Senescence in Alveolar Epithelial Type II Cells Promotes Acute Lung Injury and Impairs Regeneration.

Mortality of acute lung injury (ALI) increases with age. Alveolar epithelial type 2 cells (AEII) are the progenitor cells of the alveolar epithelium and crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII senescence in ALI, young (3 months) and old (18 months) Sftpc-Ai9 mice and young Sftpc-Ai9-Trf1 mice with inducible Trf1 knockout-mediated senescence in AEII were treated with 1 µg lipopolysaccharide (LPS)/g BW (n=9-11). Control mice received saline (n=7). Mice were sacrificed 4 or 7 days later. Lung mechanics, pulmonary inflammation and proteomes were analyzed and parenchymal injury, AEII proliferation and AEI differentiation rate were quantified using stereology. Old mice showed 55% mortality by day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by day 7, while Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII was only measured in young Sftpc-Ai9 mice at day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII in Sftpc-Ai9-Trf1 mice also affected de-novo differentiation after injury. In conclusion, telomere dysfunction-mediated AEII senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. While Differentiation rate remained functional with old age and AEII senescence, AEII proliferative capacity was impaired in ALI, affecting the regenerative ability.

Proton density fat fraction of the spinal column: an MRI cadaver study.

BACKGROUND: The increased popularity of minimally invasive spinal surgery calls for a revision of guidance techniques to prevent injuries of nearby neural and vascular structures. Lipid content has previously been proposed as a distinguishing criterion for different bone tissues to provide guidance along the interface of cancellous and cortical bone. This study aims to investigate how fat is distributed throughout the spinal column to confirm or refute the suitability of lipid content for guidance purposes. RESULTS: Proton density fat fraction (PDFF) was assessed over all vertebral levels for six human cadavers between 53 and 92 years of age, based on fat and water MR images. According to their distance to the vertebra contour, the data points were grouped in five regions of interest (ROIs): cortical bone (-1 mm to 0 mm), pre-cortical zone (PCZ) 1-3 (0-1 mm; 1-2 mm; 2-3 mm), and cancellous bone ([Formula: see text] 3 mm). For PCZ1 vs. PCZ2, a significant difference in mean PDFF of between -7.59 pp and -4.39 pp on average was found. For cortical bone vs. PCZ1, a significant difference in mean PDFF of between -27.09 pp and -18.96 pp on average was found. CONCLUSION: A relationship between distance from the cortical bone boundary and lipid content could be established, paving the way for guidance techniques based on fat fraction detection for spinal surgery.

Simple and complex rule induction performance in young and older adults: contribution of episodic memory and working memory.

This study tested the hypothesis that part of the age-related decline in performance on executive function tasks is due to a decline in episodic memory. For this, we developed a rule induction task in which we manipulated the involvement of episodic memory and executive control processes; age effects and neuropsychological predictors of task performance were investigated. Twenty-six younger (mean age, 24.0; range, 19-35 years) and 27 community-dwelling older adults (mean age, 67.5; range, 50-91 years) participated. The neuropsychological predictors consisted of the performance on tests of episodic memory, working memory, switching, inhibition and flexibility. Performance of the older adults was worse for the learning and memorization of simple rules, as well as for the more demanding executive control condition requiring the manipulation of informational content. Episodic memory was the only predictor of performance on the simple learning and memorization task condition whereas an increase in rule induction complexity additionally engaged working memory processes. Together, these findings indicate that part of the age-related decline on rule induction tests may be the result of a decline in episodic memory. Further studies are needed that examine the role of episodic memory in other executive function tasks in aging.

Fiber-Optic Pedicle Probes to Advance Spine Surgery through Diffuse Reflectance Spectroscopy.

