Renal tubular transport of glutathione in rat kidney

Filtered glutathione (-glutamyl-cysteinyl-glycine or GSH) is rapidly hydrolyzed by brush-border enzymes facing the tubular lumen and is reabsorbed in the form of the constituent amino acids. The first step of hydrolysis is catalyzed by -glutamyltransferase (-GT). We investigated localization and capacity of the rat renal glutathione degradation/reabsorption during elevation of the filtered load (intravenous infusion of 12 resp. 18 mol GSH/min). Fractional excretion went up from about 0.003 to 0.31±0.02 SEM during infusion of the lower and to 0.49±0.03 SEM during infusion of the higher glutathione dose. GSH degradation/reabsorption took place along the entire proximal tubule and was partially saturated by a 150–200-fold elevation of the normal filtered load. Net reabsorption of GSH up to the last accessible superficial loop was significantly lower during infusion of 18 mol GSH/min (0.3 mol/min) than during infusion of 12 mol GSH/min (1.6 mol/min). In further experiments, infusion of 18 mol GSH/min was preceded by the i.v. administration of acivicin (0.5 mmol/kg body wt.), an inhibitor of -GT. In these experiments, fractional glutathione deliveries to late proximal and early distal tubules did not significantly differ from 1, fractional excretion of GSH at the same time was 1.46±0.11 SEM, revealing net secretion of GSH with the final urine. Tubular secretion of GSH in the acivicin-treated animals occurred either in distal tubules and/or collecting ducts or in the proximal tubules of deep nephrons which are not accessible to micropuncture. The low net reabsorption of GSH up to the late proximal tubule during infusion of 18 mol GSH/min without prior administration of acivicin indicates tubular secretion of GSH along the proximal convolution of superficial nephrons. Net secretion of glutathione with the final urine in the acivicin-treated animals therefore probably originates from proximal tubules of deep nephrons.Supported by the Wilhelm-Sander-Stiftung. Parts of this work were presented at the 4th International Workshop on Ammoniagenesis, Cadarache, France, August 1987, and at the 65th meeting of the Deutsche Physiologische Gesellschaft, Würzburg, March 1988 (Pflügers Arch 411:R97)     

The selective processing of briefly presented affective pictures: an ERP analysis

Recent event-related potential (ERP) studies revealed the selective processing of affective pictures. The present study explored whether the same phenomenon can be observed when pictures are presented only briefly. Toward this end, pleasant, neutral, and unpleasant pictures from the International Affective Pictures Series were presented for 120 ms while event related potentials were measured by dense sensor arrays. As observed for longer picture presentations, brief affective pictures were selectively processed. Specifically, pleasant and unpleasant pictures were associated with an early endogenous negative shift over temporo-occipital sensors compared to neutral images. In addition, affective pictures elicited enlarged late positive potentials over centro-parietal sensor sites relative to neutral images. These data suggest that a quick glimpse of emotionally relevant stimuli appears sufficient to tune the brain for selective perceptual processing.     

Revealing the faults in medical journals

Medical journals hold an exalted position in medicine, but have many shortcomings. This perspective reviews some of the shortcomings of medical journals which are primarily related to inexperience, bias, and commercialism. The issues discussed include the uncertain mission of the traditional medical journal in the modern digital age, the inherent inexperience of voluntary editorial boards, the weaknesses and capricious nature of decisions made by the peer-review process, the uneven value of most journal articles, the bias in what gets submitted and published in journals, the misunderstanding about the criteria for authorship, the misunderstanding of the need for ethical review board approval of studies, the misunderstanding of the need for informed consent for research from patients and ethical review boards, the various sources of assistance to editors and authors in dealing with the many ethical issues arising in the publication process, the commercialization and manipulation of medical journals by industry, the prevalent and complex financial entanglements of authors with industry, and the imperfect impact factor, which has the potential to be abused. The perspective concludes with theorization of the role of medical journals in the future. Readers need to scrutinize data in the literature carefully and interpret the discussions and conclusions critically, as there are biases in what is published in medical journals. The editors dedicate this article to the memory of Prof. Ludwik Hirszfeld, founder of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (Wrocław, Poland) and its two journals (Postępy Higieny i Medycyny Doświadczalnej in 1949, Archivum Immunologiae et Therapiae Experimentalis in 1953), who died fifty-five years ago.     

