Assessing a system to capture stray aerosol during inhalation of nebulized liposomal cisplatin.

The aim of this study was to determine the efficacy of using a high-efficiency particulate air (HEPA) filter air cleaning system, a demistifier, to reduce the potential risk of fugitive aerosol contact in health care personnel working with patients inhaling nebulized liposomal encapsulated SLIT (Sustained-release Lipid Inhalation Targeting) Cisplatin. Filters were used to sample platinum in the air outside the tent and from the tent's exhaust stream. Air collection was performed under three conditions: (1) during patient dosing (14 h of air collection); (2) immediately after the patient has left the demistifier tent (4 h of air collection); and (3) when 7 mL of drug product was nebulized to dryness in the tent without a patient being present. Filters were collected, and placed in an extraction solvent. Subsequently, the solvent was assayed for platinum content by inductively coupled plasma-mass spectrometry (ICP-MS). Platinum levels in the extraction solvent were indistinguishable from the blank controls for all conditions. Measured levels were below workplace exposure limits established for cisplatin by the Occupational Safety and Health Administration (i.e., 2 ng . (L(1)). In addition, the demistifier was able to effectively capture aerosolized SLIT Cisplatin following nebulization of 7 mL of drug product to dryness in the tent. The demistifier tent is effective at containing any nebulized liposomal encapsulated cisplatin during patient treatment. Importantly, because the tent's HEPA filtration system is effective at removing any nebulized liposomal cisplatin, the exhausted air, which is free of platinum, can be returned into the room with no additional ventilation precautions.     

Lateral parabrachial lesions disrupt paraoxon-induced conditioned flavor avoidance.

Preliminary clinical evidence obtained in Gulf War veterans and patients suffering multiple chemical sensitivity points to the existence of a potential link between environmental exposure to organosphosphates (OPs) and the emergence of unspecific sickness syndromes in which associative Pavlovian conditioning might be partly involved. A laboratory animal model might be a useful tool for analyzing the involvement of conditioning in sickness syndromes potentially linked to OP poisoning. The first objective in the present study was to determine if paraoxon (PX), the neuroactive metabolite of the OP parathion, elicits a conditioned avoidance response to a novel stimulus (a taste-odor compound) in a conditioned flavor aversion procedure. Data obtained in Experiment 1 show conditioned flavor avoidance, demonstrative of the associative nature of the sickness properties of PX. The second objective was to characterize the nature of the specific physiological cue serving as the unconditioned stimulus in PX-induced conditioned avoidance. Despite PX administration did induce cholinergic hyperactivity, as measured by body hypothermia and increased jaw movements, lesions of the lateral parabrachial area (lPB) disrupted PX-elicited flavor avoidance responses, indicating that cholinergic signs were not sufficient as unconditioned stimuli supporting avoidance responses. Given that lPB neural integrity is necessary to process aversive interoceptive information, disruption of conditioned flavor avoidance as a result of lPB lesions is consistent with a central interruption of interoceptive processing in PX-poisoned animals. Data are discussed under the light of the hypothesis claiming the importance of associative processes and noncholinesterase targets in sickness syndromes potentially induced by OP exposure.     

Temperature related mortality and ambulance service interventions during the heat waves of 2003 in Ticino (Switzerland)

Objectives  

This study investigates a potential increase in mortality and in the demand for ambulance emergency services among the elderly in particular, in Ticino in the summer of 2003.     

Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling

In order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.     

Malleus-to-footplate ossicular reconstruction prosthesis positioning: cochleovestibular pressure optimization.

AIMS: To determine 1) the best position for hydroxylapatite malleus-to-footplate (MFP), ossicular replacement prosthesis (ORP) in reconstructed ears, and 2) whether preserving the stapes superstructure (SS), when present, has acoustic advantages. BACKGROUND: Positioning of the MFP-ORP head beneath the neck of the malleus may produce maximal force, whereas positioning beneath the manubrium of the malleus may produce the greatest displacement. It is not clear which is the optimal placement position. In addition, we look at the effect of the SS on sound transmission to the inner ear in ossicular reconstruction. METHODS: The ear-canal air pressure and vestibular hydro-pressure were measured in human cadaver temporal bones with incus intact, removed, and replaced with the MFP-ORP; the ORP head was placed at three different positions on the malleus (head, mid-manubrium, and umbo) while keeping its base at the center of stapes footplate with intact or removed stapes SS. The vestibular pressure ratio between the ear with intact incus and MFP-ORP reconstructed ear is defined as Lmfp, the loss caused by the prosthesis in relation to the normal ossicular chain. RESULTS: The mean magnitude of Lmfp, averaged in the important speech frequency region of 0.5 to 3 kHz, is approximately 7.8 dB at the neck with stapes SS. In comparison, mean magnitude of Lmfp for mid-manubrium without stapes SS is 15 dB (p = 0.04), and with the stapes SS it is 16 dB (p = 0.05), whereas at the umbo without SS it is 15 dB (p = 0.03). In the 8 kHz region, the mean magnitude of Lmfp is approximately 1 dB with the stapes SS intact and approximately 8.5 dB when it was removed (p < 0.09). CONCLUSION: There are significant physiologic advantages to placing the hydroxylapatite MFP-ORP beneath the neck of the malleus and preserving the SS.     

