Phosphorylated MAP1B is induced in central sprouting of primary afferents in response to peripheral injury but not in response to rhizotomy

A peripheral nerve lesion induces sprouting of primary afferents from dorsal root ganglion (DRG) neurons into lamina II of the dorsal horn. Modifications of the environment in consequence to the axotomy provide an extrinsic stimulus. A potential neuron-intrinsic factor that may permit axonal sprouting is microtubule-associated protein 1B (MAP1B) in a specific phosphorylated form (MAP1B-P), restricted to growing or regenerating axons. We show here that both in rat and mouse, a sciatic nerve cut is rapidly followed by the appearance of MAP1B-P expression in lamina II, increasing to a maximum between 8 and 15 days, and diminishing after three months. Evidence is provided that sprouting and induction of MAP1B-P expression after peripheral injury are phenomena concerning essentially myelinated axons. This is in accordance with in situ hybridization data showing especially high MAP1B-mRNA levels in large size DRG neurons that give rise to myelinated fibers. We then employed a second lesion model, multiple rhizotomy with one spared root. In this case, unmyelinated CGRP expressing fibers do indeed sprout, but coexpression of MAP1B-P and CGRP is never observed in lamina II. Finally, because a characteristic of myelinated fibers is their high content in neurofilament protein heavy subunit (NF-H), we used NF-H-LacZ transgenic mice to verify that MAP1B-P induction and central sprouting were not affected by perturbing the axonal organization of neurofilaments. We conclude that MAP1B-P is well suited as a rapidly expressed, axon-intrinsic marker associated with plasticity of myelinated fibers.     

Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes

Tumors of glial origin such as glioblastoma multiforme (GBM) comprise the majority of human brain tumors. Patients with GBM have a very poor survival rate, with an average life expectancy of <1 year. We asked whether we could identify a survival pathway in high-grade glioma and oligodendroglioma cells that when suppressed, would induce apoptosis of these tumor cells but not of normal human adult astrocytes. To identify these pathways, we selectively suppressed the activity of a number of proteins (Ras, Rac1, Akt1, RhoA, c-jun, and MEK1/2) hypothesized to play roles in cell survival. We found that suppression of Rac1, a small GTP-binding protein, inhibited survival and produced apoptosis in three human glioma cell lines (U87, U343, and U373). Serum induced the activity of Rac1 and the activity or phosphorylation state of p21-activated kinase 1 and c-Jun NH(2)-terminal kinase (JNK), two intracellular targets of Rac1. Suppression of Rac1 also induced apoptosis in 19 of 21 short-term cultures of human primary cells from grades II and III oligodendroglioma and grade IV glioblastoma that varied in p53, epidermal growth factor receptor, epidermal growth factor receptor vIII, MDM2, and p16/p19 mutational or amplification status. In contrast, inhibition of Rac1 activity did not induce apoptosis of normal primary human adult astrocytes. In both established glioma cell lines and primary glioma cells, apoptosis induced by the inhibition of Rac was partially rescued by activated mitogen-activated protein kinase kinase 1, an activator of JNK, suggesting that JNK functions downstream of Rac1 in glioma cells. These results indicate that Rac1 regulates a major survival pathway in most glioma cells, and that suppression of Rac1 activity stimulates the death of virtually all glioma cells, regardless of their mutational status. Agents that suppress Rac1 activity may therefore be useful therapeutic treatments for malignant gliomas.     

Use of an Amplatzer ductal occluder to close a persistent left superior caval vein which reopened after a total cavopulmonary anastomosis

A 7-year-old boy developed increasing cyanosis after a total cavopulmonary connection with a 3 mm fenestration in the baffle. Catheterisation performed 4 years and 7 months after the operation showed reopening of a left superior caval vein draining into the pulmonary venous atrium. Due to the large size of the left superior caval vein, and the absence of intrinsic stenosis, we chose to use an Amplatzer ductal device to occlude the reopened vein. The procedure was safe and successful.     

Impact of an infection control program in an intensive care unit in France.

