Search

The strict correlation between abnormal invasive placentation and postpartum hemorrhage suggests that a widespread antenatal diagnosis of placental anomalies would improve the management of these challenging patients; acting preventive solutions at the moment of delivery reduces blood loss and avoid hysterectomies. The role of endovascular procedures in this field has been encouraged by multiple studies reporting prophylactic uterine arteries embolization and iliac/aortic balloon catheters positioning. This paper aims to review the main imaging diagnostic findings of placental implant anomalies and summarize the principal preventive endovascular strategies proposed in literature.

Thiazides are associated with glucose intolerance and new onset diabetes mellitus, but the molecular mechanisms remain elusive. The aim of this study was to decipher the molecular basis of thiazide-induced glucose intolerance. In mice, hydrochlorothiazide induced a pathological glucose tolerance, characterized by reduced first phase insulin secretion but normal insulin sensitivity. In vitro, thiazides inhibited glucose-and sulfonylurea-stimulated insulin secretion in islets and the murine β-cell line Min6 at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO2/HCO3--dependent, not additive to unselective carbonic anhydrase (CA) inhibition with acetazolamide and independent of extracellular potassium. In contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC (SLC12A3) or NDCBE (SLC4A8). CA expression profiling with subsequent knock-down of individual CA isoforms suggested mitochondrial CA5b as molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxalacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and insulin secretion of islets isolated from CA5b KO mice was unaffected by thiazides.In summary, our study reveals attenuated insulin secretion due to inhibition of the mitochondrial CA5b isoform in β-cells as molecular mechanism of thiazide-induced glucose intolerance.

In humans, there are three paralogs of the Orai Ca2+ channel, which lie at the heart of the store-operated calcium entry (SOCE) machinery. While the STIM-mediated gating mechanism of Orai channels is still being actively investigated, several artificial and natural variants are known to cause constitutive activity of the human Orai1 channel. Surprisingly, little is known about the conservation of the gating mechanism among the different human Orai paralogs and orthologs in other species. In our work, we show that the mutation corresponding to the activating mutation H134A in transmembrane helix 2 (TM2) of human Orai1 also activates Orai2 and Orai3, likely via a similar mechanism. However, this cross-paralog conservation does not apply to the “ANSGA” nexus mutations in TM4 of human Orai1 which mimic the STIM1-activated state of the channel. Investigating the mechanistic background of these differences, we identified two positions, H171 and F246 in human Orai1, which directly control the channel activation triggered by the “ANSGA” mutations in Orai1. Our results shed new light on these important gating checkpoints and show that the gating mechanism of the Orai channels is affected by multiple factors that are not necessarily evolutionarily conserved, such as the TM4-TM3 coupling.

In humans, there are three paralogs of the Orai Ca2+ channel that form the core of the store-operated calcium entry (SOCE) machinery. While the STIM-mediated gating mechanism of Orai channels is still under active investigation, several artificial and natural variants are known to cause constitutive activity of the human Orai1 channel. Surprisingly, little is known about the conservation of the gating checkpoints among the different human Orai paralogs and orthologs in other species. In our work, we show that the mutation corresponding to the activating mutation H134A in transmembrane helix 2 (TM2) of human Orai1 also activates Orai2 and Orai3, likely via a similar mechanism. However, this cross-paralog conservation does not apply to the "ANSGA" nexus mutations in TM4 of human Orai1, which is reported to mimic the STIM1-activated state of the channel. In investigating the mechanistic background of these differences, we identified two positions, H171 and F246 in human Orai1, that are not conserved among paralogs and that seem to be crucial for the channel activation triggered by the "ANSGA" mutations in Orai1. However, mutations of the same residues still allow gating of Orai1 by STIM1, suggesting that the ANSGA mutant of Orai1 may not be a surrogate for the STIM1-activated state of the Orai1 channel. Our results shed new light on these important gating checkpoints and show that the gating mechanism of Orai channels is affected by multiple factors that are not necessarily conserved among orai homologs, such as the TM4-TM3 coupling.

