The molecular and cellular anatomy of a fetal programming defect - the impact of low protein diet on the developing kidney.

Low nephron number correlates with the development of hypertension and chronic kidney disease later in life. While intrauterine growth restriction caused by maternal low protein diet (LPD) is thought to be a significant cause of reduced nephron endowment in impoverished communities, its influence on the cellular and molecular processes which drive nephron formation are poorly understood. We conducted a comprehensive characterization of the impact of LPD on kidney development using tomographic and confocal imaging to quantify changes in branching morphogenesis and the cellular and morphological features of nephrogenic niches across development. These analyses were paired with single-cell RNA sequencing to dissect the transcriptional changes that LPD imposes during renal development. Differences in the expression of genes involved in metabolism were identified in most cell types we analyzed, yielding imbalances and shifts in cellular energy production. We further demonstrate that LPD impedes branching morphogenesis and significantly reduces the number of pretubular aggregates - the initial precursors to nephron formation. The most striking observation was that LPD changes the developmental trajectory of nephron progenitor cells, driving the formation of a partially committed cell population which likely reflects a failure of cells to commit to nephron formation and which ultimately reduces endowment. This unique profile of a fetal programming defect demonstrates that low nephron endowment arises from the pleiotropic impact of changes in branching morphogenesis and nephron progenitor cell commitment, the latter of which highlights a critical role for nutrition in regulating the cell fate decisions underpinning nephron endowment. Significance Statement: While a mother's diet and behavior can negatively impact the number of nephrons in the kidneys of her offspring, the root cellular and molecular drivers of these deficits have not been rigorously explored. In this study we use advanced imaging and gene expression analysis in mouse models to define how a maternal low protein diet, analogous to that of impoverished communities, results in reduced nephron endowment. We find that low protein diet has pleiotropic effects on metabolism and the normal programs of gene expression. These profoundly impact the process of branching morphogenesis necessary to establish niches for nephron generation and change cell behaviors which regulate how and when nephron progenitor cells commit to differentiation.

Multicenter retrospective evaluation of transmural migration of subcutaneous ureteral bypass devices within the digestive tract in cats.

BACKGROUND: Placement of a subcutaneous ureteral bypass (SUB) device is an effective method to relieve all causes of ureteral obstruction in cats. Complications involving migration within the gastrointestinal tract have been seldomly described. OBJECTIVES: To characterize transmural migration of SUB devices within the digestive tract in cats. ANIMALS: Eleven migrated SUB catheters identified in 8 cats between 2017 and 2021. METHODS: Retrospective review of medical records of cats with a SUB device in which migration into the gastrointestinal tract was identified. RESULTS: The median time from SUB device placement to implant migration was 928 days (201-2298 days). Seven cats had obstruction of the SUB device and a positive urine culture at diagnosis. The migration was identified by ultrasound in 6/11, pre-operative contrast radiography in 2/2, and only at time of surgery in 3 SUB devices. All cats underwent surgical correction. Four nephrostomy and 7 cystotomy catheters migrated. Migration occurred into the duodenum (3/11), jejunum (7/11), and colon (1/11). SUB devices were removed in 7 cats and replaced in 2 cats, with 1 cat diagnosed with 2 migration events. Gastrointestinal resection and anastomosis were performed in 7/8 cats and an enterotomy in 2 cats. Six cats survived to discharge. The median follow-up time after migration diagnosis was 365 days (range, 0-1114 days) and 2 cats are still alive. CONCLUSIONS AND CLINICAL IMPORTANCE: Although a rare complication, migration of SUB device should be considered in cats with SUB device obstruction and a positive urine culture.

Eruptive naevi associated with encorafenib for metastatic colorectal cancer: two cases.

Encorafenib is a BRAF inhibitor increasingly used as a second-line treatment for metastatic melanoma and colorectal cancer. BRAF inhibitors have been reported to be associated with new and changing melanocytic lesions, including eruptive naevi. We describe two cases of eruptive naevi secondary to encorafenib used for the treatment of BRAF-mutant metastatic colorectal cancer.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Anogenital Crohn's Disease and Granulomatosis: A Systematic Review of Epidemiology, Clinical Manifestations, and Treatment.

