Heart valve surgery in patients with homozygous sickle cell disease: A management strategy

Background:

Patients with the homozygous sickle cell disease have increased perioperative mortality. Some indications like heart valve surgery, may justify an exchange blood transfusion to reduce the proportion of hemoglobin S (HbS) and complications.

Subjects and Methods:

We report two female cases aged 20 and 27, of African origin with homozygous sickle cell anemia who underwent heart valve surgery to treat mitral valve regurgitation. This presentation describes the perioperative considerations including anesthesia and postoperative care.

Results:

A partial exchange blood transfusion decreased HbS levels from respectively, 90% and 84%, 9% to 27% and 34%, and simultaneously treated the anemia. Neither sickling crisis nor acidosis occurred in any patient, and no special postoperative complication occurred. Average hospital stay was 10 days. Currently, the two patients remain alive and free of cardiac symptoms.

Discussion:

Although the presence of sickle cell disorders is associated with increased risk of sickling and thus vaso-occlusive complications, they should not be taken as a contraindication for heart valve surgery. Nevertheless, monitoring of certain parameters such as venous, arterial oxygen content, pH, and body temperature is mandatory for a better outcome. Furthermore, preoperative exchange transfusion has a positive influence on the outcome of surgery and on the survival of patients undergoing heart valves surgery. Avoiding intraoperative hypoxia, hypothermia, and vaso-constrictive agents, minimizing HbS levels with preoperative exchange transfusion, and ensuring a stress-free environment with the judicious use of sedatives made surgery relatively safe in these cases.     

Travelling models and the challenge of pragmatic contexts and practical norms: the case of maternal health

As in other areas of international development, we are witnessing the proliferation of ‘traveling models’ developed by international experts and introduced in an almost identical format across numerous countries to improve some aspect of maternal health systems in low- and middle-income countries. These policies and protocols are based on ‘miracle mechanisms’ that have been taken out of their original context but are believed to be intrinsically effective in light of their operational devices.In reality, standardised interventions are, in Africa and elsewhere, confronted with pragmatic implementation contexts that are always varied and specific, and which lead to drifts, distortions, dismemberments and bypasses. The partogram, focused antenatal care, the prevention of mother-to-child transmission of HIV or performance-based payment all illustrate these implementation gaps, often caused by the routine behaviour of health personnel who follow practical norms (and a professional culture) that are often distinct from official norms – as is the case with midwives.Experiences in maternal and child health in Africa suggest that an alternative approach would be to start with the daily reality of social and practical norms instead of relying on models, and to promote innovations that emerge from within local health systems.     

Arterial manifestations of Behcet's disease. A report of five operated cases

Vascular involvement in Behcet's disease is common, especially in deep vein thrombosis. Aneurysmal or occlusive arterial disease is, however, rare. The authors report five cases of vascular Behcet's disease reviewed over a period of 4 years (1996-1999). All these patients were men and the mean age was 38 years. The arterial disease was the presenting symptom of Behcet's disease in 3 cases. The other patients had been followed up for Behcet's disease for 4 years. The average time of onset of arterial disease was 7.2 years with respect to the presenting symptom, the range being 2 to 20 years. In all, seven arteries were involved, two patients having two arterial sites at the same time. The femoral artery was involved in 3 cases. The iliac artery was involved twice. One patient had a coronary thrombosis and the last case was of a pseudoaneurysm of the infra-renal abdominal aorta which ruptured into the retroperitoneal space. Six lesions were aneurysmal. All patients underwent surgery. The histological analysis of the resected lesions showed non-specific panvasculitis. The postoperative period was marked by short and medium term complications: four prosthetic thromboses and two anastomotic pseudo-aneurysms which required several surgical procedures and which led to two deaths. These results and a review of the literature underline the need to search for Behcet's disease in all cases of aneurysmal or occlusive arterial disease in young patients, especially those born in the Mediterranean regions. Surgical treatment should not be delayed. In these inflammatory conditions with pronounced perivascular involvement, the surgery is difficult and postoperative complications are common, especially anastomotic disunion. Medical treatment has no surgical implication, but does not prevent progression of the disease.     

In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin

Background and Purpose

We have described a novel antidepressant peptide, spadin, that acts by blocking the TWIK-related-potassium channel, type 1 (TREK-1). Here, we examined possible mechanisms of action of spadin at both molecular and cellular levels.

Experimental Approaches

Effects of spadin were measured in primary cultures of neurons or tissues from mice injected i.v. with spadin. Western blots, qPCR, histochemical and electrophysiological techniques were used.

Key Results

In vitro, spadin increased neuronal membrane potential and activated both the MAPK and PI3K signalling pathways, in a time- and concentration-dependent manner. The latter pathway was involved in the protective effect of spadin against staurosporine-induced apoptosis. Also, spadin enhanced both mRNA expression and protein of two markers of synaptogenesis, the post-synaptic density protein of 95 kDalton (PSD-95) and synapsin. We confirmed these effects on synaptogenesis by the observation that spadin treatment significantly increased the proportion of mature spines in cortical neurons. Finally, in vivo injections of spadin led to a rapid increase in both mRNA expression and protein level of brain-derived neurotrophic factor (BDNF) in the hippocampus, confirming the antidepressant action of the peptide. We argue for a new role of spadin in synaptogenesis as both PSD-95 and synapsin mRNA expression and protein levels were further enhanced in the hippocampus, following treatment in vivo with the peptide.

Conclusions and Implications

These findings provide new mechanisms of action for the rapidly acting antidepressant peptide spadin by stimulating expression of BDNF and synaptic proteins, both in vitro and in vivo.     