The sodium/hydrogen exchanger 6 (NHE6) localizes to recycling endosomes, where it mediates endosomal alkalinization through K+/H+ exchange. Mutations in the SLC9A6 gene encoding NHE6 cause severe X-linked mental retardation, epilepsy, autism and corticobasal degeneration in humans. Patients with SLC9A6 mutations exhibit skeletal malformations, and a previous study suggested a key role of NHE6 in osteoblast-mediated mineralization. The goal of this study was to explore the role of NHE6 in bone homeostasis. To this end, we studied the bone phenotype of NHE6 knock-out mice by microcomputed tomography, quantitative histomorphometry and complementary ex vivo and in vitro studies. We detected NHE6 transcript and protein in both differentiated osteoclasts and mineralizing osteoblasts. In vitro studies with osteoclasts and osteoblasts derived from NHE6 knock-out mice demonstrated normal osteoclast differentiation and osteoblast proliferation without an impairment in mineralization capacity. Microcomputed tomography and bone histomorphometry studies showed a significantly reduced bone volume and trabecular number as well as an increased trabecular space at lumbar vertebrae of 6 months old NHE6 knock-out mice. The bone degradation marker c-terminal telopeptides of type I collagen was unaltered in NHE6 knock-out mice. However, we observed a reduction of the bone formation marker procollagen type 1 N-terminal propeptide, and increased circulating sclerostin levels in NHE6 knock-out mice. Subsequent studies revealed a significant upregulation of sclerostin transcript expression in both primary calvarial cultures and femora derived from NHE6 knock-out mice. Thus, loss of NHE6 in mice causes an increase of sclerostin expression associated with reduced bone formation and low bone volume.

NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but the role of NHA2 in kidney function and blood pressure homeostasis is currently unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure, normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were significantly reduced in the kidneys of NHA2 knock-out mice. In vitro experiments recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4 stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3). More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation. Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC pathway and is a novel regulator of blood pressure homeostasis in the kidney.

Background. In December 2019, a Coronavirus 2019 epidemic (COVID-19) was reported, caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which occurred in the city of Wuhan, Hubei province, China. Perceived risk of contracting diseases has led many Governments and Healthcare Organizations to implement a variety of control and protection measures for the population, in particular for health professionals who have made contact with positive Covid-19 patients. In this publication, we have carried out a review of the information available, in order to share the prevention and protection measures for health and safety at work, which a University Hospital of Pavia, in Northern Italy, has remodulated, according to the changed scenario in which professionals finds themselves carrying out their profession in the post lockdown, in account to the specificity of processes and methods of work organizing, which overall, they serve to characterize risks, in order to be able to prevent them in the best possible way for patients, visitors and healthcare professionals.Introduzione. Nel dicembre 2019, è stata segnalata un’epidemia di Coronavirus 2019 (COVID-19), causata da una grave sindrome respiratoria acuta coronavirus 2 (SARS-CoV-2), avvenuta nella città di Wuhan, nella provincia di Hubei, in Cina. La percezione del rischio di contrarre malattie, ha portato molti Governi e Organizzazioni Sanitarie ad attuare una varietà di misure di controllo e protezione per la popolazione, in particolare per gli operatori sanitari, che hanno avuto contatti con pazienti Covid-19 positivi. In questa pubblicazione, abbiamo effettuato una revisione delle informazioni disponibili, al fine di condividere le misure di prevenzione e protezione per la salute e la sicurezza sul lavoro, che un Ospedale Universitario di Pavia, nel nord Italia ha rimodulato, secondo il mutato scenario in cui gli operatori sanitari si ritrovano a svolgere la loro attività nel post lockdown, in considerazione della specificità dei processi e dei metodi di organizzazione del lavoro, che nel complesso servono a caratterizzare i rischi, al fine di poterli prevenire nel miglior modo possibile per pazienti, visitatori e operatori sanitari.

