Answer to “REPLY to Association between Plasmatic Oxidative Stress and Thrombosis in Primary Antiphospholipid Syndrome”

Journal of Thrombosis and Thrombolysis - Left atrial appendage (LAA), a blind pouch, accounts for more than 90% of the source of cardiac thrombus formation. Contrast retention (CR) in the LAA has...     

Synthesis and autoradiographic evaluation of a novel high-affinity Tc-99m ligand for the 5-HT2A receptor

The synthesis and in vitro autoradiography of a novel Tc-99m ligand with subnanomolar affinity to the 5-HT_2A receptor is reported. The complex combines the 4-(4-fluoro)-benzoyl piperidine portion derived from the 5-HT_2A receptor antagonist ketanserin with a neutral oxotechnetium(V) chelate in form of a mixed ligand “3+1” unit containing the SNS/S donor set. The analogous rhenium compound has been synthesized as a surrogate for the Tc-99m complex for use in receptor binding assays and for complete structural characterization. In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity toward the 5-HT_2A receptor (K_i 0.44 nM for Tc, 0.25 nM for Re). The subnanomolar 5-HT_2A receptor binding of the Re complex was confirmed by functional in vitro antagonism of contractile effects evoked by 5-HT in rat arterial tissue. Re 1 inhibited 5-HT-induced, 5-HT_2A receptor-mediated contractions of isolated rat tail artery in a competitive fashion and possessed nanomolar affinity ( pA₂=9.08, pA₂ representing the negative decadic logarithm of the Re 1/5-HT_2A-receptor dissociation constant [mol/L]). Like ketanserin, Re 1 displayed moderate affinity for adrenergic _1D ( pA₂=8.23) and histamine H₁ receptors ( pA₂=8.00), and was >600-fold up to 10,700-fold less active at several neurotransmitter receptor subtypes. In vitro autoradiographic studies clearly indicate the accumulation of the Tc-99m compound in 5-HT_2A-receptor-rich areas of the brain. This enrichment can be blocked by 5-HT_2A receptor antagonists such as mianserin and ketanserin and is therefore specific.     

Nursing Home Care Intervention Post Stroke (SHARE) 1 year effect on the burden of family caregivers for older adults in Brazil: A randomized controlled trial

The purpose of this study is to evaluate the effect of home-care nursing intervention on the burden of family caregivers for older adults surviving a stroke. A randomised clinical trial blinded for outcome evaluation. Forty-eight family caregivers of older adults surviving a stroke took part in the study. The intervention group (IG) received three home visits by nurses in 1 month after hospital discharge for guidance on the disease and care activities for the elderly people. The control group (CG) relied on the service network that had access. The Caregiver Burden Scale was applied to assess the burden outcome 1 week, 60 days and 1 year after hospital discharge. The caregivers of the intervention and CGs had no difference regarding baseline data. There was an interaction effect between the CG and the IG in the isolation domain (p = 0.037) and in the emotional involvement domain (p = 0.003) over time. These findings provide support for strengthening a care line for the elderly people after a stroke, with adequate discharge planning, indicating the importance of integrating care network services such as primary care, home care and hospital care with a view to achieving an effective care transition. It is also necessary to construct a specific instrument to evaluate other outcomes, such as the knowledge and learning of caregivers in relation to the care activities taught. This study is registered in the Clinical Trials with name Nursing Home Care Intervention Post Stroke (SHARE) and under number NCT02807012.     

Cefodizime, an aminothiazolylcephalosporin. V. Synthesis and structure-activity relationships in the cefodizime series

The synthesis as well as in vitro antibacterial activity and pharmacokinetic behavior of cefodizime (HR 221, 1a), its analogs and derivatives is described. In this comparison, cefodizime stands out for its balance between its high antibacterial activity, prolonged elimination half-life and high AUC in mice and dogs.     

Minimal residual disease in non-small-cell lung cancer.

