5-fluorouracil-interferon-α 2b adjuvant treatment of Dukes C colorectal cancer

PURPOSE: To determine whether interferon-α _2b can improve results of 5-fluorouracil adjuvant treatment of Dukes C colorectal cancer patients, we compared the outcome of patients receiving a fluorouracil-interferon combination to that of historic controls treated with fluorouracil alone. METHODS: Fifty-seven Dukes C colorectal cancer patients were given 5-fluorouracil-interferon-α in2b adjuvant treatment from October 1986 to September 1990. The results were compared with those obtained in 51 consecutive patients treated at the same institutions with 5-fluorouracil (5-FU) alone (used at the same doses and schedule) between 1983 and 1986. The main prognostic variables were similar in the two groups. RESULTS: No life-threatening toxicity occurred in either group. The addition of interferon (IFN) slighlty impaired tolerance to the treatment; however, the dose of IFN had to be reduced only in five patients and discontinued in one patient. Grade 3 and 4 myelotoxicity was rare and not substantially different in the two groups. Interferon-related side effects (fever, flu-like syndrome, malaise,etc.)were frequent, but, in general, mild or moderate. At the time of this analysis (July 1992), median followup was 49 (range, 20–70) months in the group of patients treated with 5-FU + IFN, and 86 (range, 68–103) months in the group receiving 5-FU alone. There were 17 recurrences and 15 cancer-related deaths among patients receiving combined treatment, and 27 deaths in the group treated with 5-FU alone. Both five-year relapse-free survival (65 percent vs.47 percent; P=0.043) and causespecific survival (64 percent vs.46 percent; P=0.038) were significantly better in the patients receiving combined treatment. After correction for the influence of prognostic pretreatment variables, 5-FU + IFN again afforded a significant advantage in terms of both relapse-free (P<0.01) and overall survival (P<0.001). CONCLUSION: 5-FU-IFN-α _2b treatment seems to improve the prognosis in Dukes C colorectal cancer patients.     

Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity.

Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) are the three members of the neurotrophin family known to exist in mammals. Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4), which shares all of the features found in the mammalian neurotrophins, has been identified in Xenopus and viper. We used sequences specific to the Xenopus/viper NT-4 to isolate a neurotrophin from both human and rat genomic DNA that appears to represent the mammalian counterpart of Xenopus/viper NT-4. Human NT-4 as well as a human NT-4 pseudogene colocalize to chromosome 19 band q13.3. Mammalian NT-4 has many unusual features compared to the previously identified neurotrophins and is less conserved evolutionarily than the other neurotrophins. However, mammalian NT-4 displays bioactivity and trk receptor specificity similar to that of Xenopus NT-4.     

Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients

OBJECTIVE: To analyse the clinical and radiological characteristics of patients with dementia associated with the antiphospholipid syndrome (APS). METHODS: Twenty-five patients were identified by a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of dementia associated with APS published in English, Spanish and French from 1983 to 2003. Additionally, we included five patients from our clinics. RESULTS: There were 21 (70%) females and 9 (30%) males. The mean age of patients was 49+/-15 yr (range 16-79 yr). Fourteen (47%) of the patients suffered from primary APS, 9 (30%) had systemic lupus erythematosus and 7 (23%) had 'lupus-like' syndrome. Ten (33%) patients had Sneddon's syndrome and 2 (7%) had cerebral lesions described as Binswanger's disease. Other APS-related manifestations included thrombocytopenia in 12 (40%) patients, cerebrovascular accidents in 11 (37%), heart valve lesions in 8 (27%), deep vein thrombosis in 7 (28%), migraine in 7 (23%), seizures in 4 (13%); five of the 21 (24%) female patients had nine spontaneous abortions. Lupus anticoagulant was present in 21/29 (72%) patients and anticardiolipin antibodies were present in 24/29 (83%) patients. Cortical infarcts were found in 19 (63%) patients, subcortical infarcts in 9 (30%), basal ganglia infarcts in 7 (23%) and signs of cerebral atrophy in 11 (37%). Anticoagulation was used in 14/25 (56%) patients, steroids in 12/25 (48%), aspirin in 6/25 (24%) and dypiridamole in 5/25 (20%). CONCLUSIONS: Dementia is an unusual manifestation of APS but one which has a high disability impact in a patient's daily life. In order to prevent these consequences, an echocardiographic and cerebral CT or MRI evaluation are recommended in all patients with APS. Furthermore, ruling out APS should be recommended in the clinical approach to dementia, especially in young patients.     

Procoagulant microparticles are increased in patients with Behçet’s disease but do not define a specific subset of clinical manifestations

Microparticles (MP) are considered a key component in the haemostatic response. Beyond their in vitro procoagulant properties, a number of pieces of evidence points to procoagulant MP as efficient effectors in the haemostatic response and as pathogenic markers of thrombotic disorders and vascular damage. The aim of the present study was to analyze the procoagulant activity of MP and its correlation with clinical manifestations focusing on vascular involvement in patients with Behçet’s disease (BD). We analyzed 55 BD patients in inactive phase of the disease (26 men; mean age, 35?±?15 years) of which 19 had previously suffered from thrombosis (deep venous thrombosis in 17 and ischemic stroke in 2), and 73 healthy controls matched for age and sex. Procoagulant MP were assessed by a functional assay. BD patients showed higher procoagulant MP values than controls (22.89?±?15.74 nM versus 14.47?±?7.34 nM; p?<?0.0001). Conversely, we did not find differences in the levels of procoagulant MP according to the gender of patients (22.22?±?16.23 nM for men versus 21.46?±?16.47 for women; p?=?0.846) or to previous and current treatments. Moreover, the plasmatic concentration of MP does not define any clinical phenotype and it was not related to the time of evolution of the disease. Although inactive BD patients had high values of procoagulant MP, they did not differentiate between BD patients with or without thrombosis.     