BACKGROUND AND AIMS: Metastatic Crohn's disease is an extraintestinal cutaneous manifestation characterised by non-specific inflammatory lesions anatomically separate from the gut; genital involvement is rare. We conducted a systematic review of anogenital Crohn's disease and granulomatosis, to provide a synthesis of epidemiology, clinical features, and treatment outcomes. METHODS: A systematic search of the literature was conducted via MEDLINE, EMBASE, and the Cochrane database from inception to December 1, 2020. Two investigators extracted and analysed study data. Response and remission were defined as partial improvement or complete resolution of symptoms and examination findings, respectively. RESULTS: Of 9381 screened studies, 185 articles, [410 cases: 273 female, 137 male] were included. The predominant clinical features were oedema, ulcers, fissures, and hypertrophic lesions. Adults and children present similarly. Luminal Crohn's disease was diagnosed in nearly 80% of cases including 45-80% patients without gastrointestinal symptoms (time to inflammatory bowel disease [IBD] from anogenital Crohn's disease diagnosis [range] -43 to 11 years). Antibiotics, corticosteroids, thiopurines, and anti-tumour necrosis factor [TNF] therapy were the most frequently prescribed agents. At final follow-up, non-response, response, and remission rates were 37/304 [12%], 267/304 [88%], and 114/304 [38%], respectively. Oedema was associated with a poor response to topical therapy. Greater response rates to anti-TNF therapy were seen in patients prescribed concomitant immunomodulation [24/25, 96% vs 67/90, 74%, p = 0.02]. CONCLUSIONS: We provide an illustrative summary of the clinical presentation and treatment effectiveness of this rare, under-recognised condition, and a proposed algorithm for approach and management. Prospective studies with longer follow-up are required to define optimal treatment strategies.

Lactate dehydrogenase activity staining demonstrates time-dependent immune cell infiltration in human ex-vivo burn-injured skin.

Burn injuries constitute one of the most serious accidental injuries. Increased metabolic rate is a hallmark feature of burn injury. Visualising lactate dehydrogenase (LDH) activity has been previously used to identify metabolic activity differences, hence cell viability and burn depth in burn skin. LDH activity was visualised in injured and uninjured skin from 38 sub-acute burn patients. LDH activity aided the identification of spatially correlating immunocompetent cells in a sub-group of six patients. Desorption Electrospray Ionisation Mass Spectrometry Imaging (DESI MSI) was used to describe relative lactate and pyruvate abundance in burned and uninjured tissue. LDH activity was significantly increased in the middle and deep regions of burnt skin compared with superficial areas in burnt skin and uninjured tissue and positively correlated with post-burn time. Regions of increased LDH activity showed high pyruvate and low lactate abundance when examined with DESI-MSI. Areas of increased LDH activity exhibited cellular infiltration, including CD3 + and CD4 + T-lymphocytes and CD68 + macrophages. Our data demonstrate a steady increase in functional LDH activity in sub-acute burn wounds linked to cellular infiltration. The cell types associated are related to tissue restructuring and inflammation. This region in burn wounds is likely the focus of dysregulated inflammation and hypermetabolism.

Appetite-stimulating effects of once-daily omeprazole in cats with chronic kidney disease: Double-blind, placebo-controlled, randomized, crossover trial.

