Bona fide atypical scrapie faithfully reproduced for the first time in a rodent model

Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminiscent of the incidence of idiopathic spontaneous prion diseases in humans, which account for more than 85% of the cases in humans. Hence, developing animal models that consistently reproduce this phenomenon of spontaneous PrP misfolding, is of importance to study the pathobiology of idiopathic spontaneous prion disorders. Transgenic mice overexpressing sheep PrPC with I112 polymorphism (TgShI112, 1–2 × PrP levels compared to sheep brain) manifest clinical signs of a spongiform encephalopathy spontaneously as early as 380 days of age. The brains of these animals show the neuropathological hallmarks of prion disease and biochemical analyses of the misfolded prion protein show a ladder-like PrPres pattern with a predominant 7–10 kDa band. Brain homogenates from spontaneously diseased transgenic mice were inoculated in several models to assess their transmissibility and characterize the prion strain generated: TgShI112 (ovine I112 ARQ PrPC), Tg338 (ovine VRQ PrPC), Tg501 (ovine ARQ PrPC), Tg340 (human M129 PrPC), Tg361 (human V129 PrPC), TgVole (bank vole I109 PrPC), bank vole (I109I PrPC), and sheep (AHQ/ARR and AHQ/AHQ churra-tensina breeds). Our analysis of the results of these bioassays concludes that the strain generated in this model is indistinguishable to that causing atypical scrapie (Nor98). Thus, we present the first faithful model for a bona fide, transmissible, ovine, atypical scrapie prion disease.info:eu-repo/semantics/publishedVersio

Bona fide atypical scrapie faithfully reproduced for the first time in a rodent model

Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminiscent of the incidence of idiopathic spontaneous prion diseases in humans, which account for more than 85% of the cases in humans. Hence, developing animal models that consistently reproduce this phenomenon of spontaneous PrP misfolding, is of importance to study the pathobiology of idiopathic spontaneous prion disorders. Transgenic mice overexpressing sheep PrPC with I112 polymorphism (TgShI112, 1–2 × PrP levels compared to sheep brain) manifest clinical signs of a spongiform encephalopathy spontaneously as early as 380 days of age. The brains of these animals show the neuropathological hallmarks of prion disease and biochemical analyses of the misfolded prion protein show a ladder-like PrPres pattern with a predominant 7–10 kDa band. Brain homogenates from spontaneously diseased transgenic mice were inoculated in several models to assess their transmissibility and characterize the prion strain generated: TgShI112 (ovine I112 ARQ PrPC), Tg338 (ovine VRQ PrPC), Tg501 (ovine ARQ PrPC), Tg340 (human M129 PrPC), Tg361 (human V129 PrPC), TgVole (bank vole I109 PrPC), bank vole (I109I PrPC), and sheep (AHQ/ARR and AHQ/AHQ churra-tensina breeds). Our analysis of the results of these bioassays concludes that the strain generated in this model is indistinguishable to that causing atypical scrapie (Nor98). Thus, we present the first faithful model for a bona fide, transmissible, ovine, atypical scrapie prion disease.info:eu-repo/semantics/publishedVersio

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Uterine Arteriovenous Malformation: Diagnostic and Therapeutic Challenges

Uterine arteriovenous malformations are a rare cause of puerperal haemorrhage, but their incidence is increasing due to both improved diagnosis and the more frequent use of uterine surgery in recent years. The use of ultrasound, both B-mode and Doppler, is recommended for diagnosis and follow-up, as it has been shown to be the simplest and most cost-effective method. Endometrial thickening associated with an anechoic and vascular intramiometrial structure is very useful for diagnosis and can help to exclude other causes of dysfunctional bleeding. Pulsed Doppler shows low-resistance vessels and high pulsatility indices with a high peak systolic velocity (PSV). In a healthy myometrium, the vessels have a peak systolic velocity of 9–40 cm/s and a resistance index between 0.6 and 0.8, whereas in the case of AVMs, the systolic and diastolic velocities are 4–6 times higher (PSV 25–110 cm/s with a mean of 60 cm/s and a resistance index of 0.27–0.75 with a mean of 0.41). For treatment, we must individualise each case, taking into account haemodynamic stability, the patient’s reproductive wishes, and the severity of the AVM as assessed by its size and PSV

A prospective observational study on the influence of the difficulty of forceps application and the avulsion of the levator ani muscle

Background: To compare the rate of levator ani muscle (LAM) avulsion between normal deliveries (ND) and forceps deliveries (FD) and to determine whether the difficulty of forceps application in FD is related to the occurrence of LAM avulsion. Methods: This prospective observational study included 240 primiparous patients (125 ND and 115 FD). FD were classified according to the difficulty of forceps application. The application was considered difficult if the fetal head was in a transverse position or if it was midforceps (head engaged by the leading part was above +2 stations) with the fetal head in the occipito-posterior position; otherwise, the application was considered easy. Ultrasound evaluation was performed 6 months after delivery, and complete avulsion was diagnosed when there was abnormal insertion of the LAM in all three central slices. Results: There were statistically significant differences between the ND and FD groups in the presence of LAM avulsion (15.6% vs. 38.3%;

Twin pregnancy in woman affected by severe recessive dystrophic epidermolysis bullosa. A case report and a literature review

