Solid phase synthesis of human growth hormone-releasing factor analogs containing a bicyclic β-turn dipeptide

Three analogs derived from the N-terminal 29-residue fragment of human growth hormone-releasing factor (hGRF) which contained a bicyclic β-turn dipeptide (BTD) at 7-8,8-9, and 9-10 positions were synthesized by solid phase methodology to ascertain if the β-turns are important for the biological activity of hGRF and also to show the applicability of the BTD unit to solid phase synthesis. All three analogs were obtained in good yield and purity indicating that the BTD unit can be used in the usual condition of solid phase synthesis. The capacity of these analogs to release growth hormone (GH) was tested in an in vitro bioassay using rat anterior pituitary cells. All three BTD-containing analogs showed the same maximal GH secretion with parallel dose-response curves to that of hGRF(1-29)NH₂, except their relative potencies were very low.     

The free-flap vaginoplasty; a new surgical procedure for the treatment of vaginal agenesis

Summary. The ideal operation for a young woman born without a vagina would be a one stage procedure, creating a functionally normal vagina without cosmetically unattractive scars, without the need for subsequent dilatation, stents or obturators. This goal was achieved with a free flap vaginoplasty using a full thickness skin graft taken from the scapula region. The blood supply of the graft was maintained by microvascular anastomosis of the graft pedicles to vessels in the groin. The operation has been performed in three young women who were born with uterine hypoplasia and vaginal agenesis. We experienced no unexpected complications, the procedure was well tolerated and left our patients with a good length, fully functional vagina. However, the operation is a major undertaking and needs to be performed by those with expertise in plastic surgery as well as in gynaecology.     

Evolution of neural crest and placodes: amphioxus as a model for the ancestral vertebrate?

Recent studies of protochordates (ascidian tunicates and amphioxus) have given insights into possible ancestors of 2 of the characteristic features of the vertebrate head: neural crest and placodes. The neural crest probably evolved from cells on either side of the neural plate–epidermis boundary in a protochordate ancestral to the vertebrates. In amphioxus, homologues of several vertebrate neural crest marker genes ( BMP2/4 , Pax3/7 , Msx , Dll and Snail ) are expressed at the edges of the neural plate and/or adjacent nonneural ectoderm. Some of these markers are also similarly expressed in tunicates. In protochordates, however, these cells, unlike vertebrate neural crest, neither migrate as individuals through embryonic tissues nor differentiate into a wide spectrum of cell types. Therefore, while the protochordate ancestor of the vertebrates probably had the beginnings of a genetic programme for neural crest formation, this programme was augmented in the earliest vertebrates to attain definitive neural crest. Clear homologues of vertebrate placodes are lacking in protochordates. However, both amphioxus and tunicates have ectodermal sensory cells. In tunicates these are all primary neurons, sending axons to the central nervous system, while in amphioxus, the ectodermal sensory cells include both primary neurons and secondary neurons lacking axons. Comparisons of developmental gene expression suggest that the anterior ectoderm in amphioxus may be homologous to the vertebrate olfactory placode, the only vertebrate placode with primary, not secondary, neurons. Similarly, biochemical, morphological and gene expression data suggest that amphioxus and tunicates also have homologues of the adenohypophysis, one of the few vertebrate structures derived from nonneurogenic placodes. In contrast, the origin of the other vertebrate placodes is very uncertain.     

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure

BackgroundMultiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure.Methods and ResultsWe retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization.ConclusionsBiomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization.     