Imaging Characteristics and First Experience of [<Superscript>68</Superscript>Ga]THP-PSMA,a Novel Probe for Rapid Kit-Based Ga-68 Labeling and PET Imaging: Comparative Analysis with [<Superscript>68</Superscript>Ga]PSMA I&amp;T

Purpose

[⁶⁸Ga]Trishydroxypyridinone (THP)–prostate-specific membrane antigen (PSMA) is a novel tracer that can be labeled in one step by cold reconstitution of a kit with unprocessed generator eluate, targeting PSMA via the lysine-urea-glutamate (KuE) motif. The aim of this study was to evaluate the human imaging characteristics of [⁶⁸Ga]THP-PSMA.

Procedures

[⁶⁸Ga]THP-PSMA positron emission tomography (PET)/x-ray computed tomography (CT) was performed in 25 patients with biochemical recurrence after radical prostatectomy for prostate cancer. Urinary and biliary excretion and tumor lesion uptake were quantified using standardized uptake values (SUVs). Imaging characteristics were assessed in terms of non-target organ uptake, background activity, target-to-background ratios (TBRs) of tumor lesions, and frequency of bladder halo artifacts. Findings were compared to a matched cohort of 25 patients undergoing PET/CT with the established agent [⁶⁸Ga]PSMA I&T.

Results

Physiologic uptake of [⁶⁸Ga]THP-PSMA was significantly lower in salivary glands (P?<?0.0001), liver (P?<?0.0001), spleen (P?<?0.0001), and kidneys (P?<?0.0001) than with [⁶⁸Ga]PSMA I&T. While biliary tracer excretion of [⁶⁸Ga]THP-PSMA was negligible, urinary tracer excretion of [⁶⁸Ga]THP-PSMA was fast, and significantly higher than for [⁶⁸Ga]PSMA I&T, contributing to a higher frequency of bladder artifacts. Malignant lesion uptake of [⁶⁸Ga]THP-PSMA assessed as either SUV or TBR was significantly lower than with [⁶⁸Ga]PSMA I&T.

Conclusion

[⁶⁸Ga]THP-PSMA yields suitable in vivo uptake characteristics. The simplified synthesis method for [⁶⁸Ga]THP-PSMA may facilitate wider application and higher patient throughput with PSMA imaging. However, direct intraindividual comparison studies are needed to assess the relative performance of [⁶⁸Ga]THP-PSMA vs other PSMA ligands in terms of clinical detection rate and image quality.

     

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes

OBJECTIVEEmerging data from animal and human pilot studies suggest potential benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) on lung function. We aimed to assess the association of GLP-1RA and chronic lower respiratory disease (CLRD) exacerbation in a population with comorbid type 2 diabetes (T2D) and CLRD.RESEARCH DESIGN AND METHODSA new-user active-comparator analysis was conducted with use of a national claims database of beneficiaries with employer-sponsored health insurance spanning 2005–2017. We included adults with T2D and CLRD who initiated GLP-1RA or dipeptidyl peptidase 4 inhibitors (DPP-4I) as an add-on therapy to their antidiabetes regimen. The primary outcome was time to first hospital admission for CLRD. The secondary outcome was a count of any CLRD exacerbation associated with an inpatient or outpatient visit. We estimated incidence rates using inverse probability of treatment weighting for each study group and compared via risk ratios.RESULTSThe study sample consisted of 4,150 GLP-1RA and 12,540 DPP-4I new users with comorbid T2D and CLRD. The adjusted incidence rate of first CLRD admission during follow-up was 10.7 and 20.3 per 1,000 person-years for GLP-1RA and DPP-4I users, respectively, resulting in an adjusted hazard ratio of 0.52 (95% CI 0.32–0.85). For the secondary outcome, the adjusted incidence rate ratio was 0.70 (95% CI 0.57–0.87).CONCLUSIONSGLP-1RA users had fewer CLRD exacerbations in comparison with DPP-4I users. Considering both plausible mechanistic pathways and this real-world evidence, potential beneficial effects of GLP-1RA may be considered in selection of an antidiabetes treatment regimen. Randomized clinical trials are warranted to confirm our findings.