Acid-base homeostasis is critical for normal growth, development, and hearing function. The sodium–hydrogen exchanger 6 (NHE6), a protein mainly expressed in early and recycling endosomes, plays an important role in regulating organellar pH. Mutations in NHE6 cause complex, slowly progressive neurodegeneration. Little is known about NHE6 function in the mouse cochlea. Here, we found that all NHE isoforms were expressed in wild-type (WT) mouse cochlea. Nhe6 knockout (KO) mice showed significant hearing loss compared to WT littermates. Immunohistochemistry in WT mouse cochlea showed that Nhe6 was localized in the organ of Corti (OC), spiral ganglion (SG), stria vascularis (SV), and afferent nerve fibres. The middle and the inner ears of WT and Nhe6 KO mice were not different morphologically. Given the putative role of NHE6 in early endosomal function, we examined Rab GTPase expression in early and late endosomes. We found no change in Rab5, significantly lower Rab7, and higher Rab11 levels in the Nhe6 KO OC, compared to WT littermates. Because Rabs mediate TrkB endosomal signalling, we evaluated TrkB phosphorylation in the OCs of both strains. Nhe6 KO mice showed significant reductions in TrkB and Akt phosphorylation in the OC. In addition, we examined genes used as markers of SG type I (Slc17a7, Calb1, Pou4f1, Cal2) and type II neurons (Prph, Plk5, Cacna1g). We found that all marker gene expression levels were significantly elevated in the SG of Nhe6 KO mice, compared to WT littermates. Anti-neurofilament factor staining showed axon loss in the cochlear nerves of Nhe6 KO mice compared to WT mice. These findings indicated that BDNF/TrkB signalling was disrupted in the OC of Nhe6 KO mice, probably due to TrkB reduction, caused by over acidification in the absence of NHE6. Thus, our findings demonstrated that NHEs play important roles in normal hearing in the mammalian cochlea.

The aim of this study is to report on a single center experience of managing patients affected by placenta previa major and/or accretism by embolizing uterine arteries immediately before the cesarean delivery to reduce blood loss and secondary the rate of hysterectomies. Sixty-nine patients have been prospectively enrolled. Inclusion criteria were radiological diagnosis of placenta anomalies and risk factors for peri/postpartum hemorrhage. The delivery was electively scheduled between the 35th week and the 36th week of pregnancy. The embolization procedure was performed in the gynecological operating room with a mobile C-arm by injecting calibrated microparticles 500–700 μm. A contrast-enhanced MRI was acquired in a subgroup of 10 patients 6 months after the delivery to evaluate the uterine wall status. Hysterectomy had been performed in 43.5%; 52.2% did not require blood transfusions; 1.2 blood units per patient had been meanly transfused. The mean fluoroscopy beam-on time was 195 s per patient. The mean uterine dose was 26.75 mGy. No pH anomalies were measured from the umbilical cord blood; the Apgar score at 5 min was ≥8. The analysis of the neuro-developmental milestones showed normal cognitive development in all children at 6 months. The uterine wall enhancement evaluated with contrast-enhanced MRI 6 months after the embolization procedure showed preserved myometrial perfusion without area of necrosis. In this series of patients, the predelivery uterine arteries’ embolization was a safe and effective procedure; this may represent a technical alternative that interventional radiologists can consider when facing this challenging scenario.

2020 started on a high note with the restoration of our ceilings, which had commenced prior to Christmas and continued till 23rd February of this year. We had hoped to mark the 199th anniversary of...

