Exploring a New Systematic Route for Left Ventricular Pacing in Cardiac Resynchronization Therapy.

BACKGROUND: Frequency and distribution of left ventricular (LV) venous collaterals were studied in vivo to evaluate the ease and feasibility of implanting a new ultra-thin LV quadripolar microlead for cardiac resynchronization therapy (CRT).Methods and Results:Evaluable venograms were analyzed to define the prevalence of venous collaterals (>0.5 mm diameter) between: (1) different LV segments; and (2) different major LV veins in: unselected patients who underwent CRT from 2008 to 2012 at Rouen Hospital, France (retrospective); and CRT patients from the Axone Acute pilot study in 2018 (prospective). In prospective patients with evaluable venograms, LV microlead implantation was attempted. Thirty-six (21/65 retrospective, 15/20 prospective) patients had evaluable venograms with ≥1 visible venous collaterals. Collaterals were found between LV veins in all CRT patients with evaluable venograms. Regionally, prevalence was highest between: the apical inferior and apical lateral (42%); and mid inferior and mid inferolateral (42%) segments. Collateral connections were most prevalent between: the inferior interventricular vein (IIV) and lateral vein (64% [23/36]); and IIV and infero-lateral vein (36% [13/36]). Cross-vein microlead implantation was possible in 18 patients (90%), and single-vein implantation was conducted in the other 2 patients (10%). CONCLUSIONS: Venous collaterals were found in vivo between LV veins in all CRT patients with evaluable venograms, making this network an option for accessing multiple LV sites using a single LV microlead.

Very high stereoselectivity in organocatalyzed desymmetrizing aldol reactions of 3-substituted cyclobutanones.

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized cyclobutanones with control over three contiguous stereogenic centers.

Stereoselective preparation of ß,γ-methano-GABA derivatives.

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected ß,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.

Efficacy of indapamide SR compared with enalapril in elderly hypertensive patients with type 2 diabetes.

BACKGROUND: Blood pressure control is the main influential variable in reducing microalbuminuria in patients with type 2 diabetes. In this subanalysis of the Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with micrOalbuminuRia (NESTOR) study, we have compared the effectiveness of indapamide sustained release (SR) and enalapril in reducing blood pressure and microalbuminuria in patients > or =65 years of age. METHODS: Of the 570 hypertensive patients with type 2 diabetes and persistent microalbuminuria in the NESTOR study, 187 (33%) individuals > or =65 years of age were included in this analysis. Of these, 95 patients received indapamide SR 1.5 mg and 92 patients received enalapril 10 mg, taken once daily in both cases. Adjunctive amlodipine and/or atenolol was added if required. RESULTS: The urinary albumin-to-creatinine ratio decreased by 46% in the indapamide SR group and 47% in the enalapril group. Noninferiority of indapamide SR over enalapril was demonstrated (P = .0236; 35% limit of noninferiority) with a ratio of 0.95 (95% CI: 0.68, 1.34). Mean arterial pressure decreased by 18 mm Hg and 15 mm Hg in the indapamide SR and the enalapril groups, respectively (P = .1136). The effects of both treatments seen in these elderly patients were similar to those observed in the main population, although the extent of the reduction in microalbuminuria was slightly higher. Both treatments were well tolerated, and no difference between groups was observed regarding glucose or lipid profiles. CONCLUSION: Indapamide SR is not less effective than enalapril in reducing microalbuminuria and blood pressure in patients aged >65 years of age with type 2 diabetes and hypertension.

Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study.

