Diabetic mastopathy: a case report

Diabetic mastopathy (DMP) is an uncommon collection of clinical, radiological, and histological features, classically described in premenopausal women with long-term insulin-dependent diabetes mellitus. This entity can mimic breast carcinoma, but, in the appropriate clinical and imaging setting, the diagnosis can be made by core biopsy, avoiding unnecessary surgeries. We report the case of a 34-year-old female, with a 12-year history of type 1 diabetes, who presented with bilateral breast lumps. Mammography, ultrasonography, and magnetic resonance imaging could not exclude the suspicion of malignancy, and a core biopsy was performed showing the typical histologic features of DMP. The literature is briefly reviewed.     

Carbon Monoxide and Nitric Oxide interactions in Magnocellular Neurosecretory Neurones during Water Deprivation

Nitric oxide (NO) and carbon monoxide (CO) are diffusible gas messengers in the brain. Previously, we have shown their independent involvement in central fluid/electrolyte homeostasis control. In the present study, we investigated a possible functional interaction between NO/CO in the regulation of vasopressin (VP) and oxytocin (OT) magnocellular neurosecretory cells (MNCs) activity in euhydrated (EU) and dehydrated [48‐h water‐deprived (48WD)] rats. Using brain slices from EU and 48WD rats, we measured, by immunohistochemistry, the expression of neuronal NO synthase (nNOS, which synthesises NO) and haeme‐oxygenase (HO‐1, which synthesises CO) in the hypothalamic supraoptic nucleus (SON). In addition, we used patch‐clamp electrophysiology to investigate whether regulation of SON MNC firing activity by endogenous CO was dependent on NO bioavailability and GABAergic inhibitory synaptic function. We found a proportion of OT and VP SON MNCs in EU rats to co‐express both of HO‐1 and nNOS (33.2 ± 2.9% and 15.3 ± 1.4%, respectively), which was increased in 48WD rats (55.5 ± 0.9% and 21.0 ± 1.7%, respectively, P < 0.05 for both). Inhibition of endogenous HO activity [chromium mesoporphyrin IX chloride (CrMP) 20 μm ] induced MNC membrane hyperpolarisation and decreased firing activity, and these effects were blunted by previous blockade of endogenous NOS activity (l ‐NAME, 2 mm ) or blockade of inhibitory GABA function [Picrotoxin (Sigma‐Aldrich, St Louis, MO, USA), 50 μm ]. No significant changes in SON NO bioavailability (4,5 diaminofluorescein diacetate fluorescence) were observed after CrMP treatment. Taken together, our results support a state‐dependent functional inter‐relationship between NO and CO in MNCs, in which CO acts as an excitatory gas molecule, whose effects are largely dependent on interactions with the inhibitory SON signals NO and GABA.     

Nine equivalents of nursing manpower use score (NEMS)

Objectives: To develop a simplified Therapeutic Intervention Scoring System (TISS) based on the TISS-28 items and to validate the new score in an independent database. Design: Retrospective statistical analysis of a database and a prospective multicentre study. Setting: Development in the database of the Foundation for Research on Intensive Care in Europe with external validation in 64 intensive care units (ICUs) of 11 European countries. Measurements and results: Development of NEMS on a random sample of TISS-28 items, cross validation on another random sample of TISS-28, and external validation of NEMS in comparison with TISS-28 scored by two independent raters on the day of the visit to the ICUs participating in an international study. Multivariable regression techniques, Pearson's correlation, and paired sample t-tests were used (significance at p < 0.05 level). Intraclass correlation, rate of agreement, and kappa statistics were used for interrater reliability tests. The TISS-28 items were reduced to NEMS (9 items) in a random sample of 2000 records; the means of the two scores were no different: TISS-28 26.23 ± 10.38, NEMS 26.19 ± 9.12, NS. Cross-validation in a random sample of 996 records; mean TISS-28 26.13 ± 10.38, NEMS 26.17 ± 9.38, NS; R ² = 0.76. External validation on 369 pairs of TISS-28 and NEMS has shown that the means of the two scores were no different: TISS-28 27.56 ± 11.03, NEMS 27.02 ± 8.98, NS; R ² = 0.59. Reliability tests have shown an “almost perfect” interrater correlation. Similar to studies correlating TISS with Simplified Acute Physiology Score (SAPS)-I and/or Acute Physiology and Chronic Health Evaluation II scores, the value of NEMS scored on the first day accounts for 30.4 % of the variation of SAPS-II score. Conclusions: NEMS is a suitable therapeutic index to measure nursing workload at the ICU level. The use of NEMS is indicated for: (a) multicentre ICU studies; (b) management purposes in the general (macro) evaluation and comparison of workload at the ICU level; (c) the prediction of workload and planning of nursing staff allocation at the individual patient level.     

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNAs, selected in defined disease entities and age cutoffs from 5217 individuals in the German Chronic Kidney Disease cohort. We identified 33 pathogenic variants. Of these 27 (81.8%) were in COL4A3/4/5, the largest group being 15 COL4A5 variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a HNF1B duplication/deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication (“c.428dupC”) in any individual, implying that ADTKD-MUC1 is rare. Our study shows that >10% of selected individuals carry disease-causing variants in genes partly associated with tubulointerstitial kidney diseases. COL4A3/4/5 genes constitute the largest fraction, implying they are regularly overlooked using clinical Alport syndrome criteria and displaying the existence of phenocopies. We identified variants easily missed by some ES pipelines. The clinical filtering criteria applied enriched for an underlying genetic disorder.Subject terms: End-stage renal disease, Genetics research, Alport syndrome, Nephrosclerosis     

Immunogenic Cell Death Role in Urothelial Cancer Therapy

Purpose: Bladder cancer is the 13th most common cause of cancer death with the highest lifetime cost for treatment of all cancers. This scoping review clarifies the available evidence on the role of a novel therapeutic approach called immunogenic cell death (ICD) in urothelial cancer of the bladder. Methods: In accordance with the recommendations of the Joanna Briggs Institute, we searched MEDLINE (Ovid), EMBASE, CENTRAL databases, and supplemented with manual searches through the conferences, Google scholar, and clinicaltrials.gov for published studies up to April 2022. We included literature that studied molecular mechanisms of ICD and the role of certain danger-associated molecular patterns (DAMPs) in generating ICD, safety and efficacy of different ICD inducers, and their contributions in combination with other urothelial cancer treatments. Results: Oncolytic viruses, radiotherapy, certain chemo/chemo radiation therapy combinations, photodynamic therapy, and novel agents were studied as ICD-inducing treatment modalities in the included studies. ICD was observed in vitro (murine or human urothelial carcinoma) in ten studies, eight studies were performed on mouse models (orthotopic or subcutaneous), and five clinical trials assessed patient response to ICD inducing agents. The most common studied DAMPs were Calreticulin, HMGB1, ATP, and Heat Shock Proteins (HSP) 70 and 90, which were either expressed on the cancer cells or released. Conclusion: ICD inducers were able to generate lasting antitumor immune responses with memory formation in animal studies (vaccination effect). In clinical trials these agents generally had low side effects, except for one trial, and could be used alone or in combination with other cancer treatment strategies in urothelial cancer patients.