The all-glass Lüer syringe: Historical facts around concepts, introduction and patents.

More than 125 years have elapsed since the "Maison Lüer" in Paris produced their quintessential all-glass hypodermic syringe. The product would subsequently conquer the medical world, with billions of plastic syringes produced on a yearly basis nowadays. One wonders how a world would look without this priceless diagnostic and therapeutic tool, facilitating the administration of drugs, fluids, and blood products to billions of patients worldwide. The Lüer syringe dates to 1894, when Parisian medical instrument maker Hermann Wülfing-Lüer manufactured a unique graduated all-glass hypodermic syringe. Its conical tip allowed accurate injections with rapid leak-free connections, and was heat-resistant without breaking while autoclaving at 120 °C. The authors of this article rectified several inaccuracies of historical facts, and obtained copies of original patents, documents and syringes to reveal accurate details regarding the originators of the all-glass syringes. The Lüer fittings are simple devices that connect virtually all syringes, needles and tubing. They are used in medicine and beyond, whether it is a Lüer-Slip or a Lüer-Lok™ (Lüer-Lock) version. In 1995, The International Organization of Standardization recommended the standard use of the Lüer-tipped syringe worldwide. Despite this, their popularity has sustained significant setbacks at times, including when reports were published on misconnections and wrong-route administration of drugs, resulting in harm to patients with sometimes fatal outcomes. Healthcare workers mistakenly connected devices with a specific use to other devices used for a different application. Current syringes are now mostly mass-produced, disposable plastic syringes, which still come with Lüer fittings for intravascular and hypodermic needles, whereas specific non-Lüer connectors are designed for other systems.

A CZT-based blood counter for quantitative molecular imaging.

BACKGROUND: Robust quantitative analysis in positron emission tomography (PET) and in single-photon emission computed tomography (SPECT) typically requires the time-activity curve as an input function for the pharmacokinetic modeling of tracer uptake. For this purpose, a new automated tool for the determination of blood activity as a function of time is presented. The device, compact enough to be used on the patient bed, relies on a peristaltic pump for continuous blood withdrawal at user-defined rates. Gamma detection is based on a 20 × 20 × 15 mm3 cadmium zinc telluride (CZT) detector, read by custom-made electronics and a field-programmable gate array-based signal processing unit. A graphical user interface (GUI) allows users to select parameters and easily perform acquisitions. RESULTS: This paper presents the overall design of the device as well as the results related to the detector performance in terms of stability, sensitivity and energy resolution. Results from a patient study are also reported. The device achieved a sensitivity of 7.1 cps/(kBq/mL) and a minimum detectable activity of 2.5 kBq/ml for 18F. The gamma counter also demonstrated an excellent stability with a deviation in count rates inferior to 0.05% over 6 h. An energy resolution of 8% was achieved at 662 keV. CONCLUSIONS: The patient study was conclusive and demonstrated that the compact gamma blood counter developed has the sensitivity and the stability required to conduct quantitative molecular imaging studies in PET and SPECT.

Economic Impact of Gene Expression Profiling in Patients with Early-Stage Breast Cancer in France.

BACKGROUND AND AIMS: The heterogeneous nature of breast cancer can make decisions on adjuvant chemotherapy following surgical resection challenging. Oncotype DX is a validated gene expression profiling test that predicts the likelihood of adjuvant chemotherapy benefit in early-stage breast cancer. The aim of this study is to determine the costs of chemotherapy in private hospitals in France, and evaluate the cost-effectiveness of Oncotype DX from national insurance and societal perspectives. METHODS: A multicenter study was conducted in seven French private hospitals, capturing retrospective data from 106 patient files. Cost estimates were used in conjunction with a published Markov model to assess the cost-effectiveness of using Oncotype DX to inform chemotherapy decision making versus standard care. Sensitivity analyses were performed. RESULTS: The cost of adjuvant chemotherapy in private hospitals was estimated at EUR 8,218 per patient from a national insurance perspective and EUR 10,305 from a societal perspective. Cost-effectiveness analysis indicated that introducing Oncotype DX improved life expectancy (+0.18 years) and quality-adjusted life expectancy (+0.17 QALYs) versus standard care. Oncotype DX was found cost-effective from a national insurance perspective (EUR 2,134 per QALY gained) and cost saving from a societal perspective versus standard care. Inclusion of lost productivity costs in the modeling analysis meant that costs for eligible patients undergoing Oncotype DX testing were on average EUR 602 lower than costs for those receiving standard care. CONCLUSIONS: As Oncotype DX was found both cost and life-saving from a societal perspective, the test was considered to be dominant to standard care. However, the delay in coverage has the potential to erode the quality of the French healthcare system, thus depriving patients of technologies that could improve clinical outcomes and allow healthcare professionals to better allocate hospital resources to improve the standard of care for all patients.