The role of autonomic arousal in problem gambling

The present study investigated the role of arousal in problem gambling. Three groups of subjects were recruited into the study corresponding to problem gamblers, high and low frequency social gamblers. For the two gambling groups, the preferred form of gambling was poker machine playing. Five different conditions were employed in order to determine under which conditions gambling related cues were related to increased autonomic arousal, as measured by skin conductance level (SCL), heart rate (HR) and frontalis electromyography (EMG). The five conditions were a neutral task, a videotaped poker machine gambling scenario presented with and without distraction, a personally relevant “win” situation and a videotaped horse race. Comparisons between responses for the videotaped poker machine gambling stimuli versus a horse-racing video task demonstrated differences only for the problem gambling group and only for SCL. No differences between these tasks emerged on the HR and EMG indices and no differences were evident for either of the social gambling groups. No changes were observed in any group when subject's cognitions were prevented by asking patients to count the number of wins made during the video play period while watching the same poker machine video. However, when personally relevant situations were presented and compared to a neutral task, differences were observed in all three groups. However, the nature of these differences varied between the groups and the different indices of arousal. For problem gamblers, increases were evident in all three measures. Increases were also observed for the control groups in comparison to the neutral task, but only in HR and SCL and not for EMG. For HR, the increases were equivalent across all three gambling groups. However, for SCL the problem gambling group became significantly more aroused than the control groups, but no differences were observed between the high and low frequency gamblers. Only the problem gambling groups evidenced significant increases in the personally relevant task compared to the neutral task for EMG. Theoretical and clinical implications of these results for the development, maintenance and treatment of problematic levels of gambling are discussed.     

Myopotential Interference in Unipolar Rate Responsive Pacemakers

The effects of myopotential interference on unipolar rate responsive pacemakers were assessed in 22 patients. Six types of pacemakers (from four manufacturers) were studied: five TX2 (QT sensing), seven Biorate (five RDP3 and two MB-1, respiratory rate sensing), seven Activitrax (activity sensing), two Medtronic 2503 (dP/dt sensing), and one Sensolog P703 (activity sensing). Provocative tests using arm exercises were performed in both VVI and rate responsive modes. At nominal sensitivity settings (1.8-2.5 mV), 55% of these patients were myopotential positive for at least 1 provocative test. Pressing the palms together was found to be the most sensitive provocative test. Rate response was achieved with treadmill exercise (all patients), hyperventilation (RDP3 and MB-1) and tapping (Activitrax) or wobbling the pacemaker in its pocket (Sensolog). During continued rate acceleration, myopotential interference was induced by arm exercises. The duration of inhibition was shorter when the provocative tests were performed during rate response compared to that occurred at rest. Short periods of myopotential interference resulted in temporary inhibition of pacing but rate response continued immediately on removal of the interference. In one patient with a RDP3 pacemaker, a prolonged episode of myopotential interference during treadmill exercise resulted in reversion of the pacemaker to the interference mode. Appropriate adjustment of the sensitivity setting effectively controlled the symptoms in most patients. However, one patient with a QT sensing pacemaker and symptomatic myopotential interference required programming to the VVT pacing mode. Two out of five patients with RDP3 required pacemaker replacement because of uncontrolled myopotential interference.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic Accuracy of Cardiac Magnetic Resonance Imaging in the Detection and Characterization of Left Atrial Catheter Ablation Lesions: A Multicenter Experience

MRI Detection of Left Atrial Ablation Lesions . Introduction: We tested the hypothesis that cardiovascular magnetic resonance (CMR) imaging can reliably distinguish the presence or absence of left atrial (LA) ablation lesions by blinded analysis of pre‐ and postablation imaging. Methods: Consecutive patients at 2 centers undergoing pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation by either wide area circumferential radiofrequency ablation (WACA) or ostial ablation with a cryoballoon underwent CMR late gadolinium enhancement (LGE) imaging pre‐ and 3 months postablation. Imaging was anonymized for blinded analysis of (1) LGE images, and (2) a 3D fusion image with LGE projected onto a segmented LA surface. Scans were categorized using both assessment techniques separately as pre‐ or postablation, and if postablation, whether lesions were in an ostial or WACA distribution. Results: LGE imaging was performed in 50 patients (aged 60 ± 10 years, 68% male, 24 underwent WACA and 26 had cryoablation). Sensitivity and specificity for detection of ablation lesions was 60% and 96% on LGE imaging. Sensitivity was higher using 3D fusion imaging (88%; P = 0.003). The proportion in whom lesions were both detected and the distribution correctly assessed as WACA or ostial was higher with 3D fusion imaging compared to LGE imaging (54% vs 28%; P = 0.014). There was no difference in the detection of radiofrequency ablation lesions compared to cryoablation lesions (58% vs 62%; P = 1.000). Conclusion: LGE imaging of atrial scar is not yet sufficiently accurate to reliably identify ablation lesions or to determine lesion distribution. (J Cardiovasc Electrophysiol, Vol. 24, pp. 396‐403, April 2013)