Long-term Intrinsic Rhythm Evaluation in Dogs with Atrioventricular Block

Background: Atrioventricular block (AVB) is a conduction abnormality along the atrioventricular node that, depending on etiology, may lead to different outcomes. Objectives: To evaluate variations of intrinsic rhythm (IR) in dogs that underwent pacemaker implantation (PMI). Animals: Medical records of 92 dogs affected by 3rd degree atrioventricular block (3AVB), advanced 2nd degree AVB (2AVB), paroxysmal 3AVB, 2:1 2AVB, or 3AVB with atrial fibrillation (AF) were retrospectively reviewed. Method: The patient IR was documented with telemetry on the day of 1 - (95% CI, 1-2), 33 - (95% CI, 28-35), 105 - (95%CI, 98-156), and 275 days (95%CI, 221-380) after PMI. According to AVB grade at different examinations, AVB was defined as progressed, regressed, or unchanged. Results: In 48 dogs, 3AVB remained unchanged, whereas in 7 it regressed. Eight cases of 2AVB progressed, 3 regressed and 2 remained unchanged. Eight cases of paroxysmal 3AVB progressed and 3 remained unchanged. Four dogs affected by 2:1 2AVB progressed, 2 regressed, and 1 remained unchanged. All cases with 3AVB with AF remained unchanged. Regression occurred within 30 days after PMI, whereas progression was documented at any time. Variations in IR were associated with type of AVB (P <03) and time of follow-up (P <0001). Conclusions and clinical importance: The degree of AVB assessed at the time of PMI should not be considered definitive because more than one-third of the cases in this study either progressed or regressed. Additional studies would be necessary to elucidate possible causes for transient AVB in dogs

Fatal pulmonary hypertension and right-sided congestive heart failure in a kitten infected with Aelurostrongylus abstrusus

Aelurostrongylus abstrusus is considered the most important respiratory nematode of domestic cats worldwide. This parasite inhabits the alveoli, alveolar ducts, and bronchioles and causes a subacute to chronic respiratory clinical disease. Clinical signs may occur in domestic cats of any age, though they aremore oftendescribedin young animals. Physical examination, echocardiography, thoracic radiography, pulmonary and cardiac pathological findings, classical, and molecular parasitological analysis of a six-month-old kitten referred at the Veterinary Teaching Hospital of the University of Pisa (Italy) led to a diagnosis of parasitic bronchopneumonia caused by A. abstrusus, which was complicated by severe pulmonary hypertension (PH) and right-sided congestive heart failure (R-CHF) that caused the death of the animal. Cases of reversible PH associated with A. abstrusus infection have been seldom reported in cats. This is the first report of fatal PH and R-CHF in a kitten with clinical aelurostrongylosis

Nearctic Pleistocene ungulates from the Pampean region (Argentina) in the historical collections of Santiago Roth in Switzerland: an overview

Nearctic ungulates such as artiodactyls, perissodactyls, and proboscideans arrived in South America during the Great American Biotic Interchange. Among them are camelids, cervids, tayassuids, equids, tapirids and gomphotherids. A historical collection of Nearctic ungulates from Pleistocene deposits of the Pampean region in Argentina is here studied and described. The collection consists of specimens collected by Santiago Roth in the nineteenth century and brought to Europe, where they are housed in the paleontological collections of the University of Zurich and the Natural History Museum of Geneva. Among the taxa reported here are Notiomastodon platensis,Lama guanicoe, Hemiauchenia paradoxa, Tayassu pecari, Morenelaphus sp., Hippidion cf. H. principale, Equus cf. E. neogeus, and other indeterminate gomphotherids, camelids, tayassuids, cervids, and equids. The exact stratigraphic position of these fossils collected more than 130 years ago is in many cases uncertain. The historical collection is still relevant for taxonomic studies and for offering new insights into palaeobiogeography and palaeobiology of mammalian fauna of the region during the Pleistocene

Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for &gt; 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials

Quantification of the effect of mammographic screening on fatal breast cancers: The Florence Programme 1990–96