Can treatment with Cocculine improve the control of chemotherapy-induced emesis in early breast cancer patients? A randomized, multi-centered, double-blind, placebo-controlled Phase III trial.

BACKGROUND: Chemotherapy induced nausea and vomiting (CINV) remains a major problem that seriously impairs the quality of life (QoL) in cancer patients receiving chemotherapy regimens. Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. A randomized, placebo-controlled Phase III study was conducted to evaluate the efficacy of a complex homeopathic medicine, Cocculine, in the control of CINV in non-metastatic breast cancer patients treated by standard chemotherapy regimens. METHODS: Chemotherapy-naïve patients with non-metastatic breast cancer scheduled to receive 6 cycles of chemotherapy including at least three initial cycles of FAC 50, FEC 100 or TAC were randomized to receive standard anti-emetic treatment plus either a complex homeopathic remedy (Cocculine, registered in France for treatment of nausea and travel sickness) or the matching placebo (NCT00409071 clinicaltrials.gov). The primary endpoint was nausea score measured after the 1st chemotherapy course using the FLIE questionnaire (Functional Living Index for Emesis) with 5-day recall. Secondary endpoints were: vomiting measured by the FLIE score, nausea and vomiting measured by patient self-evaluation (EVA) and investigator recording (NCI-CTC AE V3.0) and treatment compliance. RESULTS: From September 2005 to January 2008, 431 patients were randomized: 214 to Cocculine (C) and 217 to placebo (P). Patient characteristics were well-balanced between the 2 arms. Overall, compliance to study treatments was excellent and similar between the 2 arms. A total of 205 patients (50.9%; 103 patients in the placebo and 102 in the homeopathy arms) had nausea FLIE scores > 6 indicative of no impact of nausea on quality of life during the 1st chemotherapy course. There was no difference between the 2 arms when primary endpoint analysis was performed by chemotherapy stratum; or in the subgroup of patients with susceptibility to nausea and vomiting before inclusion. In addition, nausea, vomiting and global emesis FLIE scores were not statistically different at any time between the two study arms. The frequencies of severe (Grade ≥ 2) nausea and vomiting were low in our study (nausea: P: 17.6% vs C: 15.7%, p=0.62; vomiting: P: 10.8% vs C: 12.0%, p=0.72 during the first course). CONCLUSION: This double-blinded, placebo-controlled, randomised Phase III study showed that adding a complex homeopathic medicine (Cocculine) to standard anti-emetic prophylaxis does not improve the control of CINV in early breast cancer patients.

[Did the Queen of Pount suffer from cutis laxa?]. / La reine de Pount souffroit-elle de Cutis Laxa?

A bas-relief of the temple of Deir el-Bahari, Luxor, Egypt, discovered in 1867 by Mariette, shows a queen (Queen of Pount) with wide cutaneous folds on arms, abdomen and legs, hyperlordosis, a steatopygia and abnormally short lower limbs. Various assumptions about the diagnosis (steatopygia, partial achondroplasia, neurofibromatosis) were proposed at the beginning of the XXth century, neither taking into account all morphological abnormalities of the queen. We propose a novel hypothesis taking into account all signs: a Cutis Laxa.