Targeting two-pore domain K+ channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept

Depression is a disease that is particularly frequent, affecting up to 20% of the population in Western countries. The origins of this pathology involve multiple genes as well as environmental and developmental factors leading to a disorder that remains difficult to treat. Several therapies for depression have been developed and these mainly target monoamine neurotransmitters. However, these treatments are not only associated with numerous adverse effects, but they are also ineffective for more than one-third of patients. Therefore, the need to develop new concepts to treat depression is crucial. Recently, studies using knockout mouse models have provided evidence for a crucial role of two members of the two-pore domain potassium channel (K_2P) family, tandem P-domain weak inward rectifying K⁺ (TWIK)-related K⁺ channel 1 (TREK-1) and TWIK-related acid-sensitive K⁺ channel 3 (TASK-3) in the pathophysiology of depression. It is believed that TREK-1 and TASK-3 antagonists could lead to the development of new antidepressants. Herein, we describe the discovery of spadin, a natural peptide released from the maturation of the neurotensin receptor-3 (also known as sortilin), which specifically blocks the activity of the TREK-1 channel and displays particular antidepressant properties, with a rapid onset of action and the absence of adverse effects. The development of such molecules may open a new era in the field of psychiatry.     

Surgery of active-phase infective endocarditis: report of 13 cases

OBJECTIVE: Infective endocarditis is always a disease at the present time. In this work we report our initial experience of infective endocarditis surgical treatment during the acute phase. METHODS AND RESULTS: Between September 1993 and December 1997, 13 patients underwent valvular surgery for native infective endocarditis. Mean age was 31 +/- 11 years (range: 9 to 42 years); 92.3% of the patients presented with pre-existing rheumatical valvular lesion. Surgical indication was the occurrence of heart failure in all these patients. Surgery consisted on aortic valvular replacement in four patients, mitral and aortic valvular replacement in nine patients. Tricuspid valvuloplasty was required in two patients. Early mortality was 15% (two patients). A third patient developed cardiac failure and died three years postoperatively. CONCLUSION: This work emphasises the interest of the surgical treatment in the active phase of the infective endocarditis.     

Cu(ii)-alginate-based superporous hydrogel catalyst for click chemistry azide–alkyne cycloaddition type reactions in water

A novel sustainable hydrogel catalyst based on the reaction of sodium alginate naturally extracted from brown algae Laminaria digitata residue with copper(ii) was prepared as spherical beads, namely Cu(ii)-alginate hydrogel (Cu(ii)-AHG). The morphology and structural characteristics of these beads were elucidated by different techniques such as SEM, EDX, BET, FTIR and TGA analysis. Cu(ii)-AHG and its dried form, namely Cu(ii)-alginate (Cu(ii)-AD), are relatively uniform with an average pore ranging from 200 nm to more than 20 μm. These superporous structure beads were employed for the copper catalyzed [3 + 2] cycloaddition reaction of aryl azides and terminal aryl alkynes (CuAAC) via click chemistry at low catalyst loading, using water as a solvent at room temperature and pressure. The catalytic active copper(i) species was generated by the reduction of copper(ii) by terminal alkyne via the oxidative alkyne homocoupling reaction. The prepared catalysts were found to be efficient (85–92%) and regioselective by affording only 1,4-disubstituted-1,2,3-triazoles. They were also recoverable and reused in their dried form for at least four consecutive times without a clear loss of efficiency. A mechanistic study was performed through density functional theory (DFT) calculations in order to explain the regioselectivity outcome of Cu(ii)-alginate in CuAAC reactions. The analysis of the local electrophilicity (ω_k) at the electrophilic reagent and the local nucleophilicity (N_k) at the nucleophilic confirms the polar character of CuAAC. This catalyst has the main advantage of being sustainably ligand-free and recyclable.

The Cu(ii)-alginate-based superporous hydrogel was prepared and used as a heterogenous catalyst in the regioselective click of 1,4-disubstituted-1,2,3-triazoles by CuAAC reactions.     

The peptidic antidepressant spadin interacts with prefrontal 5-HT4 and mGluR2 receptors in the control of serotonergic function

This study investigates the mechanism of action of spadin, a putative fast-acting peptidic antidepressant (AD) and a functional blocker of the K⁺ TREK-1 channel, in relation with the medial prefrontal cortex (mPFC)–dorsal raphé (DRN) serotonergic (5-HT) neurons connectivity. Spadin increased 5-HT neuron firing rate by 113 %, an augmentation abolished after electrolytic lesion of the mPFC. Among the few receptor subtypes known to modulate TREK-1, the stimulation of 5-HT₄ receptors and the blockade of mGluR_2/3 ones both activated 5-HT impulse flow, effects also suppressed by mPFC lesion. The combination of spadin with the 5-HT₄ agonist RS 67333 paradoxically reduced 5-HT firing, an effect reversed by acutely administering the 5-HT_1A agonist flesinoxan. It also had a robust synergetic effect on the expression of Zif268 within the DRN. Together, these results strongly suggest that 5-HT neurons underwent a state of depolarization block, and that the mechanisms underlying the influences exerted by spadin and RS 67333 are additive and independent from each other. In contrast, the mGluR_2/3 antagonist LY 341495 occluded the effect of spadin, showing that it likely depends on mPFC TREK-1 channels coupled to mGluR_2/3 receptors. These in vivo electrophysiological data were confirmed by in vitro Ca²⁺ cell imaging performed in cultured cortical neurons. Altogether, our results indicate that spadin, as a natural compound, constitutes a very good candidate to explore the “glutamatergic path” of fast-acting AD research. In addition, they provide the first evidence of 5-HT depolarization block, showing that the combination of 5-HT activators for strategies of AD augmentation should be performed with extreme caution.