A novel design of posterior leaflet butterfly resection for mitral valve repair

A new design for posterior leaflet resection, "butterfly resection," is proposed. It is a combination of two triangular resections in the prolapsing posterior leaflet segment. This method minimizes resection in the target segment, and it prevents systolic anterior motion by reducing the height of the posterior leaflet according to the amount of excess tissue. We have used this technique for 60.4% (29 of 48) of posterior leaflet prolapse cases with zero hospital mortality and no morbidity. Postbypass transesophageal echocardiography identified no more than mild regurgitation and no sign of systolic anterior motion. During 13.1 ± 6.8 months of follow-up, patients neither died nor needed reoperation.     

Early mitral valve repair versus watchful waiting in patients with severe asymptomatic organic mitral regurgitation; rationale and design of the Dutch AMR trial, a multicenter, randomised trial

Background

Asymptomatic severe mitral valve (MV) regurgitation with preserved left ventricular function is a challenging clinical entity as data on the recommended treatment strategy for these patients are scarce and conflicting. For asymptomatic patients, no randomised trial has been performed for objectivising the best treatment strategy.

Methods

The Dutch AMR (Asymptomatic Mitral Regurgitation) trial is a multicenter, prospective, randomised trial comparing early MV repair versus watchful waiting in asymptomatic patients with severe organic MV regurgitation. A total of 250 asymptomatic patients (18–70 years) with preserved left ventricular function will be included. Intervention will be either watchful waiting or MV surgery. Follow-up will be 5 years. Primary outcome measures are all-cause mortality and a composite endpoint of cardiovascular mortality, congestive heart failure, and hospitalisation for non-fatal cardiovascular and cerebrovascular events. Secondary outcome measures are total costs, cost-effectiveness, quality of life, echocardiographic and cardiac magnetic resonance parameters, exercise tests, asymptomatic atrial fibrillation and brain natriuretic peptide levels. Additionally, the complication rate in the surgery group and rate of surgery in the watchful waiting group will be determined.

Implications

The Dutch AMR trial will be the first multicenter randomised trial on this topic. We anticipate that the results of this study are highly needed to elucidate the best treatment strategy and that this may prove to be an international landmark study.     

Assessment of valve implantation in the descending aorta as an alternative for aortic regurgitation patients not treatable with conventional procedures

Background:

Aortic Regurgitation (AR) produces the entrance of an abnormal amount of blood in the left ventricle. This disease is responsible for high morbidity and mortality worldwide and may be caused by an aortic valve dysfunction. Surgical and transcatheter aortic valve replacement (TAVR) are the current options for treating AR. They have replaced older procedures such as Hufnagel’s one. However, some physicians have reconsidered this procedure as a less aggressive alternative for patients not eligible for surgical or TAVR. Although Hufnagel suggested a 75% regurgitation reduction when a valve is placed in the descending aorta, a quantification of this value has not been reported.

Methods:

In this paper, CFD/FSI numerical simulation is conducted on an idealized geometry. We quantify the effect of placing a bileaflet mechanical heart valve in the descending aorta on a moderate-severe AR case. A three-element Windkessel model is employed to prescribe pressure outlet boundary conditions. We calculate the resulting flow rates and pressures at the aorta and first-generation vessels. Moreover, we evaluate several indices to assess the improvement due to the valve introduction.

Results and conclusions:

Regurgitation fraction (RF) is reduced from 37.5% (without valve) to 18.0% (with valve) in a single cardiac cycle. This reduction clearly shows the remarkable efficacy of the rescued technique. It will further ameliorate the left ventricle function in the long-term. Moreover, the calculations show that the implantation in that location introduces fewer incompatibilities’ risks than a conventional one. The proposed methodology can be extended to any particular conditions (pressure waveforms/geometry) and is designed to assess usual clinical parameters employed by physicians.

