Redimune NF Liquid, a ready-to-use, high-concentration intravenous immunoglobulin therapy preparation, is safe and typically well tolerated in the routine clinical management of a broad range of conditions.

In clinical practice, intravenous immunoglobulin therapy (IVIG) is used in the management of a wide variety of medical conditions. Observational studies examining IVIG use in routine clinical practice are therefore an important means of validating findings from more strictly randomized controlled trials of patients with specific conditions. In this observational study, we examined the tolerability of a high-concentration (12%) ready-to-use liquid IVIG (Redimune NF Liquid) when used in the standard management of a diverse range of conditions (including primary immunodeficiency diseases, neurology conditions, oncology conditions and immune thrombocytopaenic purpura). IVIG regimen and dose were selected by the physician based on the summary of product characteristics. During the study, 193 infusions were administered to 51 patients in 153 infusion cycles (per infusion cycle: one to five infusions; mean dose, 347.6 mg/kg; mean duration, 202.4 min). The mean maximum infusion rate per cycle was 2.9 mg/kg/min, demonstrating that the infusion rate was often higher than that recommended in the summary of product characteristics. Redimune NF Liquid was well tolerated: there were 36 adverse reactions (at least probably associated with IVIG) in 10 patients (19.6% of sample, 0.24 per infusion cycle, 0.19 per infusion). The most common adverse reaction was headache (50% of reactions), followed by chills (13.8%). Most reactions (69%) were mild and there were no serious or unexpected reactions. In conclusion, in routine clinical practice involving patients with many different conditions, Redimune NF Liquid was well tolerated by the majority of patients.

Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver.

Coffee consumption has been associated with a significant decrease in the risk of developing chronic diseases such as Parkinson disease, diabetes type-2 and several types of cancers (e.g. colon, liver). In the present study, a coffee-dependent induction of enzymes involved in xenobiotic detoxification processes was observed in rat liver and primary hepatocytes. In addition, coffee was found to induce the mRNA and protein expression of enzymes involved in cellular antioxidant defenses. These inductions were correlated with the activation of the Nrf2 transcription factor as shown using an ARE-reporter luciferase assay. The induction of detoxifying enzymes GSTs and AKR is compatible with a protection against both genotoxicity and cytotoxicity of aflatoxin B1 (AFB1). This hypothesis was confirmed in in vitro and ex vivo test systems, where coffee reduced both AFB1-DNA and protein adducts. Interestingly, coffee was also found to inhibit cytochrome CYP1A1/2, indicating that other mechanisms different from a stimulation of detoxification may also play a significant role in the chemoprotective effects of coffee. Further investigations in either human liver cell line and primary hepatocytes indicated that the chemoprotective effects of coffee against AFB1 genotoxicity are likely to be of relevance for humans. These data strongly suggest that coffee may protect against the adverse effects of AFB1. In addition, the coffee-mediated stimulation of the Nrf2-ARE pathway resulting in increased endogenous defense mechanisms against electrophilic but also oxidative insults further support that coffee may be associated with a protection against various types of chemical stresses.

MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at a dose causing a significant incidence of renal carcinoma.

Kidney samples of male Fischer 344 (F-344) rats fed a carcinogenic dose of OTA over 7 days, 21 days and 12 months were analysed for various cell signalling proteins known to be potentially involved in chemical carcinogenicity. OTA was found to increase the phosphorylation of atypical-PKC. This was correlated with a selective downstream activation of the MAP-kinase extracellular regulated kinases isoforms 1 and 2 (ERK1/2) and of their substrates ELK1/2 and p90RSK. Moreover, analysis of effectors acting upstream of PKC indicated a possible mobilisation of the insulin-like growth factor-1 receptor (lGFr) and phosphoinositide-dependent kinase-1 (PDK1) system. An increased histone deacetylase (HDAC) enzymatic activity associated with enhanced HDAC3 protein expression was also observed. These findings are potentially relevant with respect to the understanding of OTA nephrocarcinogenicity. HDAC-induced gene silencing has previously been shown to play a role in tumour development. Furthermore, PKC and the MEK-ERK MAP-kinase pathways are known to play important roles in cell proliferation, cell survival, anti-apoptotic activity and renal cancer development.