[The elderly and surgery in the Middle Ages]. / Le vieillard et la chirurgie au Moyen-Age.

Until the end of the nineteenth century, the elderly were considered to be high risk patients, on whom surgeons wishing to preserve their reputation should not operate. A study of the works of four medieval surgeons, Paul ofAegina, Henri de Mondeville, Guillaume de Salicet and Guy de Chauliac, discloses few references to the elderly. Despite risks associated with their fragile constitution and their age, it seems that such patients did at times undergo surgery. Bleeding was not used for patients over 70 years of age and dosage of drugs was also adjusted for age. Attempts to modify the signs of old age were probably an important and lucrative part of surgical activity.

Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Studies of the early steps of HCV infection have been hampered by the lack of convenient in vitro or in vivo models. Although several cell-surface molecules that mediate the binding of HCV envelope proteins to target cells have been identified, mechanisms of viral entry into human hepatocytes are still poorly understood. Vesicular stomatitis virus/HCV pseudotyped viruses expressing the HCV envelope glycoproteins on the viral envelope were generated and it was found that their entry into human hepatocytes required co-expression of E1 and E2 on the pseudotype surface. Neutralization of pseudotype infection by anti-HCV antibodies suggested that cellular entry was mediated by HCV envelope glycoproteins and by previously characterized cell-surface molecules, including CD81. An entry assay based on the release of a fluorochrome from labelled HCV pseudotypes provided evidence for a pH-dependent fusion of the pseudotype envelope with a cellular compartment. By using a panel of endocytosis inhibitors, it is postulated that penetration of HCV into primary cultures of hepatocytes takes place by clathrin-mediated endocytosis.

Early pathological changes in the central nervous system of acutely feline-immunodeficiency-virus-infected cats.

The animal model of feline immunodeficiency virus (FIV) infection of cats was used to dissect the pathogenic role of microglia within the first 6 months of infection. Applying real-time PCR, microglia-associated FIV replication was first detectable at 14 days past inoculation (dpi) and remained at elevated levels throughout the whole observation period. In contrast, FIV RNA levels within paired serum samples declined again after an initial peak between 14 dpi and 28 dpi. Concomitant with the onset of viral reproduction, microglia transiently upregulated expression of MHC class I and class II molecules. Virus-induced microglial activation was followed by a mild infiltration of peripheral leukocytes into the CNS parenchyma. The presented data suggest that microglia is infected by FIV very early after peripheral entry of the virus. Virus replicating microglia withstands eradication by brain-infiltrating leukocytes resulting in formation of a brain-resident virus reservoir, which probably cannot be cleared by peripheral chemotherapy.

Striatal dopamine during sensorial stimulations: a [18F]FDOPA PET study in human and cats.

Sensory stimulations of the forelimb in cats are known to increase dopamine release in the ipsilateral striatum and to decrease it in the homologous contralateral structure. Using positron emission tomography in both humans and cats, the present study shows that such sensory stimulations greatly reduce [(18)F]FDOPA accumulation ipsilateral to the stimulation (by 40.4% and 26.4% in the human caudate and putamen, respectively, and by 33.3% in the cat striatum). This decrease in striatal [(18)F]FDOPA uptake suggests a reduced DA storage resulting from the increased amine release. No change was observed in the contralateral striatum in neither human or cat suggesting, in contrast, that [(18)F]FDOPA accumulation is not facilitated by decreased DA release. These results support the hypothesis that sensory stimulations activate a non-synaptic mode of dopamine release.

Ramified feline microglia selects for distinct variants of feline immunodeficiency virus during early central nervous system infection.

