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.     

Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases

Studies of immunosuppressive therapy, particularly mycophenolate mofetil (MMF), in membranous lupus nephritis (MLN) are limited. We report on our experience with primary (first-line) MMF therapy to induce and sustain renal remission in MLN with and without a concurrent proliferative lesion. Systemic lupus erythematosus (SLE) patients were studied, retrospectively, if treated with MMF for newly diagnosed MLN. Complete remission was defined as proteinuria less than 0.5 g/24 h, inactive urine sediment and normal estimated glomerular filtration rate. Response in pure MLN (Group I, n=10) was compared with mixed MLN and proliferative lupus nephritis (Group II, n=19). By 12 months, 4 (40%) patients in Group I and 7 (36.8%) in Group II achieved complete remission (P=0.87). One (10%) patient in Group I and 2 (10.5%) in Group II had worsening renal disease (P=0.97). Mean time to remission was more than seven months in both groups. The remaining patients had stable disease without improvement or worsening. Only 2 of 11 achieving initial remission had a relapse with an average of 28 months of follow-up after remission. Self-limited gastrointestinal symptoms occurred in 12 patients, none requiring withdrawal of the drug. Mycophenolate mofetil as a primary therapy in MLN was successful in inducing complete remission in about 40% of MLN, particularly in patients with mild proteinuria. However, 12 months of therapy was necessary for best outcomes. Response rate was not different in the presence or absence of a proliferative lesion.     

Individual, household and community factors associated with HIV test refusal in rural Malawi

Objective To investigate individual, household and community factors associated with HIV test refusal in a counselling and testing programme offered at population level in rural Malawi. Methods HIV counselling and testing was offered to individuals aged 18–59 at their homes. Individual variables were collected by interviews and physical examinations. Household variables were determined as part of a previous census. Multivariate models allowing for household and community clustering were used to assess associations between HIV test refusal and explanatory variables. Results Of 2303 eligible adults, 2129 were found and 1443 agreed to HIV testing. Test refusal was less likely by those who were never married [adjusted odds ratio (aOR) 0.50 for men (95% CI 0.32; 0.80) and 0.44 (0.21; 0.91) for women] and by farmers [aOR 0.70 (0.52; 0.96) for men and 0.59 (0.40; 0.87) for women]. A 10% increase in cluster refusal rates increased the odds of refusal by 1.48 (1.32; 1.66) in men and 1.68 (1.32; 2.12) in women. Women counsellors increased the odds of refusal by 1.39 (1.00; 1.92) in men. Predictors of HIV test refusal in women were refusal of the husband as head of household [aOR 15.08 (9.39; 24.21)] and living close to the main road [aOR 6.07 (1.76; 20.98)]. Common reasons for refusal were fear of testing positive, previous HIV test, knowledge of HIV serostatus and the need for more time to think. Conclusion Successful VCT strategies need to encourage couples counselling and should involve participation of men and communities.     

Prognostic implications of renal hypertrophy in diabetes mellitus

Early in the course of type 1 diabetes mellitus, hypertrophy of the kidney is a consistent finding that is easily diagnosed using current noninvasive methods, especially ultrasonography. Renal functional changes occur in association with hypertrophy, most notably glomerular hyperfiltration. The structural counterpart of this functional change is an early increase in capillary filtration surface area. In most forms of nondiabetic renal hypertrophy, kidney size is closely linked to GFR. In contrast, in diabetes, persistence of hypertrophy after the clinical onset of overt kidney disease (microalbuminuria, hypertension, decreased GFR, etc.) suggests that sustained release of one or more growth factors may continue even after kidney function declines. The fact that growth factors can act in both an autocrine and paracrine fashion raises the possibility that the local effects of such substances may act as local mediators of kidney growth. Failure of renal hypertrophy to reverse following strict glycemic control for a few months may turn out to be an important prognostic indicator of future progression of the renal disease, but this remains to be established. Prospective studies of kidney size in patients with newly diagnosed type 1 diabetes, using accurate noninvasive methods, may be helpful in establishing whether irreversible ("autonomous") hypertrophy of the kidney is indeed a useful prognostic indicator. As therapies are developed that target the different microvascular complications of diabetes (retinopathy, nephropathy, neuropathy), a noninvasive estimation of kidney size may be a cost-effective method of predicting ultimate renal involvement. Since microalbuminuria occurs relatively late in the disease process, early and persistent hypertrophy of the kidney may become a useful prognostic test in the earliest stages of the disease.     

DA1 receptor mediates dopamine-induced relaxation of opossum lower esophageal sphincter in vitro

The objective of the present experiments was to determine the specific receptor subtype through which dopamine (DA) receptor agonists relax the lower esophageal sphincter in vitro. Opossum lower esophageal sphincter smooth muscle strips were placed in oxygenated Krebs' solution containing propranolol and cocaine. The tissues were placed at a tension that gave maximum relaxation to electrical field stimulation and were then pretreated with phenoxybenzamine. The effects of DA, and the DA receptor agonists epinine and apomorphine were determined. In addition, agonist responses were studied in the presence of the selective DA2 receptor antagonist domperidone, a mixed DA1/DA2 receptor antagonist metoclopramide, and the selective DA1 receptor antagonists bulbocapnine and SK&F 83566. The DA agonists relaxed the smooth muscle strips in the following order of potency: DA greater than epinine greater than apomorphine. Domperidone did not antagonize DA- or apomorphine-induced relaxation. Metoclopramide failed to alter DA-induced relaxation. Bulbocapnine and SK&F 83566 significantly inhibited the relaxation induced by DA. These data indicate that DA-induced lower esophageal sphincter relaxation in vitro is mediated by DA1 receptors.     

Brevity of haptic force perturbations induces heightened adaptive sensitivity

We have exposed human participants to both full-movement and pulsatile viscous force perturbations to study the effect of force duration on the incremental transformation of sensation into adaptation. Traditional views of movement biomechanics could suggest that pulsatile forces would largely be attenuated as stiffness and viscosity act as a natural low-pass filter. Sensory transduction, however, tends to react to changes in stimuli and therefore could underlie heightened sensitivity to briefer, pulsatile forces. Here, participants adapted within perturbation duration conditions in a manner proportionate to sensed force and positional errors. Across perturbation conditions, we found participants had greater adaptive sensitivity when experiencing pulsatile forces rather than full-movement forces. In a follow-up experiment, we employed error-clamped, force channel trials to determine changes in predictive force generation. We found that while participants learned to closely compensate for the amplitude and breadth of full-movement forces, they exhibited a persistent mismatch in amplitude and breadth between adapted motor output and experienced pulsatile forces. This mismatch could generate higher salience of error signals that contribute to heightened sensitivity to pulsatile forces.     

Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells

Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.