Heterodetic bicyclic decapeptide cyclo (Glu1 -Leu2 -Pro3-Gly4-Ser5-Ile6-Pro7-Ala8) cyclo-(1γ-5β) Phe9-Gly10

Bycyclic peptides are useful model molecules that can mimic the constrained local folding of a great number of natural peptides and proteins, such as ionophoric peptides, enzyme active site, and ligand-receptor active site. The synthesis of the bicyclic title compound with the liquid phase method is described with experimental details. Of particular interest is the heterodetic closure of the second ring. The peptide showed a complexing activity with metal cations like Ba²⁺, Ca²⁺, and Mg²⁺ . The free bicyclic peptide conformation in solution has been studied by means of NMR spectroscopy and a plausible structure model worked out with model building on NMR constraints is proposed.     

Lack of Influence of Atrioventricular Delay on Stroke Volume at Rest in Patients with Complete Atrioventricular Block and Dual Chamber Pacing

Dual chamber pacing (DDD) maintains atrioventricular (AV) sequence; AV delay programmability modifies the relationship between atrial and ventricular contraction. To evaluate the hemodynamic effects of such a modification, ten patients with a DDD unit for complete AV block were studied by time-motion (M-mode) and Doppler echocardiography during inhibited ventricular pacing (VVI), atrial-triggered ventricular pacing (VDD) and atrioventricular sequential pacing (DVI) at different AV delay (90, 140, 190, 240 msec). A significant improvement in stroke volume (SV) (15%-20%, P less than 0.05) was seen during DDD versus VVI pacing; no changes, however, were observed in the same patient with different AV delay or during DVI versus VDD pacing. These data suggest that programming of AV delay does not affect systolic performance at rest; longer diastolic filling times recorded during DDD pacing with "short" AV delay (90-140 msec) do not seem to be a hemodynamically relevant epi-phenomenon of PM programming.     

Interventional Catheterization after Total Cavopulmonary Connection: Experience in 68 Patients

Background: Total cavopulmonary connection (TCPC) is performed in patients having a single ventricle to allow the passive flow of systemic venous blood to the lungs. Interventional catheterization is needed to treat residual defects or complications. Aims: We discuss our results concerning 68 patients who had had TCPC from January 1995 to December 2010. Methods: Initial and follow‐up catheterization data were reviewed retrospectively. Mid ‐ term results were evaluated by means of angiography and/or CT scan. Results: Mean age at TCPC was 5 years (2.5–18); mean interval between TCPC and catheterization was 5.6 years (1.5–15). Sixty‐nine catheterizations were performed in 53 patients. Eleven patients (21%) had low venous pressure, did not display a right‐to‐left shunt, and did not need any intervention. Fifteen patients (28%) had low venous pressure and only needed the closure of the fenestration. The remaining 27 patients (51%) needed the following interventions: embolization of venous vessels prompting right‐to‐left shunt (n = 15), stenting or reconnection of pulmonary arteries (n = 5), stenting or recanalization of systemic veins (n = 11), other procedures (n = 5). In 3 patients the fenestration could not be closed due to high venous pressure. After the interventions oxygen saturation increased from 90.5%± 4.8% to 94.7%± 3.6% (P = 0.002). Conclusions: Our data show that 49% of patients with TCPC are in good condition late after surgery. However, half of these patients continue to need interventions generally aimed at suppressing stenoses at various levels of TCPC or at occluding vessels prompting right‐to‐left shunt. This population should enter a multicenter program aimed at identifying patients at risk. (J Interven Cardiol 2012;25:622–627)     

Solution conformational analysis of sodium complexed [Gly6]. - and [Gly9]. -antamanide analogs

To investigate the conformational flexibility of metal-complexed cyclodecapeptides, we synthesized and studied two antamanide analogs, in which the phenylalanine residue in position 6 or 9 of the sequence was substituted by Gly. Previous conformational studies on antamanide suggested that these backbone regions are affected by conformational variation. The NMR conformational study showed a high degree of flexibility for the two analogs. With sodium ions, on the other hand, [Gly⁹]. -antamanide was able to form a fairly stable equimolar complex, whereas [Gly⁶]. -antamanide showed a conformational heterogeneity, with one prevailing conformer. For the [Gly⁹]. -antamanide analog, the whole NMR data, combined with extensive theoretical calculations, were consistent with the presence of 1) two (β-turns of type I, centered on Gly⁹-Phe¹⁰ and Ala⁴-Phe⁵, respectively; 2) a central cavity with a six-carbonyl oxygen cage, optimal for a Na⁺ hexacoordination; 3) strongly H-bonded amide protons for residues 1 and 6, both involved in the formation of the two type I β-turns, which, however, exhibited some fluctuations during the molecular dynamics simulations. For the [Gly⁶]. -antamanide-Na⁺ complex the prevailing conformer was consistent with a more open structure, with the partial solvent exposure of all the amide protons; that is, the Gly residue in position 6 increases the flexibility of this critical site more than does the Gly in position 9. These data in some way parallel the results of the cytotoxicity tests on B16-F10 transformed cells for the two analogs: [Gly⁹]. -antamanide is cytotoxic after 48 h exposure, whereas [Gly⁶]. -antamanide is almost inactive. On the contrary, both analogs are practically inactive in vivo against phalloidin.     

Carcinoma of the breast metastatic to the ureter seven years later

We present a case of ureteral metastasis from a primary breast cancer where the disease recurred with an episode of renal colic 7 years after diagnosis. A surgical operation was performed to remove the terminal ureter and the perimeatal area of the urinary bladder. Urological and radiological outcome was satisfactory after a 2-year follow up.     

1H-n.m.r. studies on the specificity of the interaction between bovine pancreatic ribonuclease A and dideoxynucleoside monophosphates

The titration curves of the C-2 histidine protons of bovine pancreatic ribonuclease A in the presence of several dideoxynucleoside monophosphates (dNpdN) were studied by means of proton nuclear magnetic resonance at 270 MHz in order to obtain information on the ligand — RNase A interaction. The changes in the chemical shift and pKs of the C-2 proton resonances of His-12, -48, -119 in the complexes RNase A — dNpdN were smaller than those previously found when the enzyme interacted with mononucleotides. The pK₂ of His-12 was not affected by the interaction of the enzyme with these ligands, whereas, the perturbation of the pK₂ of His-119 was clearly dependent on the nature of the ligand. If there is a pyrimidine nucleoside at the 3′ side of the dideoxynucleoside monophosphates, as in TpdA and TpT, an enhancement due to the well known interaction of the phosphate in p₁, the catalytic site, was found. However, when there is a purine nucleoside, as in dApT and dApdA, a decrease in the pK₂ value was observed and we propose that in such cases the phosphate group interacts in a secondary phosphate binding site, p₂. The results obtained suggest the existence of different specific interactions depending on the structure of the dideoxynucleoside monophosphate studied.     

Idiopathic Long QT Syndrome Exacerbated by Beta-Adrenergic Blockade and Responsive to Left Cardiac Sympathetic Denervation: Implications Regarding Electrophysiologic Substrate and Adrenergic Modulation

Electrophysiologic Substrate of Long QT Syndrome. Introduction: The mechanisms of T wave abnormalities and arrhythmias in patients affected by the long QT syndrome (LQTS) are unclear, as are the reasons why a high-risk subgroup (20%) continues to have syncope during therapy with beta blockers but is protected after left cardiac sympathetic denervation (LCSD). Afterdepolarizations, both early (EAD) or delayed (DAD), have been implicated as likely electrophysiologic substrates for the ECG abnormalities and arrhythmias in LQTS. To test this hypothesis, we analyzed nine Hotter recordings of a LQTS patient typical of the high-risk subgroup. Methods and Results: We applied to the ECG rules derived from previous in vitro and in vivo studies, which relate the coupling intervals of the dysrhythmic beats to the preceding cycle lengths, to discriminate among arrhythmia mechanisms. In the absence of therapy, the patient's ECG showed peaked T waves, with a notched second component accentuated by sinus pauses. The amplitude of the notches increased directly with the preceding RR interval (r = 0.58, P < 0.05), as it is observed with EAD. Therapy with the beta blocker propranolol did not modify the notches, which maintained their amplitude and their relationship with the preceding RR (r = 0.62, P < 0.05). Moreover, during beta-blocker therapy, ventricular premature beats, couplets, and runs of ventricular tachycardia (VT) occurred. The coupling intervals of ventricular premature beats and couplets were not influenced by the preceding RR intervals. By contrast, the coupling interval of the first beat of VT decreased as the preceding RR shortened, as it occurs with DAD-induced triggered activity. After LCSD, T wave notch amplitude was reduced (P < 0.05) and was no longer influenced by the preceding RR (r = 0.31, P = 0.22). The same was true when the calcium entry blocker verapamil was administered. Conclusion: In this patient, T wave abnormalities and some ventricular arrhythmias had the behavior observed in vitro for EAD and the consequent triggered activity. However, the cycle length dependence of VT manifested the behavior observed in vitro for DAD and the related triggered activity. The fact that these phenomena were accentuated by beta blockade and disappeared after LCSD suggests that the alpha-adrenergic receptor-effector system may be a modulator of T wave abnormalities and arrhythmias in some patients unresponsive to beta blockade and protected by LCSD. (J Cardiovasc Electrophysiol, Vol. 3, pp. 295–305, August 1992)     

Basal ganglia calcification: a Fahr's disease case report

Idiopathic basal ganglia calcification (IBGC), known as Fahr''s disease, is a rare neurological disorder characterized by metabolic, biochemical, neuroradiological and neuropsychiatric alterations caused by symmetrical and bilateral intracranial calcifications. The disease has, in most cases, an autosomal dominant pattern of inheritance and genetic heterogeneity. Overlap of neuropsychiatric symptoms is common with movement disorders accounted for 55% of the manifestation. Here we present the case of a 58-year-old woman, presenting to the emergency department because of an accidental fall. Her past medical history was unremarkable and she denied any neurological symptoms a part from insomnia and anxiety. Patient was sent to the emergency department to perform a Brain Computed Tomography (CT) exam that showed bilateral symmetrical calcifications in cerebellar white matter, the corpus striatum, the posterior thalami, and the centrum semiovale of both cerebral hemispheres. Beeing a case of IBGC without relevant symptoms, diagnosis was mainly obtained thanks to the characteristics features of CT examination.