It is widely accepted that human immunodeficiency virus (HIV) invades the central nervous system (CNS) shortly after peripheral infection to establish a persistent infection of tissue-resident microglial cells. To what extent this early CNS infection is of pathogenic relevance is a matter of discussion. It is conceivable, however, that infected microglia releases virus variants of enhanced neurotropism and/or neurovirulence compared to peripheral isolates. Moreover, microglial variants may exhibit high resistance to antiviral therapeutics that poorly penetrate into brain tissue. The molecular basis of these biological properties is suspected to be associated with specific sequences in the viral env gene, particularly within the V3 loop. Therefore, we analyzed in the animal model of feline immunodeficiency virus (FIV) infection of cats lentiviral V3 sequences in highly purified microglial cells and blood from acutely infected animals. Compared to the inoculated virus, nucleotide sequence alterations in serum samples were rarely detectable, if at all. In contrast, up to 19 nucleotide exchanges could be identified within FIV V3 from microglia, resulting in a mutation frequency of up to 14.5% with respect to the deduced amino acid sequence. These findings suggest selection of specific virus variants by brain-resident target cells that might have implications for antiretroviral drug design.

Tissues rich in macrophagic cells are the major sites of feline immunodeficiency virus uptake after intravenous inoculation into cats.

To track the sites of feline immunodeficiency virus (FIV) clearance in cats and follow viral localization from 30 min until 48 h post-intravenous inoculation, several kinds of cells (PBMC, splenocytes, thymocytes, Kupffer cells (KC), lymph nodes, bone marrow and alveolar cells) were collected. After co-culture with uninfected PBMC, p24 antigen was detected. Reverse transcription (RT)-nested PCR and PCR were performed on all these cells and in situ RT-PCR on liver, spleen and isolated KC. Biochemical determinations showed that viral RNA was predominantly found during the first hour post-infection (p.i.) in PBMC, splenocytes and KC and later on (24-48 h) in thymocytes and lymph node cells. In addition, viral DNA was detected as early as 24 h post-inoculation in splenocytes and KC, whereas PBMC were positive at 48 h. Microscopic studies confirmed the presence of viral RNA in hepatic KC and also in the splenic red pulp rich in macrophages and dendritic cells. Our results enabled the early identification of the cell population infected and highlight the role played by macrophagic cells in the uptake of FIV and in viral dissemination.

Inhibition of tumor growth and metastatic spreading by overexpression of inter-alpha-trypsin inhibitor family chains.

The inter-alpha trypsin inhibitor (ITI) family is a group of proteins built up from different combinations of I light chain (ITI-L) and 3 highly homologous heavy chains (ITI-HI, -H2 and -H3). To investigate a potential role of the ITI family chains in cancer and metastasis spreading, we engineered human H460M cell lines expressing both the green fluorescent protein (GFP) and one of these chains. These clones were subcutaneously injected in athymic nude mice, and lung metastasis number and primary tumor weight were determined after 28 days. Expression of the ITI-L chain considerably decreased tumor weight and fluorescent lung metastasis number. ITI-HI and ITI-H3 chain expression induced a significant decrease of metastasis number, whereas no decrease of tumor weight could be detected. In vitro, ITI-L expression significantly decreased chemotaxis and ITI-HI and ITI-H3 expression increased cell attachment. These results argue for the antitumoral or antimetastatic properties of ITI-L, -HI and -H3 chains.

Feline Langerhans cells migrate from skin and vaginal mucosa to regional lymph nodes during experimental contact sensitization with fluorescein isothiocyanate.

Recently, feline Langerhans cells (LC) were immunophenotypically characterized as CD1a+, CD4+, CD18+, CD53+ and MHC II+ cells. In mice, these cells are known to internalize antigens and to migrate to the lymph nodes (LN). In the cat, we have investigated the migration of LC from the skin and vaginal mucosa to regional LN in response to chemical exposure (fluorescein isothiocyanate). Three days after the administration of a FITC solution on the posterior limb of two male cats and in the vagina of one female, a biopsy was carried out on the draining LN of the sensitized zones. Immunostaining with monoclonal antibodies anti-CD79, anti-CD8, and antibodies recognizing LC was performed on cytospins and frozen sections of LN and showed that a majority of FITC+ cells displayed a LC immunophenotype and were localized in T-cell areas, but not in follicular areas. These results are the first evidence of migration of feline LC from skin and vaginal mucosa to the regional LN.