Chemical characterization of element 112.

The heaviest elements to have been chemically characterized are seaborgium (element 106), bohrium (element 107) and hassium (element 108). All three behave according to their respective positions in groups 6, 7 and 8 of the periodic table, which arranges elements according to their outermost electrons and hence their chemical properties. However, the chemical characterization results are not trivial: relativistic effects on the electronic structure of the heaviest elements can strongly influence chemical properties. The next heavy element targeted for chemical characterization is element 112; its closed-shell electronic structure with a filled outer s orbital suggests that it may be particularly susceptible to strong deviations from the chemical property trends expected within group 12. Indeed, first experiments concluded that element 112 does not behave like its lighter homologue mercury. However, the production and identification methods used cast doubt on the validity of this result. Here we report a more reliable chemical characterization of element 112, involving the production of two atoms of (283)112 through the alpha decay of the short-lived (287)114 (which itself forms in the nuclear fusion reaction of 48Ca with 242Pu) and the adsorption of the two atoms on a gold surface. By directly comparing the adsorption characteristics of (283)112 to that of mercury and the noble gas radon, we find that element 112 is very volatile and, unlike radon, reveals a metallic interaction with the gold surface. These adsorption characteristics establish element 112 as a typical element of group 12, and its successful production unambiguously establishes the approach to the island of stability of superheavy elements through 48Ca-induced nuclear fusion reactions with actinides.

A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat.

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4alpha may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicity.

Treatment of hairy cell leukemia with cladribine (2-chlorodeoxyadenosine) by subcutaneous bolus injection: a phase II study.

BACKGROUND: To assess the activity and toxicity of 2-chlorodeoxyadenosine (cladribine, CDA) given by subcutaneous bolus injections to patients with hairy cell leukemia (HCL). PATIENTS AND METHODS: Sixty-two eligible patients with classic or prolymphocytic HCL (33 non-pretreated patients, 15 patients with relapse after previous treatment, and 14 patients with progressive disease during a treatment other than CDA) were treated with CDA 0.14 mg/kg/day by subcutaneous bolus injections for five consecutive days. Response status was repeatedly assessed according to the Consensus Resolution criteria. RESULTS: Complete and partial remissions were seen in 47 (76%) and 13 (21%) patients, respectively, for a response rate of 97%. All responses were achieved with a single treatment course. Most responses occurred early (i.e. within 10 weeks) after start of CDA therapy, but response quality improved during weeks and even months after treatment completion. The median time to treatment failure for all patients was 38 months. Leukopenia was the main toxicity. Granulocyte nadir (median 0.2 x 10(9)/l) was strongly associated with the incidence of infections (P = 0.0013). Non-specific lymphopenia occurred early after CDA treatment, and normal lymphocytes recovered slowly over several months. No significant associations were found between infections and nadir count of lymphocytes or any lymphocyte subpopulation. No opportunistic infections were observed. CONCLUSIONS: One course of CDA given by subcutaneous bolus injections is very effective in HCL. The subcutaneous administration is more convenient for patients and care providers, and has a similar toxicity profile to continuous intravenous infusion. The subcutaneous administration of CDA is a substantial improvement and should be offered to every patient with HCL requiring treatment with CDA.

Chemical investigation of hassium (element 108).

The periodic table provides a classification of the chemical properties of the elements. But for the heaviest elements, the transactinides, this role of the periodic table reaches its limits because increasingly strong relativistic effects on the valence electron shells can induce deviations from known trends in chemical properties. In the case of the first two transactinides, elements 104 and 105, relativistic effects do indeed influence their chemical properties, whereas elements 106 and 107 both behave as expected from their position within the periodic table. Here we report the chemical separation and characterization of only seven detected atoms of element 108 (hassium, Hs), which were generated as isotopes (269)Hs (refs 8, 9) and (270)Hs (ref. 10) in the fusion reaction between (26)Mg and (248)Cm. The hassium atoms are immediately oxidized to a highly volatile oxide, presumably HsO(4), for which we determine an enthalpy of adsorption on our detector surface that is comparable to the adsorption enthalpy determined under identical conditions for the osmium oxide OsO(4). These results provide evidence that the chemical properties of hassium and its lighter homologue osmium are similar, thus confirming that hassium exhibits properties as expected from its position in group 8 of the periodic table.