Breast cancer cases diagnosed in women aged 50–69 since 1990 to 1996 in the City of Florence were partitioned into those who had been invited to screening prior to diagnosis and those who had not. All cases were followed up for vital status until 31 December 1999. The cumulative number of breast cancer deaths among the cases were divided by screening and invitation status, to give the rates of cancers proving fatal within a period of 8 years of observation (incidence-based mortality). We used the incidence-based mortality rates for two periods (1985–86, 1990–96), pre and during screening. The incidence-based mortality ratio comparing 1990–96 and 1985–86 was 0.50 (95% CI : 0.38–0.66), a significant 50% reduction. For noninvited women, compared to 1985-86, there was a 41% significant mortality reduction (RR=0.59, 95% CI : 0.42–0.82). The comparable reduction in those invited was a significant 55% (RR=0.45, 95% CI : 0.32–0.61). The incidence ratio of rates of cancers stage II or worse was close to one when the noninvited in 1990–96 were compared with 1985–86 (RR=0.97, 95% CI : 0.78–1.21). Excluding prevalent cases, the rate of stage II+ breast cancer cases was 42% lower in Screened women compared with the noninvited (RR=0.58, 95% CI : 0.45–0.74). This study confirmed that new treatments and the first rounds of the screening programme contributed to reducing mortality from breast cancer

Hypoglycaemia following upper gastrointestinal surgery: case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Hyperinsulinemic hypoglycemia is relatively recently recognized in persons undergoing bariatric surgery although knowledge and experience with this condition may not be commensurate with the number of such procedures being performed globally. This paper presents a novel case as an example of how such patients may present and how they may be investigated.</p> <p>Case Presentation</p> <p>A 69-year-old man was assessed 3 months post-fundoplication surgery for postprandial hypoglycaemia with neuroglycopenia that became progressively severe. A 72-h fast failed to show hypoglycaemia. During a clinic visit, the patient became confused and had a low plasma glucose, high plasma insulin, and high plasma C-peptide; symptoms were relieved with glucose. No tumours were visualized on CT, MRI, or endoscopic ultrasound. A total body Indium111-octreotide scan was negative. Selective arterial calcium stimulation showed a high insulin gradient in the splenic and superior mesenteric arteries, suggesting diffuse pancreatic beta cell hyperplasia. The patient declined pancreatic resection and recurrent symptomatic hypoglycaemia was successfully prevented with low dose octreotide.</p> <p>Conclusions</p> <p>Although increasingly recognized following bariatric surgery, this is the first reported development of NIPHS (non-insulinoma pancreatogenous hypoglycemia syndrome) following fundoplication surgery, as well as the first documented use of octreotide in post-operative NIPHS. Medical management may be an alternative to surgery for patients with this rare condition.</p

Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines

We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors

p.Ala541Thr variant of MEN1 gene: A non deleterious polymorphism or a pathogenic mutation?

Context Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers. Objective The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes. Patients and methods We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1− heterozygous knock-out mice, and compared with wild type (WT). Results The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein. Conclusion Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype

Shifted Symplectic Structures

This is the first of a series of papers about \emph{quantization} in the context of \emph{derived algebraic geometry}. In this first part, we introduce the notion of \emph{$n$-shifted symplectic structures}, a generalization of the notion of symplectic structures on smooth varieties and schemes, meaningful in the setting of derived Artin n-stacks. We prove that classifying stacks of reductive groups, as well as the derived stack of perfect complexes, carry canonical 2-shifted symplectic structures. Our main existence theorem states that for any derived Artin stack $F$ equipped with an $n$-shifted symplectic structure, the derived mapping stack $\textbf{Map}(X,F)$ is equipped with a canonical $(n-d)$-shifted symplectic structure as soon a $X$ satisfies a Calabi-Yau condition in dimension $d$. These two results imply the existence of many examples of derived moduli stacks equipped with $n$-shifted symplectic structures, such as the derived moduli of perfect complexes on Calabi-Yau varieties, or the derived moduli stack of perfect complexes of local systems on a compact and oriented topological manifold. We also show that Lagrangian intersections carry canonical (-1)-shifted symplectic structures.Comment: 52 pages. To appear in Publ. Math. IHE