OBJECTIVE: To evaluate the impact of an infection control program in an intensive care unit (ICU). DESIGN: Prospective before-after study. Two 6-month study periods were compared; between these periods, an infection control program based on isolation was implemented. SETTING: Polyvalent ICU of Montpellier Teaching Hospital.Patients. Any patient who was hospitalized in the ICU for >48 hours and was discharged during 1 of the 2 periods. MAIN OUTCOME MEASURES: The main patient-related variables were sex, age at admission, type of patient (surgical, medical, or trauma), Simplified Acute Physiology Score II, length of ICU stay, need for intubation, duration of exposure to invasive devices, onset of nosocomial infection and pathogens responsible, and death. We compared the 2 study periods with respect to the incidence of 4 nosocomial infections (pneumonia, urinary tract infection, bacteremia, and catheter-associated infection), the frequency of infection with the main multidrug-resistant pathogens, and patient survival. RESULTS: Patients in periods 1 and 2 were similar with regard to sex, age, physiology score, and exposure to invasive devices. The rates of infection with multidrug-resistant pathogens were significantly lower during period 2 than during period 1 (infection rate: 28.1% of patients in period 1 and 9.6% of patients in period 2 [P = .01]; pneumonia rate: 32.6% of patients in period 1 and 4.2% of patients in period 2 [P = .008]). The mortality rate among patients with nosocomial pneumonia was 38.2% in period 1 and 4.3% in period 2 (P = .009). CONCLUSIONS: After implementation of an infection control program, the rate of infection with multidrug-resistant pathogens decreased, as did the mortality rate among patients with nosocomial pneumonia.     

PET "reversed mismatch pattern" early after acute myocardial infarction: follow-up of flow, metabolism and function

The aim of this study was to evaluate changes of flow, metabolism and left ventricular function in patients revealing a "reversed mismatch" pattern (reduced glucose uptake relative to perfusion) on positron emission tomography (PET) early after myocardial infarction. In 19 out of 68 patients (28%), prospectively included in the GUSTO-I or STAR studies, a PET reversed mismatch pattern in the infarct-related region was found. All patients received thrombolytic therapy within 3 h after onset of pain and coronary angiography 90 min later. 2-[¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG)/nitrogen-13-labelled ammonia (¹³NH₃) PET was performed after 5 days and 3 months. In 12 of the 19 patients, functional recovery was investigated with two-dimensional echocardiography at the same time points. In the infarct-related region, normalized ¹³NH₃ uptake was 76%ᆟ% at 5 days and 85%ᆞ% at 3 months (P<0.00001). Absolute blood flow in this region was 75ᆭ ml/min per 100 g at 5 days and 80ᆧ ml/min per 100 g at 3 months. At 5 days, normalized ¹⁸F-FDG uptake in the infarct-related region was decreased (51%ᆠ%). At 3 months, ¹⁸F-FDG uptake in this region had significantly recovered (75%ᆟ%, P<0.00001). In the infarct-related region, absolute FDG metabolism was 17Lj µmol/min per 100 g at 5 days and 26Nj µmol/min per 100 g at 3 months (P<0.0001). At 5 days, normalized ¹⁸F-FDG uptake was more severely decreased as compared to the normalized ¹³NH₃ uptake (P<0.00001) in the infarct-related region, resulting in a reversed mismatch pattern (25%ᆡ% of the left ventricle). At 3 months, ¹⁸F-FDG metabolism had partially recovered, giving rise to a change into a PET match pattern. Reversed mismatch regions were present in only 7%lj% of the left ventricle at that time. The ratio of ¹⁸F-FDG uptake to ¹³NH₃ uptake in the infarct-related region increased from 0.67ǂ.8 at 5 days to 0.88ǂ.09 at 3 months (P<0.00001). No functional recovery was observed in the infarct-related region (the 5-day and 3-month wall motion scores were both 2.5ǂ.5). In patients with a myocardial infarction showing a PET reversed mismatch pattern 5 days after thrombolytic therapy, recovery of ¹⁸F-FDG uptake was found but no functional recovery was observed at 3-month follow-up.     

Effects of a new slow release formulation of caffeine on EEG,psychomotor and cognitive functions in sleep-deprived subjects

Caffeine is a widely-consumed psychoactive substance whose stimulant effects on mood, attention and performance are largely recognised. The central nervous system pharmacodynamic profile of a single oral dose of a new slow release (SR) caffeine formulation (600 mg) was assessed in a randomised, double-blind, crossover, placebo-controlled study. Twelve young, health, male, sleep-deprived (for 36 h) subjects were studied using EEG and various measures of psychomotor and cognitive functions, including critical flicker fusion (CFF), choice reaction task (CRT), tracking, continuous performance task (CPT), Stroop test, body sway and subjective evaluation (Stanford Sleepiness Scale). Caffeine significantly ( < 0/05) antagonised the detrimental effects of sleep-deprivation on EEG (i.e. produced a significant decrease in delta and theta relative power and a significant increase in alpha and beta (12-40 Hz) relative power) and psychomotor performance (significant increase in speed of reaction on the CRT and Stroop tests, significant decrease in body sway, significant increase in accuracy of the CPT and significant reduction in subjective sedation) compared to placebo. The effect peaked 4 h after dosing and was maintained until the end of sleep deprivation (i.e. 24 h after dosing). In conclusion, the present results demonstrate that a single dose of caffeine SR possesses alerting effects which are able to reverse the deleterious effect of 36 h sleep deprivation for at least 24 h. Copyright 2000 John Wiley & Sons, Ltd.     