Chemical characterization of bohrium (element 107)

The arrangement of the chemical elements in the periodic table highlights resemblances in chemical properties, which reflect the elements' electronic structure. For the heaviest elements, however, deviations in the periodicity of chemical properties are expected: electrons in orbitals with a high probability density near the nucleus are accelerated by the large nuclear charges to relativistic velocities, which increase their binding energies and cause orbital contraction. This leads to more efficient screening of the nuclear charge and corresponding destabilization of the outer d and f orbitals: it is these changes that can give rise to unexpected chemical properties. The synthesis of increasingly heavy elements, now including that of elements 114, 116 and 118, allows the investigation of this effect, provided sufficiently long-lived isotopes for chemical characterization are available. In the case of elements 104 and 105, for example, relativistic effects interrupt characteristic trends in the chemical properties of the elements constituting the corresponding columns of the periodic table, whereas element 106 behaves in accordance with the expected periodicity. Here we report the chemical separation and characterization of six atoms of element 107 (bohrium, Bh), in the form of its oxychloride. We find that this compound is less volatile than the oxychlorides of the lighter elements of group VII, thus confirming relativistic calculations that predict the behaviour of bohrium, like that of element 106, to coincide with that expected on the basis of its position in the periodic table.

Utility and complications of permanent venous access devices (PVAD) in oncological treatments. Follow-up of 100 cases.

BACKGROUND: Permanent venous access devices (PVAD) are nowadays routinely implanted and used with some morbidity for the oncological treatments. The adequate timing of implantation based on the number of treatments, the survival rate and the complications has not yet been well estimated. METHODS: A hundred permanent venous access devices placed in oncological patients were followed-up prospectively. RESULTS: No mortality was seen due to the surgical act. A 11% morbidity rate was noted, largely due to infections, with 6 patients needing a second surgery. On average, 6 chemotherapy cycles were done after placing of the permanent venous access device. CONCLUSIONS: Due to these results and an average survival rate of 10.7 months, we suggest the placing of a permanent venous access device early in the management of oncological patients requiring chemotherapy cycles, so as to increase the comfort of the patient and to safeguard his peripheral venous system.

In vivo local determination of tissue optical properties: applications to human brain.

Local and superficial near-infrared (NIR) optical-property characterization of turbid biological tissues can be achieved by measurement of spatially resolved diffuse reflectance at small source-detector separations (<1.4 mm). However, in these conditions the inverse problem, i.e., calculation of localized absorption and the reduced scattering coefficients, is necessarily sensitive to the scattering phase function. This effect can be minimized if a new parameter of the phase function gamma, which depends on the first and the second moments of the phase function, is known. If gamma is unknown, an estimation of this parameter can be obtained by the measurement, but the uncertainty of the absorption coefficient is increased. A spatially resolved reflectance probe employing multiple detector fibers (0.3-1.4 mm from the source) is described. Monte Carlo simulations are used to determine gamma, the reduced scattering and absorption coefficients from reflectance data. Probe performance is assessed by measurements on phantoms, the optical properties of which were measured by other techniques [frequency domain photon migration (FDPM) and spatially resolved transmittance]. Our results show that changes in the absorption coefficient, the reduced scattering coefficient, and gamma can be measured to within +/-0.005 mm(-1), +/-0.05 mm(-1), and +/-0.2, respectively. In vivo measurements performed intraoperatively on a human skull and brain are reported for four NIR wavelengths (674, 811, 849, 956 nm) when the spatially resolved probe and FDPM are used. The spatially resolved probe shows optimum measurement sensitivity in the measurement volume immediately beneath the probe (typically 1 mm(3) in tissues), whereas FDPM typically samples larger regions of tissues. Optical-property values for human skull, white matter, scar tissue, optic nerve, and tumors are reported that show distinct absorption and scattering differences between structures and a dependence on the phase-function parameter gamma.

