Early, but not late therapy with a vasopressin V1a-antagonist ameliorates the development of renal damage after 5/6 nephrectomy.

INTRODUCTION: Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I). MATERIALS AND METHODS: After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7). RESULTS: In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed. CONCLUSION: These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.     

Publication rates of pharmaceutical scientists: application of the waring distribution

The publication frequency characteristics of 1984 Journal of Pharmaceutical Sciences reviewers were investigated to provide a perspective on the state of the pharmaceutical literature, its dynamics and some of its features. The average number of per capita total publications in 1984 was 3.56, with 26.9% of the reviewers not publishing at all during the year. The average number of per capita first-authorship publications in our survey was 1.17; the percentage of reviewers not publishing a paper as senior author increased to 50.4%. The so-called elite group of scientists--that is, the top group of scientists who publish 50% of the papers--consisted of 12.8% and 11.7% of the sample for total and senior-authored papers, respectively. Waring distributions were shown to adequately characterize the data. The conceptual scheme leading to the Waring distribution assumes three fundamental characteristics: (1) a "self-reproducing" property, viz., the rate of new entrants (potential publishing scientists) is proportional to community size; (2) a "cumulative advantage" or "success breeds success" property, viz., more highly published scientists; are more likely to publish their next article than are less-published scientists; and (3) a uniform "leakage" property, viz., all scientists, regardless of publication rates, have equal likelihood of dropping out of the publication community.     

Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.     

Mitochondrial free calcium levels (Rhod-2 fluorescence) and ultrastructural alterations in neuronally differentiated PC12 cells during ceramide-dependent cell death

Mitochondrial free calcium levels measured by Rhod-2 fluorescence and ultrastructure were examined during cell death in nerve growth factor (NGF)-differentiated PC12 cells that were 1) exposed to C2-ceramide, 2) deprived of serum to induce endogenous ceramide production, or 3) treated with calcium ionophore A23187. Rhod-2 fluorescence in mitochondria and also in the nucleolus increased to a maximum within 3 hours after C2-ceramide treatment or serum withdrawal. In A23187-treated cells, Rhod-2 fluorescence remained at baseline levels. In all three models, enlargement of the endoplasmic reticulum was the first ultrastructural alteration, followed by mitochondrial shrinkage in ionophore-treated cells, but by mitochondrial swelling in the ceramide-dependent models, in which rupture of the outer mitochondrial membrane and unfolding of the inner membrane were frequently seen. Dihydro-C2-ceramide, which did not cause cell death, had no effect on cellular ultrastructure. NGF, which inhibits ceramide-dependent cell death, prevented the effects of serum deprivation on mitochondrial ultrastructure but not on endoplasmic reticulum morphology or Rhod-2 fluorescence. Nuclear shrinkage with loss of nuclear membrane integrity, characterized by nuclear pores, free or surrounded by electron-dense filaments, was a late event in ceramide-dependent cell death. Chromatin condensation and other morphological features associated with apoptosis were seen in only a few atypical cells. Ceramide-mediated cell death, therefore, did not involve classical apoptosis but was mediated by a reproducible series of events beginning in the endoplasmic reticulum, followed by the mitochondria, and then the nucleus. NGF-dependent cell death inhibition intervenes at the mitochondrial level, not by blocking the increase in Rhod-2 fluorescence but by preventing the ultrastructural changes that follow.     

A Portfolio-Based Approach to Optimize Proof-of-Concept Clinical Trials

Improving proof-of-concept (PoC) studies is a primary lever for improving drug development. Since drug development is often done by institutions that work on multiple drugs simultaneously, the present work focused on optimum choices for rates of false positive (α) and false negative (β) results across a portfolio of PoC studies. Simple examples and a newly derived equation provided conceptual understanding of basic principles regarding optimum choices of α and β in PoC trials. In examples that incorporated realistic development costs and constraints, the levels of α and β that maximized the number of approved drugs and portfolio value varied by scenario. Optimum choices were sensitive to the probability the drug was effective and to the proportion of total investment cost prior to establishing PoC. Results of the present investigation agree with previous research in that it is important to assess optimum levels of α and β. However, the present work also highlighted the need to consider cost structure using realistic input parameters relevant to the question of interest.     

Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR)

Objective: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis.

Patients and methods: We performed a retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016.

Results: There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis.

Conclusion: These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct.