Nephrotoxicity is one of the most important side effects and therapeutical limitations of aminoglycoside antibiotics, especially gentamicin. Despite rigorous patient monitoring, nephrotoxicity appears in 10-25% of therapeutic courses. Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to a significant tubular obstruction. However, a reduced glomerular filtration is necessary to explain the symptoms of the disease. Reduced filtration is not solely the result of tubular obstruction and tubular malfunction, resulting in tubuloglomerular feedback activation; renal vasoconstriction and mesangial contraction are also crucial to fully explain aminoglycoside nephrotoxicity. This review critically presents an integrative view on the interactions of tubular, glomerular, and vascular effects of gentamicin, in the context of the most recent information available. Moreover, it discusses therapeutic perspectives for prevention of aminoglycoside nephrotoxicity derived from the pathophysiological knowledge.

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still mix up CKD with chronic kidney insufficiency or failure, For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus, health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is “solved” by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated aging and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality which is 10- o 100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients (AAKP) and the European Kidney Health Alliance (EKHA). Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true.

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics.

The long-term and seasonal changes in biomass and zooplankton abundance at a station off Mallorca Island (Balearic Sea) were studied in relation to the main physical and chemical conditions. The results are based on a total of 276 samples collected every 10 days during 8 years by means of oblique hauls from bottom to surface. At this neritic station (77-m depth) located in a hydrographic area between northern Mediterranean and Atlantic southern waters, salinity ranged from 37 to 38.4 psu and temperature from 13.4°C (February 1996) to 27.4°C (August 1998). With the exception of salinity, the other environmental parameters and the most abundant zooplankton groups showed irregular but seasonal cycles. Interannual variability was also observed, with higher zooplankton abundance during the cooler and more saline years when the influence of northern water was stronger. Zooplankton abundance decreased during a warm period in 1998. Copepods were the most abundant group (54%) and their abundance was significantly correlated with temperature (negatively) and salinity (positively). Here, we summarize the changes in the zooplankton community abundance and how hydrographic forcing and other climatic factors have changed during the period from 1994 to 2001 in the Balearic Sea (Western Mediterranean).

Introduction SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). Methods We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. Results A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48–2.20). No relevant safety issues were identified. Conclusions In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00543-2.

The reactions of chlorobridged cyclometalated complexes [Pd(C−N)(μ-Cl)]2 (C−N = orthometalated N,N-dimethylbenzylamine, dmba; 2-(para-tolyl)pyridine, p-tolpy; azobenzene, azb; N,N-dimethyl-1-naphthylamine, dmna; and 2-benzylpyridine, bzpy) with Li(Fmes) (Fmes = 2,4,6-tris(trifluoromethyl)phenyl or nonafluoromesityl) give, after hydrolysis, neutral aquo complexes [Pd(C−N)(Fmes)(OH2)], where the ipso carbon atoms of the Fmes and the cyclometalated ligand are coordinated cis, as shown by an X-ray diffraction study of [Pd(dmba)(Fmes)(OH2)]. The aquo ligand is readily displaced by other ligands, giving complexes [Pd(C−N)(Fmes)L] (L = PPh3, 2,6-lutidine, NH3, CNtBu, CO) when monodentate ligands are employed or [Pd(dmba-C)(Fmes)(2,2‘-bipy)], which contains a chelating 2,2‘-bipyridyl and a monodentate C-bonded dmba. Different processes in solution are detected for the complexes containing the bulkier ligands:  ligand rotation in the complex with PPh3; inversion of the bipy ligand in [Pd(dmba-C)(Fmes)(2,2‘-bipy)]; and equilibria with residual water in the solutions of [Pd(C−N)(Fmes)(lut)] and [Pd(dmba-C)(Fmes)(2,2‘-bipy)].

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About 15-20% of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy ± radiotherapy still die following relapse or progressive disease. The outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with the ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4 and CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve a complete response, while the remainder of the patients had a probability of 82.3% (p = 0.04). This variable maintained its statistical significance in multivariate analysis (hazard ratio 3.7, 95% confidence interval 1-13, p = 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (hemoglobin level, p = 0.003; serum albumin, p = 0.05; and International Prognostic Score, p = 0.038). Thus, in the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.