Hyperthyroidism as a reversible cause of right ventricular overload and congestive heart failure

We describe a case of severe congestive heart failure and right ventricular overload associated with overt hyperthyroidism, completely reversed with antithyroid therapy in a few week. It represents a very unusual presentation of overt hyperthyroidism because of the severity of right heart failure. The impressive right ventricular volume overload made mandatory to perform transesophageal echo and angio-TC examination to exclude the coexistence of ASD or anomalous pulmonary venous return. Only a few cases of reversible right heart failure, with or without pulmonary hypertension, have been reported worldwide. In our case the most striking feature has been the normalization of the cardiovascular findings after six weeks of tiamazole therapy

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Intra-abdominal hypertension due to heparin - induced retroperitoneal hematoma in patients with ventricle assist devices: report of four cases and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Elevated intra-abdominal pressure (IAP) has been identified as a cascade of pathophysiologic changes leading in end-organ failure due to decreasing compliance of the abdomen and the development of abdomen compartment syndrome (ACS). Spontaneous retroperitoneal hematoma (SRH) is a rare clinical entity seen almost exclusively in association with anticoagulation states, coagulopathies and hemodialysis; that may cause ACS among patients in the intensive care unit (ICU) and if treated inappropriately represents a high mortality rate.</p> <p>Case Presentation</p> <p>We report four patients (a 36-year-old Caucasian female, a 59-year-old White-Asian male, a 64-year-old Caucasian female and a 61-year-old Caucasian female) that developed an intra-abdominal hypertension due to heparin-induced retroperitoneal hematomas after implantation of ventricular assist devices because of heart failure. Three of the patients presented with dyspnea at rest, fatigue, pleura effusions in chest XR and increased heart rate although b-blocker therapy. A 36-year old female (the forth patient) presented with sudden, severe shortness of breath at rest, 10 days after an "acute bronchitis". At the time of the event in all cases international normalized ratio (INR) was <3.5 and partial thromboplastin time <65 sec. The patients were treated surgically, the large hematomas were evacuated and the systemic manifestations of the syndrome were reversed.</p> <p>Conclusion</p> <p>Identifying patients in the ICU at risk for developing ACS with constant surveillance can lead to prevention. ACS is the natural progression of pressure-induced end-organ changes and develops if IAP is not recognized and treated in a timely manner. Failure to recognize and appropriately treat ACS is fatal while timely intervention - if indicated - is associated with improvements in organ function and patient survival. Means for surgical decision making are based on clinical indicators of adverse physiology, rather than on a single measured parameter.</p

Synthesis and antimalarial activities of rhenium bioorganometallics based on the 4-aminoquinoline structure

International audienceA bioorganometallic approach to malaria therapy led to the discovery of ferroquine (FQ, SSR97193). To assess the importance of the electronic properties of the ferrocenyl group, cyclopentadienyltricarbonylrhenium analogues related to FQ, were synthesized. The reaction of [N-(7-chloro-4-quinolinyl)-1,2- ethanodiamine] with the cyrhetrenylaldehyde complexes (η5-C 5H4CHO)Re(CO)3 and [η5-1,2- C5H3(CH2OH)(CHO)]Re(CO)3 produces the corresponding imine derivatives [η5-1,2-C5H 3(R)(CHN-CH2CH2NH-QN)]Re(CO)3 R = H 3a; R = CH2OH 3b; QN = N-(7-Cl-4-quinolinyl). Reduction of 3a and 3b with sodium borohydride in methanol yields quantitatively the amine complexes [η5-1,2-C5H3(R)(CH2-NH-CH 2CH2NH-QN)]Re(CO)3 R = H 4a; R = CH 2OH 4b. To establish the role of the cyrethrenyl moiety in the antimalarial activity of this series, purely organic parent compounds were also synthesized and tested. Evaluation of antimalarial activity measured in vitro against the CQ-resistant strains (W2) and the CQ-susceptible strain (3D7) of Plasmodium falciparum indicates that these cyrhetrene conjugates are less active compared to their ferrocene and organic analogues. These data suggest an original mode-of-action of FQ and ferrocenyl analogues in relationship with the redox pharmacophore

Ferrocene-indole hybrids for cancer and malaria therapy

International audienceWe report the synthesis, characterization, and cytotoxic and antimalarial activity of ferrocene-indole hybrids 8-14. The 2-phenylindole scaffold was chosen because of its potent antimitotic activity and ferrocene was chosen following the development of ferrocifens, ferrocene derivatives of tamoxifen, which are prototypes of a new family of organometallic anti-estrogens. Ferrocene-indole hybrids 8-14 and their corresponding organic analogues 1-7 showed only moderate antimalarial activities, while ferrocene-indole hybrids 11 and 12 showed excellent in vitro activities against the A549 human carcinoma cell line, with IC50 values of 5 and 7 μM respectively. These ferrocene-indole hybrids were up to 25-fold more potent as cytotoxic agents than their purely organic analogues

Insights into the Mechanism of Action of Ferroquine. Relationship between Physicochemical Properties and Antiplasmodial Activity

Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 ± 0.05). FQ is an even stronger inhibitor of -hematin formation than CQ (IC50 = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FQ are significantly different from those of CQ. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pKa values of FQ are lower (pKa1 = 8.19 and pKa2 = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FQ compared with CQ. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pKa. Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger -hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CQ-resistant parasites