Diffuse Reflectance Spectroscopy (DRS) can provide tissue feedback for pedicle screw placement in spine surgery, yet the integration of fiber optics into the tip of the pedicle probe, a device used to pierce through bone, is challenging, since the optical probing depth and signal-to-noise ratio (SNR) are affected negatively compared to those of a blunt DRS probe. Through Monte Carlo simulations and optical phantom experiments, we show how differences in the shape of the instrument tip influence the acquired spectrum. Our findings demonstrate that a single bevel with an angle of 30∘ offers a solution to anticipate cortical breaches during pedicle screw placement. Compared to a blunt probe, the optical probing depth and SNR of a cone tip are reduced by 50%. The single bevel tip excels with 75% of the optical probing depth and a SNR remaining at approximately ⅔, facilitating the construction of a surgical instrument with integrated DRS.

Optical Methods for Brain Tumor Detection: A Systematic Review.

Background: In brain tumor surgery, maximal tumor resection is typically desired. This is complicated by infiltrative tumor cells which cannot be visually distinguished from healthy brain tissue. Optical methods are an emerging field that can potentially revolutionize brain tumor surgery through intraoperative differentiation between healthy and tumor tissues. Methods: This study aimed to systematically explore and summarize the existing literature on the use of Raman Spectroscopy (RS), Hyperspectral Imaging (HSI), Optical Coherence Tomography (OCT), and Diffuse Reflectance Spectroscopy (DRS) for brain tumor detection. MEDLINE, Embase, and Web of Science were searched for studies evaluating the accuracy of these systems for brain tumor detection. Outcome measures included accuracy, sensitivity, and specificity. Results: In total, 44 studies were included, covering a range of tumor types and technologies. Accuracy metrics in the studies ranged between 54 and 100% for RS, 69 and 99% for HSI, 82 and 99% for OCT, and 42 and 100% for DRS. Conclusions: This review provides insightful evidence on the use of optical methods in distinguishing tumor from healthy brain tissue.

Diffuse reflectance spectroscopy of the spine: improved breach detection with angulated fibers.

Accuracy in spinal fusion varies greatly depending on the experience of the physician. Real-time tissue feedback with diffuse reflectance spectroscopy has been shown to provide cortical breach detection using a conventional probe with two parallel fibers. In this study, Monte Carlo simulations and optical phantom experiments were conducted to investigate how angulation of the emitting fiber affects the probed volume to allow for the detection of acute breaches. Difference in intensity magnitude between cancellous and cortical spectra increased with the fiber angle, suggesting that outward angulated fibers are beneficial in acute breach scenarios. Proximity to the cortical bone could be detected best with fibers angulated at θ f = 45 ∘ for impending breaches between θ p = 0 ∘ and θ p = 45 ∘ . An orthopedic surgical device comprising a third fiber perpendicular to the device axis could thus cover the full impending breach range from θ p = 0 ∘ to θ p = 90 ∘ .

Steering light in fiber-optic medical devices: a patent review.

INTRODUCTION: Steering light is relevant to many medical applications that require tissue illumination, sensing, or modification. To control the propagation direction of light beams, a great variety of innovative fiber-optic medical devices have been designed. AREAS COVERED: This review provides a comprehensive overview of the patent literature on light beam control in fiber-optic medical devices. The Web of Science Derwent Innovation Index database was scanned, and 81 patents on fiber-optic devices published in the last 20 years (2001-2021) were retrieved and categorized based on the working principle to steer light (refraction/reflection, scattering, diffraction) and the design strategy that was employed (within fiber, at fiber end, outside fiber). EXPERT OPINION: Patents describing medical devices were found for all categories, except for generating diffraction at the fiber end surface. The insight in the different designs reveals that there are still several opportunities to design innovative devices that can collect light at an angle off-axis, reduce the angular distribution of light, or split light into multiple beams.

Advances in Imaging of Subbasal Corneal Nerves With Micro-Optical Coherence Tomography.