BACKGROUND: Cats with moderate to advanced chronic kidney disease (CKD) often display clinical signs such as vomiting and decreased appetite, and frequently receive omeprazole or other acid suppressants despite a lack of evidence to support their use. HYPOTHESIS/OBJECTIVES: To evaluate the effect of once-daily PO omeprazole on appetite in cats with CKD. We hypothesized that omeprazole would improve subjective appetite assessments in cats with CKD. ANIMALS: Fourteen client-owned cats with International Renal Interest Society (IRIS) stage 2 or 3 CKD and hyporexia. METHODS: Cats were prospectively enrolled in a multi-institutional, double-blinded, randomized, crossover study to evaluate the effect of a 14-day trial of once-daily PO omeprazole (1 mg/kg) or placebo (lactose gel capsule) on vomiting frequency and appetite. A daily log was completed by the owner during all treatment and rest periods to assess appetite using a subjective, qualitative, and 5-point scoring system. Mixed model analyses of variance were performed to determine if average daily percentage food consumed or appetite score, as measured by subjective owner assessment, differed between treatments. RESULTS: Compared to placebo, a negligible but statistically significant difference in percentage of food consumed was observed between treatments (P = .04) with once-daily omeprazole treatment resulting in a 2.7% increase in food consumption compared to placebo. No significant difference, however, was found in appetite score, body weight, or serum creatinine concentration between treatments. CONCLUSIONS AND CLINICAL IMPORTANCE: Once-daily omeprazole does not markedly increase appetite in cats with CKD and should not be used as a first-line treatment in the absence of evidence of gastrointestinal ulceration.

Acrylate and methacrylate contact allergy and allergic contact disease: a 13-year review.

BACKGROUND: (Meth)acrylates are important causes of contact allergy and allergic contact disease, such as dermatitis and stomatitis, with new and emerging sources resulting in changing clinical presentations. OBJECTIVES: To identify the (meth)acrylates that most commonly cause allergic contact disease, highlight their usefulness for screening, and examine their relationship with occupational and clinical data. METHODS: A retrospective review of results from patch tests performed between July 2002 and September 2015, in one tertiary Cutaneous Allergy Unit, was performed RESULTS: A series of 28 (meth)acrylates was applied to 475 patients. Results were positive in 52 cases, with occupational sources being identified in 24. Industrial exposures and acrylic nails were responsible for 13 and 10 cases, respectively, with wound dressings being implicated in 7. We found that four individual (meth)acrylates (2-hydroxyethyl acrylate, 2-hydroxypropyl methacrylate, bisphenol A glycerolate dimethacrylate, and ethyl acrylate), if used as a screening tool, could have identified 47 (90.4%) of our positive cases. CONCLUSIONS: Our 13-year experience indicates a changing landscape of (meth)acrylate contact allergy and allergic contact disease, with an observed shift in exposures away from manufacturing and towards acrylic nail sources. Wound dressings are highlighted as emerging sources of sensitization. Larger studies are required to establish the sensitivity and specificity of the four (meth)acrylates proposed for potential screening.

The prevalence and clinical characteristics of punding in Parkinson's disease.

BACKGROUND: Punding (the display of stereotyped, repetitive behaviors) is a relatively recently discovered feature of Parkinson's disease (PD). Little is known about the prevalence and clinical characteristics of punding in PD. METHODS: In this review, four large scientific databases were comprehensively searched for literature in relation to punding prevalence and clinical correlates in the context of PD. RESULTS: Prevalence was found to vary greatly (between 0.34 to 14%), although there were large disparities in study populations, assessment methods, and criteria. We observed an association between punding, dopaminergic medications, and impulse control disorder. Other characteristics, which may be more common among punders, include a higher severity of dyskinesia, younger age of disease onset, longer disease duration, and male gender. DISCUSSION: More research in large clinical datasets is required in many areas before conclusions are drawn. The pathophysiology behind the punding phenomenon is also poorly understood at present, rendering it difficult to develop targeted therapy. The current mainstay of treatment is the reduction in the dose of dopaminergic medications, the evidence for other suggested therapies being purely empirical.

Structure and function of BamE within the outer membrane and the ß-barrel assembly machine.

Insertion of folded proteins into the outer membrane of Gram-negative bacteria is mediated by the essential ß-barrel assembly machine (Bam). Here, we report the native structure and mechanism of a core component of this complex, BamE, and show that it is exclusively monomeric in its native environment of the periplasm, but is able to adopt a distinct dimeric conformation in the cytoplasm. BamE is shown to bind specifically to phosphatidylglycerol, and comprehensive mutagenesis and interaction studies have mapped key determinants for complex binding, outer membrane integrity and cell viability, as well as revealing the role of BamE within the Bam complex.