TEVAR in Patients With Late Complications of Aortic Coarctation Repair

Purpose: To review the use of thoracic endovascular aortic repair (TEVAR) for late pseudoaneurysm formation after surgical repair of aortic coarctation. Methods: From May 2001 to May 2005, 8 patients (5 men; mean age 47.6 years, range 18-73) with a history of aortic coarctation repairs 17 to 40 years prior were referred to our institution for an anastomotic thoracic pseudoaneurysm. TEVAR was performed successfully in 7 patients; 1 died of suspected aneurysm rupture before the scheduled procedure. A carotid-subclavian bypass was performed in 3 patients. Results: All the procedures were immediately successful. No type I endoleaks were seen on the final control angiogram, but 2 of the patients with carotid-subclavian bypasses required additional left subclavian artery embolization due to type II endoleak. One of these patients died before embolotherapy on the 5th postoperative day from presumed aneurysm rupture (14% 30-day mortality rate). Over a follow-up period ranging from 15 to 72 months (mean 37), all the false aneurysms have remained thrombosed and the mean diameter has decreased from 44 to 23 mm. No endograft-related complications have occurred, and no further interventions have so far been necessary. Conclusion: TEVAR is a feasible alternative treatment for patients who have already undergone surgical repair of aortic coarctation. Technical issues regarding the endovascular strategy should be discussed with a multidisciplinary team to define the correct interventional plan.     

The multidrug resistance (mdr1) gene product functions as an ATP channel.

The multidrug resistance (mdr1) gene product, P-glycoprotein, is responsible for the ATP-dependent extrusion of a variety of compounds, including chemotherapeutic drugs, from cells. The data presented here show that cells with increased levels of the P-glycoprotein release ATP to the medium in proportion to the concentration of the protein in their plasma membrane. Furthermore, measurements of whole-cell and single-channel currents with patch-clamp electrodes indicate that the P-glycoprotein serves as an ATP-conducting channel in the plasma membrane. These findings suggest an unusual role for the P-glycoprotein.     

Determination of the learning curve for ultrasound-guided jugular central venous catheter placement

Purpose

Use of ultrasound (US) when introducing central venous catheters (CVC) may improve success rates, reduce the number of needle punctures, and decrease complication rates, but has been hampered by supposed difficulty in learning how to perform the technique. This study describes the learning curve for US-guided jugular CVC placement after a training program.

Methods

After an initial slide presentation and a video, intensivists who had not previously used US for CVC placement were evaluated qualitatively for US set up (score S1) and technical skills (score S2). Quantitative measures included durations of different components of the procedure (T ₁, time from entry of the US into the patient’s room to sterile dressing of the intensivist; T ₂, time needed for sterile drapes, venous line preparation, and sterile sheath placement; T ₃, time from skin puncture to venous flashback; T ₄, time from guide insertion to dressing; T _tot, total duration of the procedure); number of skin punctures; and a difficulty score allocated by the intensivist.

Results

We performed 150 evaluations of 30 intensivists: 50 % had no prior experience of CVC placement and 50 % no prior US experience. Maximal S1 and S2 scores were obtained with the fourth and eighth placement procedures, respectively. T ₁ and T ₂ did not change with ongoing training (5 and 8 min, respectively), but T ₃ and T ₄ decreased, from 5 min (first procedure) to less than 1 min (seventh procedure), and from 10 min (first procedure) to 7 min (sixth procedure), respectively. T _tot decreased from 34 to 21 min at the eighth procedure. The number of skin punctures and the difficulty score decreased rapidly with the number of evaluations.

Conclusions

Our study demonstrates that skills in US-guided CVC placement can easily be acquired with training.     

