Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses t

Geographical presences and absences. The role of Spanish academic geography in geopolitical debates

A set of factors has converged to create geopolitical issues of great importance in contemporary Spain. These relate as much to the incorporation of Spain in the process of globalization as to the internal organization of the Spanish State. This chapter examines the contribution of Spanish academic geography in the first two decades of this century to research and debate in the feld of political geography. The chapter has been prepared on the basis of a systematic review of the main Spanish academic journals in the feld, as well as references to a very considerable bibliography. The chapter comprises fve sections: the introduction presents the importance of geopolitical factors in contemporary Spain and states the hypothesis and methodology adopted to develop the chapter; the second section looks at the output of Spanish academic geography on the geopolitical position of the Iberian countries with respect to various geographical areas; the third focuses on studies concerning the borders of the Spanish state; the fourth section examines the work dealing with the institutional organization of what the 1978 Spanish Constitution calls 'nationalities and regions'; and fnally, the ffth section homes in on research into the spatial aspects of local and metropolitan governments. The chapter is then rounded off by a few brief conclusions

Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins are thought to form a signaling complex that can flux cations, including calcium. One of the earliest symptoms in ADPKD is a decline in the concentrating ability of the kidneys, occurring prior to cyst formation. We reasoned that hyperosmolality stimulates the polycystin complex, and that the loss of this function impairs water reabsorption. We found that hyperosmolality resulted in the phosphorylation of microtubule-associated protein 4 (MAP4) in a PC1-dependent manner, which then elicited ER-localized PC2 calcium signals. ER-localized PC2 hyperosmotic calcium signals were required for trafficking of the water channel aquaporin (AQP2). Precystic PC1-KO and PC2-KO murine kidneys had cytosol-localized AQP2 and diluted urine compared with their respective controls. Kidney tissue sections from ADPKD patients showed decreased AQP2 apical membrane localization in cystic and noncystic tubules. Our study demonstrates that osmolality is a physiological stimulus of the polycystin complex, and loss of polycystin osmosensing results in impaired water reabsorption via AQP2. This likely contributes to the declined concentrating ability of the kidneys and high circulating vasopressin levels in patients with ADPKD

Prevalence and molecular characterisation of carbapenemase-producing Enterobacterales in an outbreak-free setting in a single hospital in Uruguay

Objectives: This study aimed to characterise all carbapenemase-producing enterobacteria (CPE) isolates obtained from an outbreak-free setting in Uruguay. Methods: We studied 12 CPE isolated from Hospital de Clínicas between 2012–2016. Bacterial identification and antibiotic susceptibility testing were performed using VITEK®2 and Sensititre or agar dilution, respectively. Antimicrobial resistance genes and mobile genetic elements were identified by PCR and sequencing. Multilocus sequence typing was performed for Klebsiella pneumoniae. Plasmid conjugation was assessed, plasmid size was estimated by S1-PFGE and plasmid incompatibility groups were sought by PCR. Results: Among 8364 enterobacteria, 12 CPE were isolated from urine, blood culture, wound, peritoneal fluid and punch samples. NDM-1 was the most prevalent carbapenemase, followed by VIM-2 and KPC-2. All isolates were resistant to gentamicin, cefotaxime, ceftazidime, trimethoprim/sulfamethoxazole, ciprofloxacin and imipenem and were susceptible to fosfomycin. We characterised six class 1 integrons: dfrA12–orfF–aadA2; aacA4–blaOXA-2–orfD; aadB–aadA2; dfrA1; aadB–blaOXA-10–aadA1; and blaVIM-2-dfrA7. An association between various aminoglycoside, β-lactam and fluoroquinolone resistance genes were observed, some of them located in transferable plasmids belonging to incompatibility groups IncC, IncHI1 and IncM1. We described a new composite transposon (assigned Tn6935) including blaNDM-1 flanked by two directly-oriented copies of a Tn3-like element ISKox2-like family transposase. The sequence types of K. pneumoniae isolates were ST11, ST14 and ST661. Conclusions: The presence of CPE is sporadic and could be due to measures taken by the Public Health Committee. Nevertheless, the coexistence of several resistance mechanisms and their presence in conjugative plasmids and high-risk clones is worrisome

Genomic organization and mutation screening of the human ortholog of Pkdr1 associated with polycystic kidney disease in the rat

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans. Although disease-causing mutations have been found in two genes, PKD1 and PKD2, a small number of ADPKD families exist that are unlinked to either of these genes, suggesting involvement of a third, as yet unidentified PKD3 gene. Susceptibility to renal cyst formation in the (cy/+) rat is caused by a missense mutation in Pkdr1 encoding the novel protein SamCystin. To initiate studies of the human orthologous gene, we determined the location and the organization of human PKDR1. We genotyped microsatellite markers flanking the human ortholog in PKD families that either are unlinked to known PKD genes, or in which mutations have not yet been identified and carried out mutation analysis in PKD patients. We identified eight novel single nucleotide polymorphisms, including three leading to amino acid changes. These variants are unlikely to account for PKD in these patients, yet the screening of other affected populations may provide information about the involvement of PKDR1 as a modifier gene in cystic kidney disease

P674 Monitoring posologic change in adalimumab intensification dosing regimen from 40 mg every week to 80 mg every other week

Abstract Background The previous usual adalimumab (ADA) intensification regimen was 40 mg every week (ew)). Recently the original laboratory commercialised the 80 mg injection pen, with pharmacokinetic studies indicating an alternative intensification dose of 80 mg every other week (eow) similar to 40 mg ew, even though interchangeability has not been assessed in clinical practice. In the biosimilars era, this pen was sold to many Hospitals at the same price as the 40mg pen. For this fact and for patient comfort, we proposed our stable-intensificated-ADA IDB patients on a 40 mg ew regimen, to change the dose to 80 mg eow (clinical practice). Methods In this setting, we designed an observational study to monitor clinical, analytical and pharmacokinetic outcomes through this posologic change, for patients who signed the Informed Consent. Clinical (Harvey–Bradshaw index (HBI), partial Mayo score), analytic parameters and ADA trough levels were prospectively obtained at baseline, 4 and 8 months after posologic change. We describe the evolution of this cohort and calculate savings. Results 12 from 18 patients initially evaluated for new dose regimen were finally changed. All of them agreed to participate in the study. Eighty-three per cent were CD patients, 58% males, median age 51 years old (intecuartil range (IQR) 42–55). Median age at IBD diagnosis was 34 years (IQR 24–44). In 9 patients ADA was the first-line biologic. Median IBD duration before starting ADA was 6 years (IQR 5–8). Median time from ADA initiation to intensification was 31 months (IQR 14–55). The median time of ADA intensification was 37 months (IQR 30–66). Seventy per cent of patients were on immunosuppressors (IS) at the start of the study. Table 1 shows the results of clinical, analytical variables and ADA trough levels at baseline, 4 and 8 months. No differences were found. At 4 months, all patients maintained ADA 80 mg eow. Two patients referred mild worsening, (HBI from 3–4 to 5–6) without significant changes in CRP, calprotectin or ADA levels. They recovered after restoring the previous regimen (ADA 40mg ew). At 8 months, ADA was stopped in one patient in remission with undetectable ADA levels and positive ATI. Total savings in the first 8 months were 59022 €. Conclusion in IBD patients with stable response to ADA intensification regimen of 40 mg ew, changing to 80mg eow seems to maintain response and similar trough levels, although some patients may perceive mild symptoms. Economic savings are 50% per patient. </jats:sec