Action potential propagation in transverse-axial tubular system is impaired in heart failure

The plasma membrane of cardiac myocytes presents complex invaginations known as the transverse-axial tubular system (TATS). Despite TATS's crucial role in excitation-contraction coupling and morphological alterations found in pathological settings, TATS's electrical activity has never been directly investigated in remodeled tubular networks. Here we develop an ultrafast random access multiphoton microscope that, in combination with a customly synthesized voltage-sensitive dye, is used to simultaneously measure action potentials (APs) at multiple sites within the sarcolemma with submillisecond temporal and submicrometer spatial resolution in real time. We find that the tight electrical coupling between different sarcolemmal domains is guaranteed only within an intact tubular system. In fact, acute detachment by osmotic shock of most tubules from the surface sarcolemma prevents AP propagation not only in the disconnected tubules, but also in some of the tubules that remain connected with the surface. This indicates that a structural disorganization of the tubular system worsens the electrical coupling between the TATS and the surface. The pathological implications of this finding are investigated in failing hearts. We find that AP propagation into the pathologically remodeled TATS frequently fails and may be followed by local spontaneous electrical activity. Our findings provide insight on the relationship between abnormal TATS and asynchronous calcium release, a major determinant of cardiac contractile dysfunction and arrhythmias.     

Pharyngeal Electrical Stimulation for Dysphagia Associated with Multiple Sclerosis: A Pilot Study

ObjectiveTreatment options for dysphagia associated with multiple sclerosis (MS) are currently limited. In this study we investigated whether intraluminal electrical pharyngeal stimulation facilitates swallowing recovery in dysphagic MS patients.Patients and methodsTwenty dysphagic MS patients were randomized to receive 5 Hz “real” pharyngeal stimulation (10 patients) for 10 min or “sham” pharyngeal stimulation for 10 min (10 patients). Patients were evaluated by videofluoroscopic, and electromyographic examinations, and by the Penetration/Aspiration Scale (PAS) performed before (T₀) and immediately after the last session of 5 consecutive days of electrical pharyngeal stimulation (T₁), and then after two (T₂), and four (T₃) weeks of 5 consecutive days of pharyngeal electrical stimulation.ResultsPatients who received “real” stimulation showed a significant improvement in all the swallowing outcome measures as compared with those receiving “sham” stimulation.ConclusionsNo specific treatment for oro-pharyngeal dysphagia related to MS has been described to date. Our preliminary findings suggest a potential benefit of intraluminal electrical pharyngeal stimulation for the treatment of dysphagia caused by MS.     

《英国非酒精性脂肪性肝炎肝移植指南》导读

非酒精性脂肪性肝炎（non—alcoholicsteatohepatitis,NASH）现已成为肝移植愈来愈重要的基础肝病。鉴于晚期NASH患者常并存多种影响肝移植转归的临床问题,而至今尚无针对NASH患者进行肝移植的评估和治疗指南,为此英国移植学会（British Transplant Society,BTS）邀请相关专家制定了指南,以指导肝移植前后NASH患者的处理。     

Diagnosis and management for urosepsis

Urosepsis is defined as sepsis caused by a urogenital tract infection. Urosepsis in adults comprises approximately 25% of all sepsis cases, and is in most cases due to complicated urinary tract infections. The urinary tract is the infection site of severe sepsis or septic shock in approximately 10–30% of cases. Severe sepsis and septic shock is a critical situation, with a reported mortality rate nowadays still ranging from 30% to 40%. Urosepsis is mainly a result of obstructed uropathy of the upper urinary tract, with ureterolithiasis being the most common cause. The complex pathogenesis of sepsis is initiated when pathogen or damage‐associated molecular patterns recognized by pattern recognition receptors of the host innate immune system generate pro‐inflammatory cytokines. A transition from the innate to the adaptive immune system follows until a T_H2 anti‐inflammatory response takes over, leading to immunosuppression. Treatment of urosepsis comprises four major aspects: (i) early diagnosis; (ii) early goal‐directed therapy including optimal pharmacodynamic exposure to antimicrobials both in the plasma and in the urinary tract; (iii) identification and control of the complicating factor in the urinary tract; and (iv) specific sepsis therapy. Early adequate tissue oxygenation, adequate initial antibiotic therapy, and rapid identification and control of the septic focus in the urinary tract are critical steps in the successful management of a patient with urosepsis, which includes early imaging, and an optimal interdisciplinary approach encompassing emergency unit, urological and intensive‐care medicine specialists.     

Midterm results of surgical treatment of displaced proximal humeral fractures in children

Purpose

To analyse the clinical outcomes of 26 children treated surgically for displaced proximal humerus fracture.