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.Nine secretory proprotein convertases (PCs) play major roles in regulating multiple cellular and extracellular processes both in health and disease states (reviewed in refs. 1 and 2). The convertases PC1/3, PC2, Furin, PC4, PC5/6, PACE4, and PC7 cleave their substrates after single or pairs of basic amino acids, SKI-1/S1P processes protein precursors after nonbasic residues, and PCSK9 has no known substrates other than itself (1). Studies that have analyzed tissue expression, levels, regulation, ontogeny, phenotypes of model animals lacking one or more PCs, and human/mouse natural mutations are starting to provide clues as to the specific roles of these enzymes in cells and whole-animal physiological and pathological processes.The type I membrane-bound PC7 is the most ancient member of the mammalian basic amino acid-specific PC family, and it exhibits the closest homology to yeast kexin (3). Human PC7 is synthesized as an N-glycosylated zymogen (proPC7) that, like most other PCs, undergoes autocatalytic cleavage in the endoplasmic reticulum at RAKR₁₄₁↓SV. Mature PC7 can reach the cell surface by an unconventional route from the endoplasmic reticulum (4), but it also accumulates in the trans Golgi network (TGN) and can cycle between the cell surface and TGN via endosomes, in part by virtue of a Pro-Leu-Cys₇₂₆ motif in its cytosolic tail (5). The tail also contains two cysteine residues, Cys₆₉₉ and Cys₇₀₄, which are palmitoylated (3, 4, 6), that may assist in this process. Confocal and electron microscopy studies have revealed that PC7 localizes to vesicles located immediately beneath the plasma membrane (4, 7). No soluble shed forms of PC7 have been detected. Enzymatic activity assays using only the soluble luminal/extracellular domain of PC7 (sol.PC7) and fluorogenic substrates have indicated that this Ca²⁺-dependent enzyme exhibits a neutral pH optimum and a cleavage specificity similar to that of Furin, cleaving within the general motif (R/K)-2X_n-R↓ where n = 0–2 (8, 9).Only the membrane-bound PC7 induces the processing of proepidermal growth factor into a ∼115-kDa transmembrane form (10). PC7 is abundant in neurons (11) but is also expressed in microglia (12). It has been shown that PC7 exerts an important function in MHC class I-mediated antigen presentation (7), befitting its high expression within the immune system (3). Finally, PC7 is unique because it is able to shed the human transferrin receptor 1 (TfR1) into a soluble form by cleavage at KTECER₁₀₀↓LA within endosomes (13).The physiological importance of the PCs is illustrated by the early death or major phenotypes observed in mice lacking one or more convertase (1, 14). Although generated several years ago, deletion of PC7 is the only PC KO mouse for which no overt phenotype(s) has been described (15). In contrast, PC7 knockdown in Xenopus is embryonic lethal. These embryos lack eyes and brain and exhibit abnormal anterior neural development (16). Unless this knockdown is due to an off-target effect, amphibian PC7 seems to fulfill essential neuronal functions that, in mammals, may be either nonessential or redundantly assumed by other PCs. Notably, the regulation of the PC7 gene (PCSK7) has not been examined (3, 17).In the present work we describe behavioral alterations in mice lacking PC7. Our results show that PC7 KO mice have lower levels of BDNF in the hippocampus and amygdala than WT mice and exhibit learning and memory impairments. Reduced BDNF levels are likely responsible for some of these deficits, because they are rescued by an agonist to the BDNF receptor tyrosine receptor kinase B (TrkB). Therefore, PC7 seems to play unique roles in the CNS, at least in part, through regulating levels of BDNF.     

Effect of resection of the anterior chordae on cardiac function after surgical correction of mitral valve insufficiency]

The preservation of cardiac function in surgical correction of mitral regurgitation implies partially or totally preserving the subvalvular apparatus. However, the conservation of the whole subvalvular apparatus during mitral valve replacement is technically difficult as the anatomical conditions are not always favourable. In order to determine the consequences of isolated resection of the anterior chordae, the authors studied global and segmental cardiac function by isotopic angiocardiography after mitral valve repair (n = 23) or replacement with conservation of the posterior chordae (n = 16) in 39 patients with isolated, non-ischaemic mitral regurgitation. The left ventricular ejection fraction decreased after valve replacement (64.1 +/- 8.5% to 57.4 +/- 10%, p = 0.01) but not after mitral valve repair (65 +/- 11.3% to 62.1 +/- 12.2%, p = NS). The ejection fractions of segments 4 and 5, corresponding to the zones of insertion of the anterior papillary muscle, decreased after valve replacement compared with repair (segment 4: -9 +/- 13.7 versus +2 +/- 11.3, p = 0.01) (segment 5: -15 +/- 13.2 versus 2 +/- 11.7, p = 0.003). The right ventricular ejection fraction improved after valve repair (40.9 +/- 9.1% to 46.4 +/- 10.1%, p = 0.03), whereas it remained unchanged after valve replacement (42.9 +/- 10.3% to 42.8 +/- 8.6%, p = NS). These results indicate a deleterious effect of isolated resection of the anterior chordae on cardiac function during mitral valve replacement with localised abnormalities of left ventricular function. This study supports the rationale of mitral valve repair or conservation of the anterior and posterior chordae during valve replacement for isolated mitral regurgitation.