[Post-mortem evaluation following oncologic treatment of the functional and bacteriologic status of 25 permanent venous access devices]. / Evaluation post-mortem après traitement oncologique de l'état fonctionnel et bactériologique de 25 accès veineux permanents.

Permanent venous access devices allow long-term parenteral treatment under relatively safe and comfortable conditions. Nevertheless, this use is associated with some degree of (particularly infectious) morbidity. 25 permanent access devices were removed surgically in immediate autopsies and cultured. Some half were infected, with a clear prevalence (40%) for Staphylococcus coagulase negative. The results were related to clinical history and compared with the figures and conclusions of other studies. It is proposed that in certain situations cultures of native blood should be carried out more frequently through the permanent venous access, with a view to possible specific targeted antibiotic therapy associated with the heparinized lock.

[A rare complication of permanent venous access: constriction, fracture and embolization of the catheter]. / Une complication rare des accès veineux permanents: laminage, fracture et embolisation du catheter.

The pinch off syndrome due to squeezing of the implanted catheter is a rare complication of permanent venous access devices (0.1 to 1% of the cases). The cause is a mechanical catheter's compression in the costo-clavicular space, when implanted too medially in the subclavian vein. In case of lack of venous reflux or injection difficulties, sometimes complicated by local pain, a radiological control must be obtained to demonstrate signs of compression or beginning of fracture. Significant damage to the system is shown be extravasation of radioopaque contrast medium. The suspicion of catheter damage justifies early replacement of the system to avoid right heart or pulmonary artery embolism. The electron microscopic scanning tends to prove that the catheter's rupture is caused by a fatigue process.

Recombinant human granulocyte-macrophage colony-stimulating factor in acquired or chemotherapy-induced neutropenia. An open clinical trial.

This prospective open trial evaluated the efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients with established neutropenia, considering as the main endpoint the clinical benefit to the patients regarding clearing of infection or resuming chemotherapy as initially planed. Adult patients (n = 28) with absolute neutrophil counts (ANC) < 10(9)/1 for 21 days were given a fixed dose (400 micrograms) of rhGM-CSF subcutaneously, for a total of 35 cycles. Causes of neutropenia were chemotherapy for acute leukaemia, lymphoma, myeloma and solid tumours, complications after bone marrow transplantation (BMT), and neutropenia associated with AIDS. Response (ANC to > 10(9)/l) occurred in 83% of rhGM-CSF cycles (29/35). Median time to response was 2.4 days (mean 6.7 days). Kinetics of response was dependent on diagnosis and treatment history. Fever abated with increasing ANC in 13/17 patients (76%) who entered the trial with hyperpyrexia. Treatment with rhGM-CSF allowed chemotherapy to be resumed on schedule in 7/9 relevant cycles. Toxicity was mild, leading to treatment interruption in only two cycles. In conclusion, rhGM-CSF was well tolerated and associated with a rise in ANC which appeared to result in immediate clinical benefit, including resolution of infection and resumption of scheduled chemotherapy.

[Secondary polycythemias: the role of erythropoietin]. / Polyglobulies secondaires: le rôle de l'érythropoïétine.

The discovery of high hemoglobin and hematocrit values in a patient necessitates the determination of the red blood cell mass in order to confirm the absolute character of the polycythemia. If a true polycythemia is confirmed, its etiology must then be established. The diagnostic approach of polycythemia is presented in this paper. It is illustrated by a case presentation in which a polycythemia secondary to a renal carcinoma is discussed. Erythrocytosis is a classical, albeit rare manifestation of this type of tumor, and has the advantage of allowing early detection. Thus, it permits a prompt treatment plan, thereby improving the prognosis of such a neoplasia. The usefulness of a serum level of erythropoietin (EPO) is subsequently discussed. The diagnostic value of EPO remains controversial because of the overlapping values recorded amongst healthy patients, patients with polycythemia vera and others with secondary polycythemia. Finally, we discuss the presence of substances in paraneoplastic polycythemias whose biological activity is close to that of EPO. However, this molecules of a different structure would not be detected by the radioimmunoassay used to measure erythropoietin level.