Uterine arteriovenous fistulas are rare and acquired causes of life-threatening vaginal bleeding. They usually present with intermittent menometrorrhagia in young patients in childbearing age with history of gynecological procedures on uterus. Traditional management is hysterectomy; endovascular embolization represents nowadays an alternative strategy for patients wishing to preserve fertility. Here, the endovascular approach to a 29-year-old woman affected by severe menometrorrhagia caused by a uterine arteriovenous fistula with a concomitant pelvic varicocele is reported; a bilateral uterine arteries embolization with Onyx-18 (ev3, Irvine, CA, USA) has successfully resolved the fistula with clinical success.

On 22 May 2018, four members of the Keats-Shelley Memorial Association – namely our Treasurer Charles Cary-Elwes, Trustee Sue Bradbury, Chair of the Rome Committee Maria Valentini, and myself – too...

The transport and ion-coupling mechanisms of ZIP transporters remain largely uncharacterized. Previous work in our laboratory has revealed that the solute carrier family 39 member A2 (SLC39A2/ZIP2) increases its substrate transport rate in the presence of extracellular H+. Here, we used a combination of in silico and in vitro techniques involving structural modeling, mutagenesis, and functional characterization in HEK293 cells to identify amino acid residues potentially relevant for both the ZIP2–H+ interaction and substrate binding. Our ZIP2 models revealed a cluster of charged residues close to the substrate–translocation pore. Interestingly, the H63A substitution completely abrogated pH sensitivity, and substitutions of Glu-67 and Phe-269 altered the pH and voltage modulation of transport. In contrast, substitution of Glu-106, which might be part of a dimerization interface, altered pH but not voltage modulation. Substitution of Phe-269, located close to the substrate-binding site, also affected substrate selectivity. These findings were supported by an additional model of ZIP2 that was based on the structure of a prokaryotic homolog, Bordetella bronchiseptica ZrT/Irt-like protein (bbZIP), and in silico pKa calculations. We also found that residues Glu-179, His-175, His-202, and Glu-276 are directly involved in the coordination of the substrate metal ion. We noted that, unlike bbZIP, human ZIP2 is predicted to harbor a single divalent metal-binding site, with the charged side chain of Lys-203 replacing the second bound ion. Our results provide the first structural evidence for the previously observed pH and voltage modulation of ZIP2-mediated metal transport, identify the substrate-binding site, and suggest a structure-based transport mechanism for the ZIP2 transporter.

Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23.

Giuseppe Albano explores Keats’s association with Rome, one of the places that defined the poet’s life, even though Keats spent just fourteen weeks and two days there. Keats’s voice, Albano reminds us, is elusive throughout, and often mediated through Joseph Severn’s own letters and recollections. Albano explores the Eternal City through the prism of Keats’s experience, seeking traces of the poet in three connected places: the area around the Piazza di Spagna and Pincian Hill, Keats’s main territory during his time in Rome; the interior world of his intellectual energy and poetic creativity, muted but not extinguished; and his final dwelling place in the house by the Spanish Steps, where he was cared for until the end by Severn.

We previously demonstrated that the sodium/hydrogen exchanger NHA2, also known as NHEDC2 or SLC9B2, is critical for insulin secretion by β-cells. To gain more insights into the role of NHA2 on systemic glucose homeostasis, we studied the impact of loss of NHA2 during the physiological aging process and in the setting of diet-induced obesity. While glucose tolerance was normal at 2 months of age, NHA2 KO mice displayed a significant glucose intolerance at 5 and 12 months of age, respectively. An obesogenic high fat diet further exacerbated the glucose intolerance of NHA2 KO mice. Insulin levels remained similar in NHA2 KO and WT mice during aging and high fat diet, but fasting insulin/glucose ratios were significantly lower in NHA2 KO mice. Peripheral insulin sensitivity, measured by insulin tolerance tests and hyperinsulinemic euglycemic clamps, was unaffected by loss of NHA2 during aging and high fat diet. High fat diet diminished insulin secretion capacity in both WT and NHA2 KO islets and reduced expression of NHA2 in WT islets. In contrast, aging was characterized by a gradual increase of NHA2 expression in islets, paralleled by an increasing difference in insulin secretion between WT and NHA2 KO islets. In summary, our results demonstrate that loss of the sodium/hydrogen exchanger NHA2 exacerbates obesity- and aging-induced glucose intolerance in mice. Furthermore, our data reveal a close link between NHA2 expression and insulin secretion capacity in islets.