玻璃体内注射曲安奈德治疗视网膜中央静脉阻塞引起的黄斑水肿

目的：探讨玻璃体内注射丙酮化曲安奈德用于治疗视网膜中央静脉阻塞（CRVO）引起黄斑水肿的安全性和有效性。方法：在Wisconsin大学和Bascom Palmer眼科研究所．对13例（13只眼）连续的CRVO引起黄斑水肿的患者应用玻璃体内注射丙酮化曲安奈德（4mg）治疗．回顾研究其病历记录。每次玻璃体内注射时应用27G或30G针头通过睫状体平坦部注射。主要结果测量：Snellen视力的变化、黄斑水肿的临床表现、应用光学相干断层扫描仪（OCT）测量中心凹的增厚以及并发症的出现频率。结果：13例患者的平均年龄为67岁（四分位数间距为57—77岁）．注射前症状的平均持续时间为8个月（四分位数间距为4—9个月）。患眼在初诊时的平均视力为20／500．在6个月随诊检查时的平均视力为20／1踟。所有13例患者都完成了6个月的随诊检查。非缺血型CRVO患眼（n=5）的视力有显著的提高．而缺血型CRVO患眼（n=8）没有显著的视力提高。患者没有出现视力下降。初诊时OCT测量的平均中心凹厚度为590μm（视网膜增厚=416μm）。12例患者在1个月随诊检查时OCT测量的平均中心凹厚度为212pm（视网膜增厚=38μm）。13例患者在3个月随诊检查时OCT测量的平均中心凹厚度为193μm（视网膜增厚=19μm）。在3和6个月随诊检查之间．4例患者的黄斑水肿复发．其中3例患者再次接受了曲安奈德的注射。这3例患者中的2例经过再次治疗视力提高。在6个月随诊检查时．13例患者OCT测量的平均中心凹厚度为281μm（视网膜增厚=107μm）。没有发生视网膜脱离或眼内炎等并发症。1例患者出现了眼压的升高．应用2种房水生成抑制剂治疗得以控制。结论：在部分CRVO引起黄斑水肿的患者中．玻璃体内注射曲安奈德可能是一种有效的治疗方法。与缺血型CRVO患者相比．非缺血型CRVO患者可以获得更令人满意的效果。部分患者可能需要重复治疗。在本组患者中未发现严重的并发症。     

Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences.

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.     

Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS-II Nutrition Cohort.

Paraoxonase 1 (PON1) plays an important role in the high-density lipoprotein-mediated prevention of low-density lipoprotein oxidation and the metabolism of lipid-soluble radicals. In this study, we investigated the association of two common, nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M) with breast cancer risk in postmenopausal women through a nested case-control study within the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Using conditional logistic regression of genotyping results from 502 cases and 502 cancer-free controls matched on age, race/ethnicity, and date of blood draw, we found that the L55M single nucleotide polymorphism (SNP) was associated with an increased risk of breast cancer [odds ratio (OR), 1.58; 95% confidence interval (95% CI), 1.05-2.37 for MM]. No association was found for the Q192R SNP. The L55M association with breast cancer was modified by nonsteroidal anti-inflammatory drug (NSAID) use. The association was limited to women who took NSAIDs and was somewhat stronger among women who reported regular (> or = 15 times per month) NSAID use (OR, 3.24; 95% CI, 1.17-9.00) than in those who reported any NSAID use (OR, 2.46; 95% CI, 1.39-4.36). These results suggest that genetic variation in PON1, particularly at the L55M SNP, may be associated with increased risk of breast cancer in postmenopausal women. Furthermore, NSAID use seems to modify this risk.     

Cutaneous metastases of lung cancer

It is uncommon for a cancer to be diagnosed because of skin metastases. Cutaneous metastases as initial manifestation of internal neoplasias, represent only 0.8% of total cases and implies, in general, a very advanced grade of the disease and short survival. When skin metastases of an unknown primary site appear, lung cancer is the first option to be discarded in case of men, and breast cancer in case of women. Lung cancer spreads to the skin in 2.8–8.7% of the cases, in advanced phases of the disease, although just in 7–23.8% of the cases, cutaneous metastases appear as first manifestation of the primary tumor. Sometimes, a complete examination to discover the tumor reveals no metastases elsewhere.