OBJECTIVES: To test whether microalbuminuria in patients with type 2 diabetes and hypertension is primarily dependent on the severity of hypertension, and to compare the effectiveness of two antihypertensive drugs with opposite effects on the renin-angiotensin system [the diuretic, indapamide sustained release (SR), and an angiotensin-converting enzyme inhibitor, enalapril] in reducing microalbuminuria. DESIGN: A multinational, multicentre, controlled, double-blind, double-dummy, randomized, two-parallel-groups study over 1 year. METHODS: After a 4-week placebo run-in period, 570 patients (ages 60.0 +/- 9.9 years, 64% men) with type 2 diabetes, essential hypertension [systolic blood pressure (SBP) 140-180 mmHg, and diastolic blood pressure (DBP) < 110 mmHg], and persistent microalbuminuria (20-200 microg/min) were allocated randomly to groups to receive indapamide SR 1.5 mg (n = 284) or enalapril 10 mg (n = 286) once a day. Amlodipine, atenolol, or both were added, if necessary, to achieve the target blood pressure of 140/85 mmHg. RESULTS: There was a significant reduction in the urinary albumin : creatinine ratio. Mean reductions were 35% [95% confidence interval (CI) 24 to 43] and 39% (95% CI 30 to 47%) in the indapamide SR and enalapril groups, respectively. Equivalence was demonstrated between the two groups [1.08 (95% CI 0.89 to 1.31%); P = 0.01]. The reductions in mean arterial pressure (MAP) were 16.6 +/- 9.0 mmHg for the indapamide SR group and 15.0 +/- 9.1 mmHg for the enalapril group (NS); the reduction in SBP was significantly greater (P = 0.0245 ) with indapamide SR. More than 50% of patients in each group required additional antihypertensive therapy, with no differences between groups. Both treatments were well tolerated. CONCLUSIONS: Indapamide-SR-based therapy is equivalent to enalapril-based therapy in reducing microalbuminuria with effective blood pressure reduction in patients with hypertension and type 2 diabetes.

Diastereoselective titanium-mediated construction of cis-2,3-ring annelated 1-(2'-chloroethyl)cyclopropanols.

Titanium(IV)-mediated cyclopropanation induced by reaction of cycloalkylmagnesium bromides 1a-e in the presence of titanium tetraisopropoxide with ethyl beta-chloropropionate 2 yielded cis-fused 1-(2'-chloroethyl)cyclopropanols 3b-e with diastereoselectivity highly depending on the ring size. Unexpected rearrangement products 5d,e were isolated in some cases.

Cerebral hemodynamics and brain oxygen changes related to gravity-induced loss of consciousness in rhesus monkeys.

The aim of the present experiment was to study the influence of +Gz acceleration (head-to-foot inertial forces) onset on cerebral oxygenation changes (cerebral oxy- and deoxy-hemoglobin) and cerebral blood volume (CBV) in order to evaluate the role of cerebral hypoxemia and ischemia in the appearance of +Gz-induced loss of consciousness (G-LOC). We used five rhesus monkeys which were equipped with near infrared spectroscopy optodes fixed onto the parietooccipital cranial bone. G-LOC (isoelectric electrocorticogram) was detected with silver balls electrodes in contact with the dura matter. The animals were centrifuged up to +12 Gz with two onset rates (0.1 and 3 G/s). Cerebral deoxy-hemoglobin increased significantly (max: +30 +/- 6% of control, P < 0.01) only during the 0.1 G/s run. At G-LOC, CBV changes were not related to G-onset rate (P = 0.30; mean change: -32 +/- 6% of control). We conclude that cerebral ischemia is the main mechanism in the occurrence of G-LOC.

Stereoselective Synthesis of Highly Functionalized Cyclopropanes. Application to the Asymmetric Synthesis of (1S,2S)-2,3-Methanoamino Acids.

One-pot palladium(0)-catalyzed alkylation and S(N)(') cyclization of 1,4-dichlorobut-2-ene 1 by the anion of alpha-substituted carbonitriles 2a-d can provide highly functionalized cyclopropanes (E)-4a-d, diastereoselectivity, (de 88-100%). Several attempts to achieve the asymmetric synthesis of the 1-amino-2-ethenylcyclopropanecarbonitrile (E)-9, by means of this new procedure, i.e., using chiral palladium ligands, chiral aminoacetonitriles (-)- and (+)-12 (from 1-hydroxypinanone) or chiral allyl chlorides (4S)-20b-d and (4R)-20e (from (2S) ethyl lactate) have pointed up the reversibility of the palladium-catalyzed cyclization step, responsible for the low enantioselectivity observed (ee 88%) and provided the enantiomerically enriched 1-amino-2-propenylcyclopropanecarbonitrile (E)-22 (ee > 83%) suitable precursor of (1S,2S)-2,3-methanoamino acids.