Calcium is a key component of the bone mineral hydroxyapatite. During osteoclast-mediated bone resorption, hydroxyapatite is dissolved and significant quantities of calcium are released. Several calcium transport systems have previously been identified in osteoclasts, including members of the sodium/calcium exchanger (NCX) family. Expression pattern and physiological role of NCX isoforms in osteoclasts, however, remain largely unknown at the moment. Our data indicate that all three NCX isoforms (NCX1, NCX2, and NCX3) are present in murine osteoclasts. RANKL-induced differentiation of murine osteoclast precursors into mature osteoclasts significantly attenuated the expression of NCX1, while NCX2 and NCX3 expressions were largely unaffected. To study the role of NCX1 during osteoclast differentiation and bone resorption, we crossed mice with exon 11 of the NCX1 gene flanked by loxP sites with cathepsin K-Cre transgenic mice. Mature osteoclasts derived from transgenic mice exhibited an 80-90% reduction of NCX1 protein. In vitro studies indicate that NCX1 is dispensable for osteoclast differentiation, but NCX1-deficient osteoclasts exhibited increased resorptive activity. In line with these in vitro findings, mice with an osteoclast-targeted deletion of the NCX1 gene locus displayed an age-dependent loss of bone mass. Thus, in summary, our data reveal NCX1 as a regulator of osteoclast-mediated bone resorption.

On the publication of J. B. Nicolas' French translations of Omar Khayyam --collected in book form as Les quatrains de Kheyam in 1867, having initially appeared in the Revue de l'Orient, de l'Algerie et des Colonies four years earlier--Edward FitzGerald was provoked into a caustic disagreement with its translator. The Frenchman held that Omar's testaments to the benefits of drinking wine should not be taken literally, but should be seen in Sufi terms as representing an enlightened state of being. For Nicolas, there was little doubt that Omar "etait plutot porte a la contemplation des choses divines qu'aux jouissances de la vie mondaine" (was sooner inclined to the contemplation of divine things than to worldly pleasures). (1) Edward Cowell, the man who introduced FitzGerald to Omar's work in the first place, may have shared certain aspects of Nicolas' views but, for the sake of his friend's contentment, conceded that "Omar lived in an age of poetical mysticism, but he is himself no mystic." (2) FitzGerald disagreed more fully, and more ambitiously, with Nicolas, and he set about preparing a second edition partly in retaliation, the 1868 introduction to which questions Nicolas' claims to "historical Authority." (3) FitzGerald had formed staunch opinions on Omar's irreligious materialism long before Nicolas' book came along. In the introduction to his first edition, he argues that Omar's "Worldly Pleasures are what they profess to be without any Pretence at divine Allegory: his Wine is the veritable Juice of the Grape: his Tavern, where it was to be had" (Rubaiyat, p. 6). However, the rest of the introduction also suggests that FitzGerald's views on this matter were more malleable than implied by that blunt sentence, which he removed from introductions to subsequent editions. Toward the end he notes that "those [quatrains] selected are strung into something of an Eclogue, with perhaps a less than equal proportion of the 'Drink and make-merry' which (genuine or not) recurs over-frequently in the Original" (Rubaiyat, p. 9). In calling the Rubaiyat an "Eclogue," FitzGerald draws on the original Greek word ekloge, meaning "selection," while playing on the Virgilian sense of the term as a series of short pastoral lyrics. From a literary-historical perspective, this classification is timely, for, according to the editors of The Penguin Book of English Pastoral Verse, pastoral, as a specific and meaningful genre in English, expired in the second half of the nineteenth century when the distinction between urban and rural life diminished. (4) Critics have shown, however, that the implications of pastoral extend well beyond the realm of literature referring generally to the countryside, and specifically, though not indispensably, to the lives of shepherds. Taking his cue from William Empson's understanding of pastoral as "putting the complex into the simple," (5) Peter Marinelli, for one, defines pastoral as "any literature which deals with the complexities of human life against a background of simplicity." (6) In this respect, FitzGerald's casting of his work in this manner is piquant, even if it all seems a world away from classical and renaissance configurations of pastoral. As far as his Rubaiyat is concerned, the shepherds of pastoral lore are still there in spirit, but they have been transformed into drinkers (or, more precisely, one drinker who addresses at least one other). And the setting is an idyllic tavern in which, socio-economic detail being lacking, wine flows limitlessly at no apparent cost to its clientele (no money appears to change hands). In this respect, FitzGerald's work is historically important because it paved the way for subsequent poets--notably, Robert Louis Stevenson, Rudyard Kipling, A. E. Housman--to compose imitation-drinking poems that claim pastoral status through idealizing social relations. (7) The aim of this essay is to diagnose the Rubaiyat as literary pastoral. It starts from the premise that FitzGerald's tavern is an ideal arena for spirited musing, for venting complex human issues over one of the simplest human pastimes (drinking). …