Purpose: To investigate the most peripheral corneal nerve plexus using high-resolution micro-optical coherence tomography (µOCT) imaging and to assess µOCT's clinical potential as a screening tool for corneal and systemic diseases. Methods: An experimental high-resolution (1.5 × 1.5 × 1 µm) µOCT setup was applied for three-dimensional imaging of the subbasal nerve plexus in nonhuman primates (NHPs) and swine within 3 hours postmortem. Morphologic features of subbasal nerves in µOCT were compared to ß3 tubulin-stained fluorescence confocal microscopy (FCM). Parameters such as nerve density, nerve distribution, and imaging repeatability were evaluated, using semiautomatic image analysis in form of a custom corneal surface segmentation algorithm and NeuronJ. Results: Swine and NHP corneas showed the species-specific nerve morphology in both imaging modalities. Most fibers showed a linear course, forming a highly parallel pattern, converging in a vortex with overall nerve densities varying between 9.51 and 24.24 mm/mm2. The repeatability of nerve density quantification of the µOCT scans as approximately 88% in multiple image recordings of the same cornea. Conclusions: Compared to the current gold standard of FCM, µOCT's larger field of view of currently 1 × 1 mm increases the conclusiveness of density measurements, which, coupled with µOCT's feature of not requiring direct contact, shows promise for future clinical application. The nerve density quantification may be relevant for screening for systemic disease (e.g., peripheral neuropathy). Translational Relevance: Technological advances in OCT technology may enable a quick assessment of corneal nerve density, which could be valuable evaluating ophthalmic and systemic peripheral innervation.

Micro-optical coherence tomography for high-resolution morphologic imaging of cellular and nerval corneal micro-structures.

We demonstrate the highest resolution (1.5×1.5×1 µm) micrometer optical coherence tomography (µOCT) imaging of the morphologic micro-structure of excised swine and non-human primate corneas. Besides epithelial, stromal, and endothelial cell morphology, this report focuses on investigating the most peripheral corneal nerve fibers, the nerve fibers of the subbasal plexus (SBP). Alterations of SBP nerve density and composition are reportedly linked to major neurologic disorders, such as diabetic neuropathy, potentially indicating earliest onsets of denervation. Here, the fine, hyperreflective, epithelial nerve structures located just above Bowman's membrane, are i) visualized using our µOCT prototype, ii) validated by comparison to fluorescence confocal microscopy (including selective immunohistochemical staining), and iii) segmented using state-of-the-art image processing. Here, we also introduce polarization sensitive (PS) µOCT imaging, demonstrating, to the best of our knowledge, the highest resolution corneal PS-OCT scans reported to date.

Corneal Stromal Filler Injection as a Novel Approach to Correct Presbyopia-An Ex Vivo Pilot Study.

Purpose: To evaluate the ex vivo feasibility of corneal stromal filler injection to create bifocality to correct presbyopia by flattening the central posterior corneal surface and thus increase refractive power. Methods: Femtosecond laser-assisted corneal stromal pockets of varying diameters close to the posterior corneal curvature were cut into rabbit eyes ex vivo. Subsequently, hyaluronic acid was injected to flatten the central posterior curvature. Refractive parameters were determined using perioperatively acquired three-dimensional optical coherence tomography (OCT) scans. Using micrometer-resolution OCT, corneal endothelial cell morphology and density were evaluated. Results: Following filler injection into the corneal stromal pockets, a fair volume-dependent increase of central refractive power up to 4 diopters (dpt) was observed. Unremarkable refractive changes of the peripheral posterior (3 mm, 0.20 ± 0.11 dpt; 2 mm, 0.11 ± 0.10 dpt) and the anterior corneal curvature (3 mm, 0.20 ± 0.34 dpt; 2 mm, 0.33 ± 0.31 dpt) occurred. Only negligible changes in astigmatism were observed. Different sizes of optical zones could be established. Furthermore, no alterations of corneal endothelial morphology or endothelial cell density (2831 ± 356 cells/mm2 vs. 2734 ± 292 cells/mm2; P = 0.552) due to the adjacent laser treatment were observed. Conclusions: The ex vivo investigations proved the principle of injecting a filler material into femtosecond laser-created corneal stromal pockets close to the posterior corneal curvature as an efficacious, individually adjustable, and novel approach to correct presbyopia without ablating corneal tissue. Translational Relevance: Due to the aging population worldwide, presbyopia is an increasing problem; thus, our study may encourage further exploration to extend the treatment spectrum of clinically used femtosecond laser systems to correct presbyopia.