[Schizophrenia and language disorders]. / Schizophrénie et troubles du langage.

The speech of schizophrenics is idiosyncratic, possibly unrelated to thought disorders. Review of relevant literature indicates that schizophrenic speech disorders include: errors in the use of pronouns, articles, verbs and verb tenses, which are neither pointed out or corrected; absence of redundancy, skewering of the meaning of words, faulty establishment of common references with others. Sentences appear disjointed due to improvised vocabulary and the scant use of conjunctions and other linking words or phrases. Speech is slow, trite, and fails to convey information proportionate to speech production. Discourse is self-centered and the needs of others are ignored. In general, schizophrenic speech performance worsens the more ambiguous, intimate or complex the topic.

Histopathology of myelodysplastic syndromes. The FAB classification (proposals) applied to bone marrow biopsy.

Twenty-eight cases of myelodysplastic syndrome (MDS) were reviewed to evaluate whether the morphologic criteria proposed by the French-American-British (FAB) Cooperative Group for marrow smears could be applied to glycol methacrylate embedded trephine biopsies. Bone marrow biopsies and marrow smears were examined separately and then compared for the following parameters: percentage of blasts, dyserythropoiesis, ring sideroblasts, dysmegakaryopoiesis, dysgranulopoiesis, monocytes, cellularity, fibrosis, and "abnormal localization of immature precursors". The results of the histologic (biopsies) and cytologic (marrow smears) examinations were in good agreement in 24 of 28 cases. The authors' results suggest that the five MDS types proposed by the FAB group can be reliably distinguished on bone marrow biopsy with knowledge of the peripheral blood blast and monocyte counts. When the bone marrow aspiration is inadequate, the biopsy can establish diagnosis and type of MDS and rules out aplasia or tumor infiltration as possible alternative causes of cytopenia.

[Retrospective study of 30 cases of myelodysplastic syndrome according to the French-American-British classification]. / Etude rétrospective de 30 cas de syndromes myélodysplasiques selon la classification FAB.

The bone marrow smears and marrow biopsies of 30 unselected consecutive patients with a myelodysplastic syndrome have been classified retrospectively according to the proposals of the French-American-British cooperative group (FAB). The diagnoses according to the FAB classification were refractory anemia (RA) in 3, RA with ring sideroblasts (RAS) in 5, RA with excess of blasts (RAEB) in 14, REAB in transformation (RAEB-t) in 5, and chronic myelomonocytic leukemia (CMML) in 3. The group comprised 19 men and 11 women with a median age of 68 years. Of 22 patients, 9 died after progression to acute non lymphoblastic leukemia (ANLL), 7 from infections, 2 from bleeding and 4 from unrelated causes. Actuarial survival is 10.5 months, 8 patients being at risk at the time of evaluation. Although the small number of patients does not allow statistical evaluation, our results are similar to those in the literature: prognosis is less good with an increasing number of marrow blasts and degree of cytopenia, and the risk of progression to ANLL is higher for REAB-t and REAB patients. Of 4 patients treated with small doses of cytosine-arabinoside (Ara-C), one responded and remained stable without treatment for 7 months. 2 patients resistant to small-dose Ara-C showed complete response to subsequent high-dose Ara-C treatment.

Ring chromosomes and hematologic disorders.

Based on 5 years of cytogenetic evaluation in hematology, we report our observations on various hematologic proliferative disorders with ring chromosomes. Comparing our data to those previously published in the literature we analyzed the occurrence of the ring in relation to the age of onset, previous history of therapeutic or professional exposure to mutagenic agents, and mean survival. It is concluded that the presence of ring chromosomes may be linked to a poor prognosis.