Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.      

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Incidence of exertional right ventricular wall motion abnormalities in patients with coronary artery disease

To evaluate the role of analysis of right ventricular function with exercise in patients with presumed coronary artery disease referred for radionuclide ventriculography, the records of 55 patients referred to our laboratory over a 19-month period were reviewed. All underwent rest and exercise first-pass radionuclide stress testing and cardiac catheterization within a period of four months. Three groups were identified: (1) patients with normal exercise right ventricular function (n = 24); (2) patients with exercise-induced right ventricular regional wall motion abnormalities (n = 15); and, (3) patients with abnormal resting right ventricular function without new exercise abnormalities (n = 16). Patients in each group were similar in age, sex, baseline left ventricular function, medication usage, and indication for study. The incidence of right coronary artery disease was identical in the three groups, as was the incidence of left ventricular functional abnormalities with exercise. Patients with proximal right coronary artery disease were more likely to have reduced left ventricular ejection fraction and more extensive coronary artery disease than those without disease at this site. We conclude that: (1) analysis of rest and exercise right ventricular function does not allow prediction of coronary anatomy in an unselected group of patients; (2) normal right ventricular function with exercise is compatible with extensive coronary artery disease, including proximal right coronary artery disease; and (3) abnormal exercise right ventricular function may be due to exertional left ventricular dysfunction in the absence of proximal right coronary artery disease.     

Vascular Management During Live Donor Nephrectomy: An Online Survey Among Transplant Surgeons

In 2006, a survey from the American Society of Transplant Surgeons disclosed significant and sometimes fatal hemorrhagic events in live donor nephrectomies (LDN) related to failure of clips, leading to the contraindication of the Weck® Hem‐o‐lok® clip for control of the renal artery during LDN. A survey regarding vascular control techniques, their perceived safety ratings and their failures was sent to 645 European Society for Organ Transplantation members who profiled their profession as “surgeon” and selected “kidney” as organ type. Two hundred forty‐three (41%) members responded, of whom 171 (63.3%) independently perform LDN. Their responses were analyzed. For arterial and venous vascular control, the GIA? and TA?stapler are used most frequently, and were rated the safest. Of the 121 reported hemorrhagic events, slippage and dislodgement of clips occurred at least 58 times, while stapler malfunction occurred at least 40 times. One donor death from hemorrhage related to clip dysfunction was reported. Hemorrhagic complications of LDN with fatal and non‐fatal outcomes still occur. Strikingly, many surgeons do not use the vascular closing technique that they consider most safe. Failure of non‐transfixion techniques is associated with greater risks for the donor. Control of major vessels in LDN must employ transfixion techniques for optimal donor safety.