[Arterial-hypertension prevalence in the general population of Martinique]. / Prévalence de l'hypertension artérielle en population générale à la Martinique.

BACKGROUND: Since 1996, arterial hypertension has been recognized as one of the main health priorities in Martinique. However, its prevalence in the general population has never been measured. Furthermore, obesity is increasing in many countries and studies have shown that hypertension is more frequent in obese people than in people with normal body mass index. The objective of this survey is to measure hypertension prevalence in the general population and to study the link between hypertension, weight status and socioeconomic level. METHODS: Cross-sectional study of randomly selected homes in randomly selected geographical islets. All household members in these homes constituted the eligible population. Arterial hypertension was defined as systolic pressure greater than 140mmHg and/or diastolic pressure greater than 90mmHg and/or antihypertensive treatment. Weight status was estimated using the body mass index. RESULTS: Study concerned 1504 persons aged 16 years or older with a sex-ratio of 0.7 and an average age of 48.3 years for men and 48.5 years for women, p=0.88. The prevalence rate of hypertension is 29% [IC(95%): 25.9-31.8] in the sample and declines to 22.5% [IC(95%): 20.1-25.1] using weighted data. The prevalence rate is 33.1% [IC(95%): 30.2-36.6] for overweight and 20.1% [IC(95%): 17.8-22.6] for obesity. Being overweight is more frequent among persons with hypertension than among ones with normal blood pressure, 73.0 versus 47.4%; p<0.001. In those with hypertension, overweight does not differ significantly between men and women, but the prevalence of obesity is greater among women than among men (35.7 versus 20.6 %, p<0.05). CONCLUSION: The high prevalence of both hypertension and obesity in the general Martinican population has been confirmed by this study. Prevention actions are required to decrease the cardiovascular risk in this population.

Knowledge, attitudes and practices of pregnant women in Martinique in the immediate aftermath of the Zika virus outbreak.

INTRODUCTION: The WHO and the HCSP recognize the Zika virus as a public health problem of international concern primarily because of the foetal risks. During the epidemic in Martinique, several modifications to the normal obstetrical follow-up were set up and information had to be delivered to pregnant women about these modifications, the attitudes to prevent infection and the signs motivating additional visits. The objective of our work was to evaluate the knowledge, attitudes and practices of pregnant women in Martinique about the risks associated with Zika infection during pregnancy in the immediate aftermath of the epidemic. MATERIALS AND METHODS: A descriptive cross-sectional survey was conducted from February to May 2017. It took place through an anonymous and standardized face-to-face questionnaire. The questions dealt with the pregnant women general knowledge about the virus, information disseminated by media on this subject, the potential risks, the protective measures taken and the monitoring throughout the pregnancy in case of infection. RESULTS: The total sample consisted of 297 pregnant women. Despite a weak adherence to individual and domestic protection recommendations, we found a good level of knowledge about Zika virus from pregnant women in Martinique. The fetal risk in case of maternal infection was known for 96.6% of those surveyed, individual protective measures were followed by 64.6% of women, 77.0% knew where to go in case of suspected infection, and 79.4% reported that the modifications in follow-up mainly concerned ultrasound monitoring. CONCLUSION: The awareness campaign on zika virus had a significant impact on population's knowledge and main practical information was correctly captured. The information did not spill excessive fear. Nevertheless, modification of individual behavior appeared harder to obtain.