Antitumor effect of docetaxel against human endometrial tumor cell lines

The antitumor effect of docetaxel against human endometrial tumor cell lines was investigated in vitro and in vivo. In the in vitro study,docetaxel showed concentration-dependent inhibition of the growth of 4 tumor cell lines having different degrees of differentiation (AN3 CA, KLE, HEC-1-A and HEC-1-B), with IC(50) values ranging from 2.48 to 82.40 ng/ml. These values represent ca. 1/900-1/30 of the mean maximum plasma concentration of 2.27 microg/ml attained when the recommended dose of 70 mg/m(2) for patients with endometrial cancer was administered to patients with various types of cancer in phase I trial. In addition, the activity was nearly equal to paclitaxel, and much more potent than fluorouracil, cisplatin and doxorubicin. Docetaxel also showed strong antitumor activity against xenografts of the AN3 CA human endometrial adenocarcinoma cell line in nude mice. In the docetaxel treated group at its MTD (33 mg/kg/dose, q 6 d x 3, iv), all of the animals were tumor-free survivors on Day 62 after xenografting. The antitumor effect in the MTD-administered group was the strongest of all of the tested anticancer drug groups (cyclophosphamide, mitomycin C, fluorouracil, cisplatin, doxorubicin). Even at two docetaxel dosages below its MTD (20.5 and 12.5 mg/kg/day), the drug showed a marked cytotoxic activity. These results demonstrated that docetaxel shows potent antitumor efficacy against human endometrial tumor cell lines, leading to the expectation that it will be useful as a therapeutic agent for endometrial cancer.     

Recent data on lobular neoplasia of the breast: the pathologist's opinion

Lobular neoplasia is the new WHO terminology that encompasses the so-called lobular carcinoma in situ and atypical lobular hyperplasia. Besides the classical forms, particular variants have been described, which are mammographically detectable with distinct histologic patterns and behaviour. These variants are characterized by pleomorphic cells, necrosis with calcifications and may be associated to an invasive lobular carcinoma. Their clinical issue looks more like a preinvasive lesion than a marker of increased risk. Thus, their identification on biopsy requires a surgical reexcision. Hybrid forms, sharing a mixed lobular and ductal morphology and phenotype, have also been mentionned. Despite a lack of prognostic evaluation, it seems logical to recommend a subsequent surgical investigation when they are observed. Classical forms are usually managed by simple follow-up, although this attitude does not make a consensus among pathologists. Lobular neoplasia are not all indolent lesions and belong to an heterogeneous group that percutaneous guided biopsies have emphasized. They should be managed in a pluridisciplinar way and correctly diagnosed on percutaneous biopsies as well as surgical specimens.     

Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the processes of extracellular matrix degradation. Changes in their expression levels have been observed in various tumor types, including lung carcinoma. However, their clinical significance and their prognostic importance in the progression of nonsmall cell lung carcinoma (NSCLC) remain to be specified. In this study, mRNA expression levels of MMP-1, MMP-9, TIMP-1, and TIMP-2 were evaluated in patients with resected NSCLC, and their associations with disease progression and prognosis were determined. METHODS: Between June 1996 and December 1999, 116 patients underwent resection for NSCLC. Expression levels of MMPs and TIMPs were evaluated using Northern blot analysis in these NSCLC tissue samples and in 39 matched samples of normal lung tissue. RESULTS: MMP-1, MMP-9, and TIMP-1 expression levels were increased in tumor samples compared with matched, corresponding normal tissues. In contrast, TIMP-2 expression was decreased in tumor samples. MMP-1 tumor expression was correlated significantly with the evolution of lymph node status and tumor-lymph node-metastasis (TNM) stage. In contrast, MMP-9 tumor expression was correlated significantly with increased T stage. TIMP-1 overexpression was an independent predictor of worse survival in patients with NSCLC that was not associated with other prognosis factors, such as TNM stage. CONCLUSIONS: The overexpression of TIMP-1 was an independent prognostic marker in patients with NSCLC, and evaluating TIMP-1 may be important for identifying patients who are at greater risk of disease recurrence.     

The link between molecules produced by the adipose tissue, obesity and atherothrombosis

Obesity is associated with increased risk of cardiovascular morbidity. Biologically active molecules produced by adipose tissue constitute a critical link between obesity and cardiovascular complications. Adipose tissue has recently been recognized to be an important endocrine organ that controls energy metabolism. It also secretes adipocytokines, which can modify vascular responses, and antifibrinolytics, including plasminogen activator inhibitor 1, which favors fibrin accumulation, and proinflammatory cytokines, which facilitate the inflammatory response. Here we review new advances in our understanding of the mechanisms linking the endocrine activity of adipose tissue to vascular risk.