Dystrophic epidermolysis bullosa is a group of hereditary disorders that has very low prevalence. It is characterized by an extreme cutaneous fragility as a consequence of a cohesion alteration of the epidermis and dermis junction. However, the clinical manifestations also affect other systems and organs, being able to cause malnutrition and anemia. We present the case of a 34-year-old woman affected by severe recessive dystrophic epidermolysis bullosa, with a bichorial and biamniotic twin pregnancy, whom we have followed throughout the pregnancy. The low prevalence of this disease makes the management of the pregnancy a challenge for the obstetrician. Although the published cases suggest that gestation does not modify the natural course of the disease, it is recommended that these pregnancies are monitored by a multidisciplinary team. Some published cases describe vaginal delivery. Nevertheless, it is not clear that this should be the first choice.La epidermolisis bullosa distrófica es un grupo de trastornos hereditarios de muy baja prevalencia que se caracterizan por una extrema fragilidad cutánea como consecuencia de una alteración de la cohesión de la unión epidermodérmica. Sin embargo, las manifestaciones clínicas van más allá de las lesiones cutáneas, habiéndose descrito afectación de la mayoría de aparatos y sistemas y siendo frecuente también cierto grado de desnutrición y anemia de origen multifactorial. Presentamos el caso de una paciente de 34 años, secundigesta, con epidermólisis bullosa distrófica recesiva severa, gestante gemelar bicorial y biamniótica, que seguimos durante todo el embarazo y su finalización. La baja prevalencia de la enfermedad hace que el manejo de la gestación suponga un reto para el ginecobstetra. A pesar de que los casos publicados hacen creer que la gestación no modifica el curso natural de la enfermedad, lo cierto es que se recomienda que el embarazo sea seguido por un equipo multidisciplinar. Existen publicados casos en los que se finaliza la gestación por vía vaginal, sin embargo, no existe evidencia suficiente para considerar ésta como la vía de elección

Rickettsia parkeri: Patógeno rickettsial transmitido por garrapatas en áreas endémicas de rickettsiosis por fiebre manchada en el sur de Uruguay

At first Rickettsia conorii was implicated as the causative agent of spotted fever in Uruguay diagnosed by serological assays. Later Rickettsia parkeri was detected in human-biting Amblyomma triste ticks using molecular tests. The natural vector of R. conorii, Rhipicephalus sanguineus, has not been studied for the presence of rickettsial organisms in Uruguay. To address this question, 180 R. sanguineus from dogs and 245 A. triste from vegetation (flagging) collected in three endemic localities were screened for spotted fever group (SFG) rickettsiosis in southern Uruguay. Tick extracted DNA pools were subjected to PCR using primers which amplify a fragment of the rickettsial gltA gene. Positive tick DNA pools with these primers were subjected to a second PCR round with primers targeting a fragment of the ompA gene, which is only present in SFG rickettsiae. No rickettsial DNA was detected in R. sanguineus. However, DNA pools of A. triste were found to be positive for a rickettsial organism in two of the three localities, with prevalences of 11.8% to 37.5% positive pools. DNA sequences generated from these PCR-positive ticks corresponded to R. parkeri. These findings, joint with the aggressiveness shown by A. triste towards humans, support previous data on the involvement of A. triste as vector of human infections caused by R. parkeri in Uruguay.Inicialmente, Rickettsia conorii fue señalada como el agente causal de la fiebre manchada en Uruguay, diagnosticada mediante pruebas serológicas. Posteriormente, Rickettsia parkeri fue detectada mediante técnicas moleculares en garrapatas Amblyomma triste colectadas sobre humanos. El vector natural de R. conorii, Rhipicephalus sanguineus, no ha sido estudiado en cuanto a rickettsias en Uruguay. Para abordar este tema, 180 R. sanguineus fueron colectados sobre perros y 245 A. triste sobre vegetación en tres localidades consideradas endémicas para fiebres manchadas en el sur de Uruguay. El ADN de las garrapatas fue extraído en pools y sometido a una primera PCR utilizando cebadores que amplifican un fragmento del gen gltA, presente en prácticamente todas las especies de Rickettsia. Las muestras positivas fueron sometidas a una segunda PCR con cebadores que amplifican un fragmento del gen ompA, presente sólo en rickettsias del grupo de las fiebres manchadas (GFM). No se detectó ADN rickettsial en R. sanguineus. Sin embargo, muestras de A. triste fueron positivas a rickettsiales en dos de las tres localidades estudiadas, con prevalencias de pools positivos del 11.8 y 37.5% respectivamente. La secuenciación del ADN evidenció la presencia de R. parkeri. Basados en estos resultados junto a los anteriores y la agresividad de A. triste hacia los humanos, se concluye que esta garrapata es vector de rickettsiosis humana por R. parkeri en Uruguay.Fil: Venzal, José M.. Universidad de la República; UruguayFil: Estrada Peña, Agustín. Universidad de Zaragoza; EspañaFil: Portillo, Aránzazu. Centro de Investigación Biomédica de La Rioja; EspañaFil: Mangold, Atilio Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria Rafaela; ArgentinaFil: Castro, Oscar. Universidad de la República; UruguayFil: de Souza, Carlos G.. Universidad de la República; UruguayFil: Félix, María L.. Universidad de la República; UruguayFil: Pérez Martínez, Laura. Centro de Investigación Biomédica de La Rioja; EspañaFil: Santibánez, Sonia. Centro de Investigación Biomédica de La Rioja; EspañaFil: Oteo, José A.. Centro de Investigación Biomédica de La Rioja; Españ