Purpose To assess the safety and outcomes of uterine artery embolization (UAE) performed before delivery in patients with placental implant anomalies at high risk for peripartum or postpartum hemorrhage. Materials and Methods From January 2013 to January 2015, 50 consecutive patients with placental implant anomalies at 35–36 weeks of pregnancy were recruited. UAE was performed superselectively by injecting reabsorbable pledgets. We applied 5 dosimeters to patients' backs to measure the uterine radiation dose, considered to be the same radiation dose that the fetus received. Newborns were assessed immediately after birth and at 6-month follow-up. Results All procedures were technically successful. Of patients, 64% did not require transfusions. Mean blood units transfused was 0.7 U (range, 0–4 U). No patient was transferred to the intensive care unit. Hysterectomy was performed in 13 patients (26%). Mean fluoroscopy operative time was 3 minutes 42 seconds (range, 1 min 21 s–6 min 58 s), and mean uterine radiation dose was 15.61 mGy (range, 8.15–38.18 mGy). Mean time between embolization and delivery was 6 minutes 4 seconds (range, 4 min 18 s–8 min 12 s). The 1-minute and 5-minute Apgar scores were 8–9 in all newborns; 8 newborns were lost to follow-up at 6 months. A normal cognitive outcome was evident in all 42 children studied. Conclusions UAE before delivery appeared to reduce bleeding during cesarean sections in this consecutive series of patients with placental implant anomalies. In the hands of experienced staff, radiation dose to the fetus was minimal.

A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo. However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.

Mutations in the vacuolar-type H(+)-ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G>A; p.E161K) that causes greatly diminished pump function in vitro To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P

PURPOSE OF REVIEW: Sodium/hydrogen exchangers (NHEs) are a large family of transport proteins catalyzing the exchange of cations for protons across lipid bilayer membranes. Several isoforms are expressed in β cells of the endocrine pancreas, including the recently discovered and poorly characterized isoform NHA2. This review will summarize advances in our understanding of the roles of NHEs in the regulation of insulin secretion in β cells. RECENT FINDINGS: Plasmalemmal full-length NHE1 defends β cells from intracellular acidification, but has no role in stimulus-secretion coupling and is not causally involved in glucose-induced alkalinization of the β cell. The function of a shorter NHE1 splice variant, which localizes to insulin-containing large dense core vesicles, remains currently unknown. In contrast, in-vitro and in-vivo studies indicate that the NHA2 isoform is required for insulin secretion and clathrin-mediated endocytosis in β cells. SUMMARY: Recent data highlight the importance of NHEs in the regulation of cellular pH, clathrin-mediated endocytosis and insulin secretion in β cells. Based on these studies, a pathophysiological role of NHEs in human disorders of the endocrine pancreas seems likely and should be investigated.