Enzyme immunoassay of estrogen receptors in fine needle aspirates of breast tumors.

Enzyme immunoassay of estrogen receptors (ER-EIA) was compared to radioligand assay (ER-RLA) in fine needle aspirates of breast tumors. Fine needle aspiration is a relatively atraumatic means of harvesting malignant cells from breast tumors. Fine needle aspiration provides a homogeneous suspension (about 90% malignant cells) with a sufficient amount of cellular material (10 to 50 micrograms DNA per sample) for single point radioligand assays of extractable estrogen (ER) and/or progesterone receptor (PR) in about 85% of primary adenocarcinomas at the time of diagnosis. Sixty-one different samples of malignant mammary cells were obtained by fine needle aspiration from 43 adenocarcinomas, 11 metastatic axillary nodes or 7 cutaneous nodules. Thirteen patients were under antiestrogen therapy (tamoxifen). ER-EIA was performed with Abbott's reagents, following the manufacturer's protocol. ER-RLA was a single saturation (5 nM) dextran-charcoal assay with [3H]R2858 as the labeled estrogen. The sensitivity of ER-EIA allowed dilution of the sample up to 10 times (according to sample cellularity and ER level) with less than 20% deviation from undiluted samples. Three levels of dilution of the samples (1/1, 1/2, and 1/10) allowed them to fall at least once into the range of the ER-EIA standard curve. Quantitative correlation between ER-EIA and ER-RLA was high (r = 0.86), and highest (r = 0.97) when samples from patients undergoing tamoxifen treatment were excluded. Major discrepancies between ER-EIA and ER-RLA appeared in those patients undergoing tamoxifen therapy; much higher values were obtained by ER-EIA. Eight of 13 of these patients were ER negative by ER-RLA but ER positive by ER-EIA. This preliminary observation indicates that in vivo ER modulation by hormones and antihormones should be reevaluated.

Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors.

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.

Functional evidence for a role of vascular chymase in the production of angiotensin II in isolated human arteries.

BACKGROUND: In human arteries, angiotensin-converting enzyme (ACE) inhibitors incompletely block the production of angiotensin (Ang) II from Ang I. This ACE-independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase. However, several serine proteases may produce Ang II, and the exact role of chymase in the vascular production of Ang II has never been directly evaluated using selective chymase inhibitors. METHODS AND RESULTS: Rings of human mammary arteries were subjected to either Ang I or the chymase-selective substrate [pro,(11) D-Ala(12)] Ang I in the absence or the presence of the ACE inhibitor captopril, the serine protease inhibitor chymostatin, or the selective chymase inhibitor C41. Captopril only partially inhibited (by 33%) the response to Ang I. In the absence of captopril, C41 markedly reduced (by 44%) the response to Ang I, and this effect was identical to that of chymostatin. C41 also significantly reduced the response to Ang I in the presence of captopril, although this inhibitory effect was slightly less than that of captopril in combination with chymostatin. [Pro,(11)D-Ala(12)] Ang I induced potent contractions that were not affected by captopril but were abolished by chymostatin and markedly reduced by C41. In addition, we found that prior treatment of the patients with an ACE inhibitor did not affect the in vitro response to Ang I (in the absence or the presence of captopril) or to [Pro,(11)D-Ala(12)] Ang I. CONCLUSIONS: Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACE-independent production of Ang II in human arteries.

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer.

