C-fos mRNA pattern and corticotropin-releasing factor neuronal activity throughout the brain of rats injected centrally with a prostaglandin of E2 type.

The present study investigated the effect of central administration of the prostaglandin of E2 type (PGE2) on the distribution of the immediate early gene (IEG) c-fos mRNA and the transcriptional activity of corticotropin-releasing factor (CRF) and its type 1 receptor in the brain of conscious rats. Adult male rats were sacrificed 30 min and 2 h after a single infusion of PGE2 into the right lateral ventricle (2 micrograms/10 microliters) and their brains cut from the olfactory bulb to the end of the medulla in 30 micrometer coronal sections. mRNAs encoding the IEG c-fos and CRF1 receptor were assayed by in situ hybridization histochemistry using 35S-labeled exonic riboprobes whereas the primary transcript (heteronuclear (hn)RNA) for CRF was detected using intronic probe technology as an index of CRF transcriptional activity. Colocalization of c-fos mRNA within CRF, vasopressin (AVP), and oxytocin (OT) neurons was determined by means of a combination of immunocytochemistry and in situ hybridization techniques on the same brain sections. Thirty min after PGE2 injection, a moderate to strong positive signal for c-fos mRNA was detected in multiple structures of the brain such as the medial preoptic area/organum vasculosum of the lamina terminalis, supraoptic nucleus (SON), parvocellular and magnocellular divisions of the paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala, nucleus of the solitary tract, dorsal motor nucleus of the vagus, area postrema, dorsal division of the ambiguus nucleus, and throughout the choroid plexus and leptomeninges. A smaller but significant c-fos expression was observed in various structures including the subfornical organ, bed nucleus of the stria terminalis, arcuate nucleus, and periventricular nucleus of the hypothalamus. Two h after treatment with the PG, the signal for c-fos mRNA in most of these brain nuclei vanished. In the parvocellular nucleus of the PVN, c-fos was expressed in CRF-immunoreactive (ir) and OT-ir neurons, whereas in the magnocellular part of that nucleus and in the SON, this transcript was essentially colocalized in OT-ir neurons. Activation of CRF neuroendocrine cells was also associated with an increase in CRF transcription as revealed by the selective presence of CRF primary transcript (hnRNA), which was stimulated only in the PVN but not in any other nuclei in the brains of PGE2-treated rats. Central administration of PGE2 also induced expression of the CRF type 1 receptor in the parvocellular PVN. Taken together, these results provide clear anatomical evidence that central PGE2 injection causes specific and selective expression of c-fos in several brain structures recognized to be activated in the brains of endotoxin-challenged rats. It is therefore possible that PG of E2 type plays a crucial role within the CNS in the interface between the immune and nervous systems to modulate neuroendocrine responses, such as the hypothalamic-pituitary-adrenal axis.

Nilutamide pneumonitis: a report on eight patients.

BACKGROUND: Nilutamide is a new, specific synthetic antiandrogen, released in several countries for the treatment of metastatic carcinoma of the prostate. Eight patients at the University Medical Centre at Dijon and affiliated referring hospitals developed reversible pulmonary opacities and respiratory symptoms while taking the drug. METHODS: Records of eight patients who developed new, otherwise unexplained chest opacities while taking nilutamide were reviewed. In each patient a careful aetiological search was made for other environmental or endogenous causes. Six patients underwent bronchoalveolar lavage, and lavage fluid was cultured. Corticosteroids were not given, unless gas exchange was compromised (two patients). RESULTS: The eight patients (all male) had had carcinoma of the prostate diagnosed on average 10.2 months earlier. All had improved with nilutamide, with a dramatic decrease of prostate specific antigen levels. Seven had received nilutamide at the recommended dosage of 150 mg/day, and one had received twice that amount. Treatment had lasted on average 113 (range 10-225) days, and the mean cumulated exposure was 21.8 (3-38) grams. The chest radiographs showed bilateral infiltrates, with no consistent topographic predilection. A restrictive lung defect was present in six patients and hypoxia in all (mean arterial oxygen tension (PaO2) 6.6 kPa). Bronchoalveolar lavage showed lymphocytosis in four patients and neutrophilia in two. The outcome was favourable in all patients after they had stopped nilutamide only (five patients), with corticosteroids (two patients) or a simple reduction of nilutamide from 300 to 150 mg/day (one patient). Recovery was associated with improvement of pulmonary function and PaO2. CONCLUSION: Nilutamide is associated with interstitial pneumonitis in about 1% of patients and appears reversible.