Qualitative manipulation of amino acid supply during total parenteral nutrition in surgical patients.

We investigated whether a qualitative manipulation of amino acid mixture could improve the nutritional status of patients undergoing surgery. Patients received total parenteral nutrition for 2 consecutive 5-day periods. Energy and nitrogen supplies were calculated using a modified Harris-Benedict equation, with an energy-to-nitrogen ratio of 125 kcal/g nitrogen (N). The mean kilocalorie lipids-to-glucose ratio was 35% to 65%. There were 6 patients in the control group and 7 patients in the experimental group. The control group received the same standard amino acid solution (Vintène, Baxter-Clintec, Maurepas, France) for the entire 10 days. The experimental group received the standard solution during the first 5 days but was switched to a more individualized solution during the last 5 days. The second solution was determined from a linear regression performed on day 3 comparing rate of infusion of each amino acid and its plasma variations after 3 hours of infusion with basal values. Amino acids were defined as oversupplied or undersupplied when not within the 95% confidence interval (above or below the curve, respectively). Daily nitrogen balance and urinary excretion of 3-methylhistidine were measured from day 1 to day 10 in all patients. For the patients in whom these measures were made, amino acid variations except those of lysine (11 of 12), ornithine (6 of 12), alanine (5 of 12), arginine (5 of 12), and glutamate (5 of 12) were within the 95% confidence interval. During the second 5-day period, imbalances persisted in the control group but were almost gone in the experimental group. Daily nitrogen balance was not significantly different between groups. However, when expressed as a mean over each period, nitrogen balance was significantly higher during the second period in the experimental group than in the control group: 4.5+/-0.8 g N/d versus 0.2+/-0.7 g N/d, p < .01. The ratio of urinary 3-methylhistidine to creatinine decreased from day 1 to day 10 in both groups. These findings suggest that the relationship between rate of infusion and plasma amino acid variation may offer a rational basis for choosing the most appropriate amino acid mixture for catabolic patients. An appropriate mixture would limit plasma amino acid imbalances and improve nitrogen retention. This therapy must now be tested in a larger population of patients.

[Brain natriuretic peptide in acute coronary syndromes: utility of NT-pro BNP assay]. / Peptide natriurétique B et syndromes coronariens aigus: utilité du dosage du fragment NT-pro BNP.

Better risk stratification strategies are required for patients with acute coronary syndromes. Plasma myocardial troponin is a specific but poorly sensitive marker. Levels of B natriuretic peptide, a 32-amino-acid peptide synthesized and released by left ventricular myocytes, correlate strongly both with the presence of acute myocardial lesions and with vital outcome. To address the possible influence of the sampling time, we measured NT-pro BNP plasma concentrations on emergency admission and 8 and 24 hours later in 64 patients with acute coronary syndromes. Troponin levels were abnormal in respectively 44%, 51% and 52% of patients, while NT-pro BNP levels were abnormal in 75%, 83% and 79% of patients (p < 10(-4)). Both troponin and NT-pro BNP levels were abnormal in patients with ST elevation MI (n = 15; 93% and 87%, NS) and in patients with non ST elevation MI (n = 19; 73% and 68%). In contrast, among 30 patients with unstable angina, troponin levels were always normal whereas NT-pro BNP levels were elevated in 73% of cases (p < 10(-4)). This suggests that more than 50% patients with acute coronary syndromes who have normal troponin levels 8 hours after admission--and would therefore be discharged--would qualify for further investigations on the basis of natriuretic peptide levels. NT-pro BNP is thus more sensitive than troponin as a marker of myocardial damage. In addition, its clinical significance is not influenced by the precise sampling time within 24 hours following emergency admission. NT-pro BNP therefore adds important information for patient stratification.