PURPOSE: A phase I/II trial of vinorelbine (VRL) administered by continuous infusion (CIV) was conducted in advanced breast carcinoma (ABC) patients to determine the maximum-tolerated dose (MTD) and to evaluate the toxicity pattern and antitumor activity of this alternative administration schedule to the currently recommended weekly short intravenous (IV) administration. PATIENTS AND METHODS: Between February 1990 and July 1991, 64 consecutive, eligible patients with ABC were treated; 33 had received one or two previous palliative chemotherapy combinations and 31 had not received chemotherapy for metastatic disease. VRL was administered, after an initial IV bolus of 8 mg/m2 on day 1, by a 4-day CIV at five different 24-hour dose levels (DLs) to be repeated every 21 or 28 days: DL1, 5.5 mg/m2; DL2, 7 mg/m2; DL3, 8 mg/m2, DL4, 9 mg/m2; and DL5, 10 mg/m2. RESULTS: The limiting noncumulative toxicity was neutropenia, with the MTD established at 8 mg/m2 bolus plus 10 mg/m2/d for 4 days (total dose per cycle, 48 mg/m2). At DL3 and DL4, we observed mucositis (14% of patients; five percent of cycles > grade 2), alopecia, and asthenia. By contrast, neurotoxicity was minor. The toxicity was otherwise predictable and manageable. Pharmacokinetic data obtained at DL1 and DL3 showed a mean VRL plasma concentration of 967 +/- 331 ng/mL after the initial 8 mg/m2 IV bolus dose, which declined rapidly thereafter to reach mean steady-state levels of 12 ng/mL (n = 5) for the 30-mg/m2 dose and 8 ng/mL (n = 2) for the 40-mg/m2 dose. These levels were maintained over the 96-hour CIV. The mean residence time (MRT) was 29 +/- 7 hours (terminal half-life [t1/2], 23 hours), the total-body clearance (CL) was 24 +/- 11 L/hr/m2, and the volume of distribution at steady-state (Vss) was high at 1,832 +/- 359 L/m2. Two patients achieved a complete response (CR) and 21 a partial response (PR), for an objective response rate of 36% (95% confidence interval [Cl], 23 to 49). The median duration of response was 6 months. The median survival duration was 24 months (range, 3 to 37). A relationship between given dose-intensity and objective response rate was found, with an overall response (OR) rate of 13.3% (two of 15) for 8 to 10 mg/m2/wk, 35.4% (11 of 31) for 10 to 12 mg/m2/wk, and 55.5% (10 of 18) for 12 to 14.5 mg/m2/wk. CONCLUSION: This trial, while confirming VRL activity in ABC, shows the feasability of a CIV administration schedule. A decrease of the administrated total dose per 3- to 4-week cycle to less than the weekly schedule with the same therapeutic activity suggests a better therapeutic index. The data are also suggestive of a dose-response relationship and a dose-intensity/activity correlation.

Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. European Organization for Research and Treatment of Cancer Gastrointestinal Treat Cancer Cooperative Group.

PURPOSE: To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma. PATIENTS AND METHODS: Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion. RESULTS: Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1). CONCLUSION: These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.

Visual phenotype of multiple sclerosis in the Afro-Caribbean population and the influence of migration to metropolitan France.

PURPOSE: To describe the visual phenotype of multiple sclerosis (MS) in the Afro-Caribbean population living in Martinique (French West Indies) and to specify the influence of the migration to metropolitan France on ocular impairment. DESIGN: Prospective consecutive observational case series. METHODS: A complete ophthalmologic examination was performed. PARTICIPANTS: A total of 112 patients of Afro-Caribbean origin with MS satisfying McDonald's diagnostic criteria, divided into 53 cases (47.3%), the non-migrant patients (group NM), who had never left the Caribbean basin, and 59 cases (52.7%), the migrant patients (group M), who had lived in metropolitan France for at least 1 year before age 15. RESULTS: MS first manifested as an impairment of the optic nerve in 41 cases (36.6%): 25 cases (47.1%) in group NM and 16 cases (27.1%) in group M. Visual function was recovered in 13/25 cases (52%) in group NM compared to 13/16 cases (81%) in group M. Two-thirds of patients presented with a clinical ocular impairment, which was bilateral in 58.5% of cases in group NM. Fourteen cases (12.5%) met the criteria of neuromyelitis optica, nine cases (17%) in group NM and five cases (8.5%) in group M. In group NM, when the initial visual attack did not regress, the visual Expanded Disability Status Scale (EDSS) score was 5+/-1.5 ; 75% of patients had monocular blindness and 50% binocular. CONCLUSIONS: In the non-migrants (group NM), MS manifested more frequently with an optical neuropathy, the ocular impairment was more severe, and corresponded to neuromyelitis optica in 17% of the cases; a visual presentation and the absence of complete recovery from the first attack represented a factor of poor prognosis. This series is the largest description of the visual phenotype of MS in patients of African origin. The results confirm the preferential impairment of the optic nerve in the black population in the course of the disease. The migration towards an area of high prevalence of MS influences the visual phenotype in terms of a lower incidence and less severe prognosis of ocular impairment.