Lagging strand replication of rolling-circle plasmids: Specific recognition of the ssoA-type origins in different gram-positive bacteria

Many bacterial plasmids replicate by a rolling-circle mechanism that involves the generation of single-stranded DNA (ssDNA) intermediates. Replication of the lagging strand of such plasmids initiates from their single strand origin (sso). Many different types of ssos have been identified. One group of ssos, termed ssoA, which have conserved sequence and structural features, function efficiently only in their natural hosts in vivo. To study the host specificity of sso sequences, we have analyzed the functions of two closely related ssoAs belonging to the staphylococcal plasmid pE194 and the streptococcal plasmid pLS1 in Staphylococcus aureus. The pLS1 ssoA functioned poorly in vivo in S. aureus as evidenced by accumulation of high levels of ssDNA but supported efficient replication in vitro in staphylococcal extracts. These results suggest that one or more host factors that are present in sufficient quantities in S. aureus cell-free extracts may be limiting in vivo. Mapping of the initiation points of lagging strand synthesis in vivo and in vitro showed that DNA synthesis initiates from specific sites within the pLS1 ssoA. These results demonstrate that specific initiation of replication can occur from the pLS1 ssoA in S. aureus although it plays a minimal role in lagging strand synthesis in vivo. Therefore, the poor functionality of the pLS1 in vivo in a nonnative host is caused by the low efficiency rather than a lack of specificity of the initiation process. We also have identified ssDNA promoters and mapped the primer RNAs synthesized by the S. aureus and Bacillus subtilis RNA polymerases from the pE194 and pLS1 ssoAs. The S. aureus RNA polymerase bound more efficiently to the native pE194 ssoA as compared with the pLS1 ssoA, suggesting that the strength of RNA polymerase–ssoA interaction may play a major role in the functionality of the ssoA sequences in Gram-positive bacteria.     

Synthesis,Biological Evaluation,and Molecular Simulation of Chalcones and Aurones as Selective MAO‐B Inhibitors

A series of chalcones and aurones were synthesized and evaluated in vitro as monoamine oxidase inhibitors (MAOi). Our results show that aurones, which had not been previously reported as MAOi, are MAO‐B inhibitors. Thus, both families inhibited selectively the B isoform of MAO in the micromolar range, offering novel scaffolds for the design of new and potent MAO inhibitors. The main structural requirements for their activity were characterized with the aid of 3D‐QSAR and docking studies.     

Effect of gold addition by the recharge method on silver supported catalysts in the catalytic wet air oxidation (CWAO) of phenol

Catalysts Ag/ZrO₂–CeO₂ and Au/ZrO₂–CeO₂ were synthesized by a deposition–precipitation method and Ag–Au/ZrO₂–CeO₂ was prepared using a recharge method for the second metal (Au). The materials were characterized by physisorption of N₂, XRD, ICP, UV-vis RDS, H2-TPR, XPS and TEM. The results obtained show that the specific areas for monometallic materials were 29–37 m² g⁻¹ and 27–74 m² g⁻¹ for bimetallics. The tetragonal crystal phase of ZrO₂ stabilizes when CeO₂ quantity increases. Using XPS an increment in Ce³⁺ species abundance was determined for bimetallic catalysts in contrast to the monometallic ones; according to the Ag 3d region, this metal oxidation was observed when augmenting the content of CeO₂ in the materials, and with Au the opposite effect was produced. It was determined by TEM, that the average size of the metallic particles was smaller at bimetallic catalysts due the preparation method. Catalytic activity was evaluated by CWAO of phenol, the Ag–Au/ZrO₂–CeO₂ catalyst with 20% wt of cerium reached a degradation of 100% within an hour, being the most active catalyst. Maleic, formic and oxalic acid were identified as reaction intermediates; and at the end of the reaction acetic acid was identified as the main by-product, because it is the most refractory and the conditions for oxidation must be more severe.

Addition of gold changed the properties of silver monometallic catalysts by inhibiting the low formation of intermediates and changed of reaction route by formic acid to CO₂ and water. Furthermore, the bimetallic catalyst showed in the reuse cycles the better stability in CWAO of phenol.     

Selectivity of antagonists for the Cys‐loop native receptors for ACh, 5‐HT and GABA in guinea‐pig myenteric neurons

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Improving Amphetamine Therapeutic Selectivity: N,N‐dimethyl‐MTA has Dopaminergic Effects and does not Produce Aortic Contraction

Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N‐dimethyl‐thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N‐dimethyl‐thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N‐dimethyl‐ thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N‐dimethyl‐thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects.     

Hematopoietic stem cells: to be or Notch to be

Notch is a well-conserved signaling pathway and its function in cell fate determination is crucial in embryonic development and in the maintenance of tissue homeostasis during adult life. Notch activation depends on cell-cell interactions that are essential for the generation of cell diversity from initially equivalent cell populations. In the adult hematopoiesis, Notch is undoubtedly a very efficient promoter of T-cell differentiation, and this has masked for a long time the effects of Notch on other blood lineages, which are gradually being identified. However, the adult hematopoietic stem cell (HSC) remains mostly refractory to Notch intervention in experimental systems. In contrast, Notch is essential for the generation of the HSCs, which takes place during embryonic development. This review summarizes the knowledge accumulated in recent years regarding the role of the Notch pathway in the different stages of HSC ontology from embryonic life to fetal and adult bone marrow stem cells. In addition, we briefly examine other systems where Notch regulates specific stem cell capacities, in an attempt to understand how Notch functions in stem cell biology.