The aim of this study was to evaluate the efficacy and the safety of selective uterine artery embolisation in patients with a high risk of haemorrhage due to obstetric issues. We retrospectively reviewed the angiographic examinations of 63 patients (average age ± SD, 32.6 years ± 4.8), affected by an obstetric disease with a high risk of haemorrhage (22 cases of ectopic pregnancy, 41 of postpartum haemorrhage) and treated with an interventional approach. In particular, we considered the rate of second treatment with interventional technique or conservative or radical surgery, the incidence of postprocedural complications, and the absorbed radiation dose. Immediate technical success, defined as the cessation of active bleeding, was achieved in all cases. Uterine artery embolisation was able alone to control the haemorrhage in 95.24 % of cases. Three patients required a second treatment to achieve haemostasis. No peri- or postprocedural complications were observed. At the 12-month follow-up after embolisation, 22/49 conservatively treated patients were found to be pregnant and successfully completed their pregnancy. Selective uterine artery embolisation allows for safe and complete control of haemorrhage in patients with obstetric disease, with a very low incidence of complications and preservation of fertility.

ResumenObjetivoMostrar la efectividad del neumodesplazamiento en hemorragia subretiniana y agujero macular postraumático.MétodoReporte de caso.ResultadosPaciente masculino de 39 años de edad quien tras trauma contuso en ojo izquierdo presenta disminución de agudeza visual. Examen oftalmológico: agudeza visual del ojo izquierdo: movimiento de mano. Fundoscopia ojo izquierdo: hemorragia subretiniana en polo posterior y agujero macular. Se coloca burbuja de gas (C3F8), obteniéndose desplazamiento de la hemorragia subretiniana del área foveolar con cierre del agujero macular.ConclusionesEl trauma ocular representa todo un desafío para el oftalmólogo, en este caso producto de un trauma ocular contuso. Para la resolución de la hemorragia subretiniana producto de una rotura coroidea yuxtapapilar y del agujero macular traumático, tenemos varias opciones quirúrgicas que dependerán de la decisión del especialista en cuanto conocimiento, experiencia y experticia del mismo. El neumodesplazamiento sin vitrectomía vía pars plana ha sido utilizado para desplazar sangre subretiniana secundaria a degeneración macular relacionada con la edad. Usando el mismo principio pero aplicado a diferente patología, se decidió realizar desplazamiento neumático, obteniendo como resultado drenaje a cavidad vítrea de la hemorragia subretiniana y cierre del agujero macular. El neumodesplazamiento puede ser considerado una opción terapéutica eficaz versus la vitrectomía vía pars plana en el manejo de esta dolencia.AbstractObjectiveShow the effectiveness of pneumodisplacement in subretinal hemorrhage and post traumatic macular hole.MethodCase report.ResultsMale patient, 39 years of age who after blunt trauma left eye have decreased visual acuity. Eye exam: visual acuity left eye: hand movement. Funduscopy left eye: subretinal hemorrhage in the posterior pole and macular hole. Gas bubble is placed (C3F8), whereby displacement of subretinal hemorrhage foveal area with macular hole closure.ConclusionsOcular trauma represents a challenge for the ophthalmologist, in this case the result of a blunt ocular trauma. For the resolution of subretinal hemorrhage juxtapapillary product of choroidal rupture and traumatic macular hole, we have several surgical options that depend on the decision as specialist knowledge, experience and expertise of it. The pneumatic displacement without vitrectomy has been used to displace subretinal blood secondary to macular degeneration related to age. Using the same principle but applied to different diseases, we decided to perform pneumatic displacement resulting in vitreous cavity drainage of sub-retinal hemorrhage and macular hole closure. The pneumatic displacement can be considered an effective treatment option versus vitrectomy in the management of this condition.