Results of an aggressive surgical approach in the management of postoperative peritonitis.

BACKGROUND: Treatment of postoperative peritonitis (POP) necessitates adequate control of the source of peritoneal contamination. For most patients, a surgical approach to this requires reoperation to restore intestinal continuity. The aim of this study was to audit our results for the surgical treatment of POP. METHODS: Medical records of patients treated for POP using a standardized surgical protocol in a dedicated intensive care unit at the Saint-Antoine Hospital between 1995 and 2003 were reviewed. The aim of the study was to consider the effectiveness of our surgical protocol in the eradication of all sources of peritoneal contamination in patients presenting with POP. RESULTS: There were 87 patients (34 women, mean age of 58.4 +/- 14.7) with a mean Acute Physiology and Chronic Health Evaluation II score of 17.2 +/- 4.7 (median 16.5, range 9-28). Eight patients died and there were complications in 60 patients. Nine patients of the 79 survivors either did not require or could not have an operation to restore intestinal continuity. Intestinal continuity was re-established through a parastomal incision for 26 patients, whereas 44 patients required a further laparotomy. Two patients of the latter group died and 11 patients had a complication. It was not possible to restore intestinal continuity at laparotomy for one patient. CONCLUSION: An aggressive surgical approach, as reported in this series, including stoma formation whenever possible, diversion or intubation, provides effective control of the source of peritoneal contamination. Restoration of intestinal continuity is possible in most patients. The overall mortality rate for this treatment is 11.5%.

High grade primary breast lymphoma: is it a different clinical entity?

Primary lymphoma of the breast (PBL) is a rare neoplasm, its outcome remains unclear compared to other lymphomas. We performed a retrospective study of 19 cases of high grade PBL. There were 17 Diffuse large B cell lymphoma (DLBCL) and 2 follicular and diffuse grade 3 lymphomas. Four patients were treated with local treatment only, 15 received chemotherapy including 11 treated with CHOP or ACVBP regimens followed by involved field radiotherapy. The actuarial survival for the whole population was 38%. Three of the 4 patients treated only with a local treatment died of their lymphoma. Three patients progressed on therapy and 5 relapsed in the first year of follow-up including 2 central nervous system recurrences. Among the 11 patients treated with chemotherapy, 2 died of their lymphoma. The overall survival of this subgroup was 73% (median follow-up of 57 months). We observed, like others in the literature, a better prognosis for lymphomas co-expressing Bcl6 and CD 10. The treatment should be based on the same modalities, but including a CNS prophylaxis even if poor prognosis factors are lacking. A radical mastectomy increases the risk of treatment failure and has to be avoided.

Construction of medium-ring oxacycloalkenones. Extension towards benzo-fused cyclic ethers.

Application of the intramolecular Kulinkovich cyclopropanation of oxa-omega-alkenoic esters followed by Saegusa oxidation and dehydrohalogenation led to simple or benzo-fused oxacycloalkenones, basic structural elements in a wide range of naturally occurring compounds.

Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids.

Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines 16, 18-21, 33, 34, 38a, and 61, in the presence of a protic acid at 70-110 degrees C, yielded 3,4-cis ring-fused azetidin-2-ones 22-26,41, 42, 46, and 62 with concomitant extrusion of ethylene, in good yields. So far, the collected evidences strongly support a mechanism started by a homolytic cleavage of the protonated N-O bond for the rearrangement of 5-spirocyclopropane isoxazolidines to beta-lactams. Some different competitive pathways can then follow depending on the stability or the stereoelectronic properties of cationic diradical intermediates. The two-step process, intramolecular 1,3-dipolar cycloaddition/thermal rearrangement under acidic conditions, represents a general synthesis of a new class of 3,4-cis-fused bicyclic azetidin-2-ones starting from easily available compounds such as amino acids, hydroxy acids, and dicarbonyl or amino alcohol derivatives.