Patients with long-standing diabetes frequently demonstrate gastric hypersensitivity with an unknown mechanism. The present study was designed to investigate roles for nuclear factor-B (NF-B) and the endogenous H 2 S-producing enzyme cystathionine-␤-synthetase (CBS) signaling pathways by examining cbs gene methylation status in adult rats with diabetes. Intraperitoneal injection of streptozotocin (STZ) produced gastric hypersensitivity in female rats in response to gastric balloon distention. Treatment with the CBS inhibitor aminooxyacetic acid significantly attenuated STZ-induced gastric hypersensitivity in a dose-dependent fashion. Aminooxyacetic acid treatment also reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI in diabetic rats. Conversely, the H 2 S donor NaHS enhanced neuronal excitability of gastric DRG neurons. Expression of CBS and p65 were markedly enhanced in gastric DRGs in diabetic rats. Blockade of NF-B signaling using pyrrolidine dithiocarbamate reversed the upregulation of CBS expression. Interestingly, STZ treatment led to a significant demethylation of CpG islands in the cbs gene promoter region, as determined by methylation-specific PCR and bisulfite sequencing. STZ treatment also remarkably downregulated the expression of DNA methyltransferase 3a and 3b. More importantly, STZ treatment significantly enhanced the ability of cbs to bind DNA at the p65 consensus site, as shown by chromatin immunoprecipitation assays. Our findings suggest that upregulation of cbs expression is attributed to cbs promoter DNA demethylation and p65 activation and that the enhanced interaction of the cbs gene and p65 contributes to gastric hypersensitivity in diabetes. This finding may guide the development and evaluation of new treatment modalities for patients with diabetic gastric hypersensitivity.

BackgroundHydrogen sulfide (H2S), an endogenous gaseotransmitter/modulator, is becoming appreciated that it may be involved in a wide variety of processes including inflammation and nociception. However, the role and mechanism for H2S in nociceptive processing in trigeminal ganglion (TG) neuron remains unknown. The aim of this study is to investigate distribution of endogenous H2S synthesizing enzyme cystathionine-β-synthetase (CBS) expression and role of H2S on excitability and voltage-gated potassium channels of TG neurons.MethodsImmunofluorescence studies were carried out to determine whether CBS was co-expressed in Kv1.1 or Kv1.4-positive TG neurons. Whole cell patch clamp recordings were employed on acutely isolated TG neurons from adult male Sprague Dawley rats (6–8 week old). von Frey filaments were used to examine the pain behavioral responses in rats following injection of sodium hydrosulfide.ResultsIn rat TG, 77.3±6.6% neurons were immunoreactive for CBS, 85.1±3.8% for Kv1.1 and 97.8±1.1% for Kv1.4. Double staining showed that all CBS labeled cells were Kv1.1 and Kv1.4 positive, but only 92.2±6.1% of Kv1.1 and 78.2±9.9% of Kv1.4 positive cells contained CBS. Application of H2S donor NaHS (250 μM) led to a significant depolarization of resting membrane potential recorded from TG neurons. NaHS application also resulted in a dramatic reduction in rheobase, hyperpolarization of action potential threshold, and a significant increase in the number of action potentials evoked at 2X and 3X rheobase stimulation. Under voltage-clamp conditions, TG neurons exhibited transient A-type (IA) and sustained outward rectifier K+ currents (IK). Application of NaHS did suppress IK density while did not change IA density of TG neurons (n=6). Furthermore, NaHS, a donor of hydrogen sulfide, produced a significant reduction in escape threshold in a dose dependent manner.ConclusionThese data suggest that endogenous H2S generating enzyme CBS was co-localized well with Kv1.1 and Kv1.4 in TG neurons and that H2S produces the mechanic pain and increases neuronal excitability, which might be largely mediated by suppressing IK density, thus identifying for the first time a specific molecular mechanism underlying pain and sensitization in TG.

The automated classification of heart sounds plays a significant role in the diagnosis of cardiovascular diseases (CVDs). With the recent introduction of medical big data and artificial intelligence technology, there has been an increased focus on the development of deep learning approaches for heart sound classification. However, despite significant achievements in this field, there are still limitations due to insufficient data, inefficient training, and the unavailability of effective models. With the aim of improving the accuracy of heart sounds classification, an in-depth systematic review and an analysis of existing deep learning methods were performed in the present study, with an emphasis on the convolutional neural network (CNN) and recurrent neural network (RNN) methods developed over the last five years. This paper also discusses the challenges and expected future trends in the application of deep learning to heart sounds classification with the objective of providing an essential reference for further study.

Background The differential diagnosis of cystic renal masses still faces great challenges. There has been no systematically assessment to compare the value of contrast-enhanced ultrasound (CEUS) with magnetic resonance imaging (MRI) in the diagnosis of cystic renal masses. Purpose To perform a meta-analysis to compare the diagnostic efficacy of CEUS with that of MRI for cystic renal masses. Material and Methods A systematic search was performed for literature evaluating the diagnostic performance of CEUS or MRI in cystic renal masses. Quality assessment of diagnostic studies 2 (QUADAS-2) was used to evaluate the quality of each study included. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and the areas under the summary receiver operating characteristic (AUCs-SROC) curve for CEUS and MRI were calculated, respectively. Results Seventeen studies with 1142 lesions were included. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for CEUS /MRI were 0.95/0.92, 0.84/0.91, 5.62/6.74, and 0.09/0.13, respectively. The AUCs-SROC curves for the two methods were 95.66% and 94.65%. The subgroup analysis indicated that the scanning slice thickness may influence the diagnostic efficacy of MRI. Conclusion Both CEUS and MRI have good diagnostic performance for cystic renal masses and can provide the reference for clinicians. CEUS is more sensitive but less specific than MRI.

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