Materials and methods

From January 2008 to December 2012, 26 children/adolescents (14 boys, 12 girls) were treated surgically for displaced fractures at the proximal extremity of the humerus. Ten were grade III and 16 were grade IV according to the Neer–Horowitz classification with a mean age of 12.8 ± 4.2 years. Twenty young patients were surgically treated with a closed reduction and direct percutaneous pinning; six required an open approach. To obtain a proper analysis, we compared the Costant scores with the contralateral shoulder (Δ Costant).

Results

The mean follow-up period was 34 months (range 10–55). Two grade IV patients showed a loss in the reduction after percutaneous treatment. This required open surgery with a plate and screws. On average, the treated fractures healed at 40 days. The mean Δ Costant score was 8.43 (range 2–22). There was a statistically significant improvement in the mean Δ Costant score in grade III patients. In grade IV patients, there was a significant improvement in the mean Δ Costant score in those treated with open surgery versus mini-invasive surgery.

Conclusions

Our study shows excellent results with percutaneous k-wires. This closed surgery had success in these patients, and the excellent outcomes noted here lead us to prefer the mini-invasive surgical approach in NH grade III fractures. In grade IV, the best results were noted in patients treated with open surgery. We suggest an open approach for these patients.

Level of evidence

III.

     

Interleukin-3 treatment of rhesus monkeys leads to increased production of histamine-releasing cells that express interleukin-3 receptors at high levels

To understand the hematopoietic and nonhematopoietic responses to interleukin-3 (IL-3), expression of cell-surface IL-3 receptors (IL-3R) was examined on bone marrow (BM) cells and peripheral blood (PB) cells of rhesus monkeys during the course of in vivo IL-3 treatment. Whereas IL-3R expression is low in untreated monkeys, IL-3 administration led to a gradual increase in both low- and high-affinity binding sites for IL-3. This increase reflected the total number of cells expressing IL- 3Rs, as detected by flow cytometry using biotinylated IL-3. Most of these IL-3R+ cells in both BM and PB could be characterized as basophilic granulocytes that contained high levels of histamine. In contrast to the effect on these differentiated cells, IL-3 administration did not significantly alter the low level IL-3R expression on immature, CD34+ cells. Further flow cytometric analysis using biotinylated growth factors showed that the IL-3R+ basophils also expressed receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), but not for IL-6 or Kit ligand. These findings indicated that the IL-3R+ cells included neither monocytes, which express GM-CSFRs and IL-6Rs abundantly, nor mast cells, which express c- kit. By combining flow cytometric and Scatchard data, it was calculated that the basophils contain as many as 1 to 2 x 10(3) high-affinity IL- 3Rs and 15 to 30 x 10(3) low-affinity sites. The finding that in vivo IL-3 treatment leads to the production of large numbers of cells that express high levels of IL-3R and are capable of producing histamine provides an explanation for the often severe allergic reactions that occur during prolonged IL-3 administration. It also indicates that IL- 3, in addition to its direct effects on hematopoietic cells, may also stimulate hematopoiesis through the release of secondary mediators such as histamine by IL-3-responsive mature cells.     

Impact of caloric restriction on peripheral nerve injury‐induced neuropathic pain during ageing in mice

The incidence of peripheral neuropathy development and chronic pain is strongly associated with the arrival of senescence. The gradual physiological decline that begins after the mature stage produces myelin dysregulation and pathological changes in peripheral nervous system, attributed to reduction in myelin proteins expression and thinner myelin sheath. Moreover in elder subjects, when nerve damage occurs, the regenerative processes are seriously compromised and neuropathic pain (NeP) is maintained. We previously demonstrated that caloric restriction (CR) in adult (4 months) nerve‐lesioned mice was able to facilitate remyelination and axons regeneration, to have anti‐inflammatory action and to prevent NeP chronification. Here, we show CR therapeutic potential on nerve injury‐induced neuropathy in mice at the beginning of the senescence (12 months). Long lasting decrease in hypersensitvity induced by peripheral nerve lesion and powerful reduction in proinflammatory circulating agents have been observed. Moreover, our results evidence that CR is able to counteract the ageing‐related delay in axonal regeneration, enhancing Schwann cells proliferation and accelerating recovery processes. Differently from adults, it does not affect fibres myelination. In light of a continuous growth in elderly population and correlated health problems, including metabolic disorders, the prevalence of neuropathy is enhancing, generating a significant public cost and social concern. In this context energy depletion by dietary restriction can be a therapeutic option in NeP.