The p53-positive phenotype of breast cancers.

One hundred and eighty-one breast cancer specimens were analyzed for nuclear p53 staining by immunochemical methods. There were 123 fine-needle cytological specimens and 58 frozen tissue sections of surgical biopsies. The microscopic evaluation of the staining fitted with a 4 group classification. Ninety-one samples (50.6%) were devoid of any staining (-), while 42 (23.3%) showed only few stained nuclei (+/-), typically around 1%. Thirty-two (17.8%) samples presented with strong nuclear staining (++) which in practically all cases concerned more than 50% of the nuclei, but a few cases showed staining heterogeneity. A further 17 cases (9.4%) presented with nuclear staining which concerned 10-20% of the cancer cells (+). This four class system was used to compare p53 expression with other prognostic parameters. A strong inverse correlation was observed with steroid hormone receptor content and p53 positivity was highly significantly associated with higher S-phase. All but one of the highly positive cases were aneuploid. Twenty-five percent (29/120) of the aneuploid tumors were strongly stained and a further 10% were considered positive (+). On the other hand, only 5 out of 59 DNA-diploid tumors were considered as + and one ++. The DNA index distribution according to p53 positivity showed peaks of positivity for hypodiploid, triploid and hypertetraploid values. Negative tumors were in all regards similar to those with only few stained nuclei, in particular mean S-phases of 2.8 and 3.3% respectively. Altogether, the typical strong p53 phenotype concerned a DNA-aneuploid tumor with above median S-phase fraction (mean of 7.1%), negative steroid hormone receptors and cytoprognostic index III. The p53 positive cases (+), were frequently steroid hormone receptor positive and had on the average intermediate S-phase fractions (4.3%). The proportion of immunochemical positivity (27% in our series), is compatible with the published frequency of p53 mutations detected in breast cancers, but the differences in the phenotype according to the level of positivity should be further investigated.

The complementary roles of surface-immunoglobulin clonality and fluorescence intensity, mouse rosettes, and cd5 in the diagnosis of B-chronic lymphocytic-leukemia.

Peripheral blood from 77 cases of B-CLL was analyzed to evaluate the diagnostic value of SIg clonality and fluorescence intensity, mouse rosettes (MR), and CD5. Monoclonal SIg (L-chain restriction or H-chain restriction or both) was detected in 69 cases (89.61%), with weak fluorescence (mean channel number on flow cytometry <200) in 65 (94.2%); MR was positive in 66 (85.71%); CD5 positive in 64 (83.12%). The association of SIg intensity, MR, and CD5 was as follows: weak SIg/MR+/CD5+, 41 cases (53.25%); weak SIg/MR+/CD5-, 13 (16.88%); weak SIg/MR-/CD5+, 11 (14.29%); strong SIg/MR+/CD5+, 4 (5.19%); and undetected SIg/MR+/CD5+, 8 (10.39%). Thus, by performing the three markers and accepting either two or three positive results (weak SIg, MR+, CD5+) as sufficient for diagnosis, all 77 cases (100%) were diagnosed. The study demonstrated the complementary roles between L- and H- chains, and between SIg intensity, MR, and CD5 in immunophenotyping CLL.