Early metastatic relapse after complete resection (R0) of apparently localized primary tumors is frequent in patients with non-small-cell lung cancer (NSCLC). This observation indicates an occult tumor cell dissemination already present at the time of primary surgery but undetectable by current tumor staging methods. During the past 10 years ultrasensitive immunohisto-/-cytochemical and molecular assays have been developed that are able to detect single tumor cells and small tumor cell clusters present in lymph nodes classified as tumor-free by conventional histopathologic analysis, bone marrow, or peripheral blood. Here we present an overview of the incidence and prognostic impact of such early disseminated tumor cells in patients with NSCLC.     

Synthesis and structure-activity relationships in the cefpirome series. I. 7-[2-(2-Aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-[(su bstituted-1-pyridinio)methyl]ceph-3-em-4-carboxylate s

7-[2-(2-Aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-[(s ubs tituted-1-pyridinio)methyl]ceph-3-em-4-carboxylates II are a group of beta-lactam antibiotics with extraordinary high antibacterial activity. The promising member of this group, cefpirome (HR 810, II-1) is a candidate for clinical use. Synthetic pathways to II starting from cefotaxime derivatives I or 7-aminocephalosporanic acid (7-ACA) are described. A preferred method for the conversion of I to II or 7-ACA to precursors III respectively employs iodotrimethylsilane and an excess of the pyridine base. Structure-activity studies reveal an optimum overall activity in the series of pyridines with fused saturated and unsaturated rings or cyclopropyl- and alkoxy substituents. Favorable oxyimino substituents are methyl, ethyl, difluoromethyl and carbamoylmethyl groups. Acidic substituents lead to decreased activity against Staphylococcus aureus SG 511. Introduction of halogen in the thiazole nucleus causes improvement of activity against the K1 beta-lactamase producing Klebsiella aerogenes 1082 E strain.     

Synthesis and structure-activity relationships in the cefpirome series. II. Analogues of cefpirome with different 7-heteroarylacetamido and 3'-ammonium substituents

The synthesis and antibacterial activity in vitro of 7-(2-heteroarylacetamido)-3-[(2,3- cyclopentenopyridinium)methyl]cephalosporins and of some related compounds with different ammonium functions in 3'-position are described. The 7-[5-amino-1,2,4-thiadiazol-3-yl] and the 7-[4-aminopyrimidin-2-yl] analogues of cefpirome and compounds with 3-aliphatic ammoniummethyl functions have excellent antibacterial activity. Cephalosporins with different N-heterocycles other than pyridine in 3'-position are less active than their 3-pyridiniummethyl analogues. Attachment of a pyridinium group to a cephem at C-3 via a thiomethyl or an aminomethyl bridge causes reduction of antibacterial activity.     

Glutamate Promotes Cell Growth by EGFR Signaling on U-87MG Human Glioblastoma Cell Line

Accumulating evidences suggest that glutamate plays a key role in the proliferation and invasion of malignant glioblastoma (GBM) tumors. It has been shown that GBM cells release and exploit glutamate for proliferation and invasion through AMPA glutamate receptors. Additionally, amplification of the epidermal growth factor receptor (EGFR) gene occurs in 40–50% of GBM. Since, PI3K/Akt is considered one of the main intracellular pathways involved in EGFR activation, AKT functions could trigger EGFR signaling. Thus, we investigated whether EGFR-phospho-Akt pathway is involved on the glutamate inducing U-87MG human GBM cell line proliferation. For these purpose, we treated the U-87MG cell line with 5 to 200 mM of glutamate and assessed the number of viable cells by trypan blue dye exclusion test. An increase in cell number (50%) was found at 5 mM glutamate, while the addition of DNQX (500 μM), an antagonist of AMPA receptor, inhibited the effect of glutamate on the U87-MG cells proliferation. Also, at 5 mM glutamate we observed an increase on the EGFR and phospho-Akt contents evaluated by immunohistochemistry. Moreover, U-87MG cells treated with glutamate exhibited an increase about 2 times in the EGFR mRNA expression. While, in the presence of the anti-EGFR gefitinib (50 μM) or the PI3K inhibitor wortmannin (5 μM), the U-87MG proliferation was restored to control levels. Together, our data suggest that glutamate signaling mediated by AMPA receptor induces U-87MG human GBM cell line proliferation via EGFR-phospho-Akt pathway.