     

Increased risks of malaria due to limited residual life of insecticide and outdoor biting versus protection by combined use of nets and indoor residual spraying on Bioko Island, Equatorial Guinea

ABSTRACT: BACKGROUND: Malaria is endemic on Bioko Island, Equatorial Guinea, with year-round transmission. In 2004 an intensive malaria control strategy primarily based on indoor residual spraying (IRS) was launched. The limited residual life of IRS poses particular challenges in a setting with year-round transmission, such as Bioko. Recent reports of outdoor biting by Anopheles gambiae are an additional cause for concern. In this study, the effect of the short residual life of bendiocarb insecticide and of children spending time outdoors at night, on malaria infection prevalence was examined. METHODS: Data from the 2011 annual malaria indicator survey and from standard WHO cone bioassays were used to examine the relationship between time since IRS, mosquito mortality and prevalence of infection in children. How often children spend time outside at night and the association of this behaviour with malaria infection were also examined. RESULTS: Prevalence of malaria infection in two to 14 year-olds in 2011 was 18.4 %, 21.0 % and 28.1 % in communities with median time since IRS of three, four and five months respectively. After adjusting for confounders, each extra month since IRS corresponded to an odds ratio (OR) of 1.44 (95 % CI 1.15-1.81) for infection prevalence in two to 14 year-olds. Mosquito mortality was 100 %, 96 %, 81 % and 78 %, at month 2, 3, 4 and 5 respectively after spraying. Only 4.1 % of children spent time outside the night before the survey between the hours of 22.00 and 06.00 and those who did were not at a higher risk of infection (OR 0.87, 95 % CI 0.50-1.54). Sleeping under a mosquito net provided additive protection (OR 0.68, 95 % CI 0.54-0.86). CONCLUSIONS: The results demonstrate the epidemiological impact of reduced mosquito mortality with time since IRS. The study underscores that in settings of year-round transmission there is a compelling need for longer-lasting IRS insecticides, but that in the interim, high coverage of long-lasting insecticidal nets (LLINs) may ameliorate the loss of effect of current shorterlasting IRS insecticides. Moreover, continued use of IRS and LLINs for indoor-oriented vector control is warranted given that there is no evidence that spending time outdoors at night increases infection prevalence in children.     

A short course of granulocyte-colony-stimulating factor to accelerate wound repair in patients undergoing surgery for sacrococcygeal pilonidal cyst: proof of concept

Background aimsStem cells, namely easily accessible bone marrow-derived cells (BMC), are reportedly capable of tissue repair in different damaged organs and might favor wound healing. The present study was undertaken to evaluate the feasibility and safety of BMC mobilization induced by granulocyte–colony-stimulating factor (G-CSF) in patients undergoing surgery for sacrococcygeal pilonidal cysts (SPC). To evaluate the possible clinical benefit of G-CSF in reducing the time to complete resolution, a comparison with a control group receiving surgery without G-CSF was performed.MethodsEight patients with complex SPC were included in this prospective trial. Patients were treated with G-CSF (5 µg/kg b.i.d.) for 3 consecutive days; standard surgical exeresis of the pilonidal cyst was scheduled on day 2 of mobilization. Mobilization was assessed in terms of circulating CD34⁺ cells and granulocyte–macrophage colony-forming unit (CFU-GM) progenitors.ResultsMobilization of CD34⁺ cells and CFU-GM occurred in all patients, along with a marked increase in white blood cells (median peak value 28 435/µL, day 3). G-CSF was well tolerated and no adverse events occurred. All patients received the planned surgical treatment without any complications. Interestingly, the G-CSF group patients had a median time to resolution (117 days, range 110–130) significantly shorter than control patients (145 days, range 118–168) (P = 0.034).ConclusionsG-CSF administration, along with BMC mobilization, is feasible and well tolerated in patients undergoing surgery for SPC; clinical results compare favorably with those observed in controls not receiving G-CSF; the results suggest the potential use of G-CSF as an additional treatment to accelerate wound healing in patients undergoing surgery.     

Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy

Ventricular loading conditions are crucial determinants of cardiac function and prognosis in heart failure. B-type natriuretic peptide (BNP) is mainly stored in the ventricular myocardium and is released in response to an increased ventricular filling pressure. We examined, therefore, the hypothesis that BNP serum concentrations are related to ventricular wall stress. Cardiac magnetic resonance imaging (MRI) was used to assess left ventricular (LV) mass and cardiac function of 29 patients with dilated cardiomyopathy and 5 controls. Left ventricular wall stress was calculated by using a thick-walled sphere model, and BNP was assessed by immunoassay. LV mass (r = 0.73, p < 0.001) and both LV end-diastolic (r = 0.54, p = 0.001) and end-systolic wall stress (r = 0.66, p < 0.001) were positively correlated with end-diastolic volume. LV end-systolic wall stress was negatively related to LV ejection fraction (EF), whereas end-diastolic wall stress was not related to LVEF. BNP concentration correlated positively with LV end-diastolic wall stress (r = 0.50, p = 0.002). Analysis of variance revealed LV end-diastolic wall stress as the only independent hemodynamic parameter influencing BNP (p < 0.001). The present approach using a thick-walled sphere model permits determination of mechanical wall stress in a clinical routine setting using standard cardiac MRI protocols. A correlation of BNP concentration with calculated LV stress was observed in vivo. Measurement of BNP seems to be sufficient to assess cardiac loading conditions. Other relations of BNP with various hemodynamic parameters (e.g., EF) appear to be secondary. Since an increased wall stress is associated with cardiac dilatation, early diagnosis and treatment could potentially prevent worsening of the outcome.     

Evaluation of alterations on mitral annulus velocities, strain, and strain rates due to abrupt changes in preload elicited by parabolic flight.

We tested the hypothesis that in normal subjects, cardiac tissue velocities, strain, and strain rates (SR), measured by Doppler tissue echocardiography (DTE), are preload dependent. To accomplish it, immediately preceding image acquisition, reversible, repeatable, acute nonpharmacological changes in preload were induced by parabolic flight. DTE has been proposed as a new approach to assess left ventricular regional myocardial function by computing tissue velocities, strain, and SR. However, preload dependence of these parameters in normal subjects still remains controversial. DTE images (Philips) were obtained in 10 normal subjects in standing upright position at normogravity (1 Gz), hypergravity (1.8 Gz), and microgravity (0 Gz) with and without -50 mmHg lower body negative pressure (LBNP). Myocardial velocity curves in the basal interventricular septum were reconstituted offline from DTE images, from which peak systolic (S'), early (E') and late (A') diastolic velocities, SR, and peak systolic strain (PSepsilon) were measured and averaged over four beats. At 1.8 Gz (reduced venous return), S', E', and A' decreased by 21%, 21%, and 26%, respectively, compared with 1-Gz values, while at 0 Gz (augmented venous return), E', A', and PSepsilon increased by 57%, 53%, and 49%, respectively. LBNP reduced E' and PSepsilon. In conclusion, our results were in agreement with those obtained in animal models, in which preload was changed in a controlled, acute, and reversible manner, and image acquisition was performed immediately following preload modifications. The hypothesis of preload dependence was confirmed for S', E', A', and PSepsilon, while SR appeared to be preload independent, probably reflecting intrinsic myocardial properties.     

Influence of cooling rate on the ability of frozen-thawed sperm to bind to heterologous zona pellucida, as assessed by competitive in vitro binding assays in the ocelot (Leopardus pardalis) and tigrina (Leopardus tigrinus)

We evaluated the influence of two cooling rates (from 25 to 5 degrees C) on post-thaw function of frozen sperm in ocelots (Leopardus pardalis; n=3 males) and tigrinas (Leopardus tigrinus; n=4 males). Seven normospermic (>70% normal sperm) electroejaculates from each species were diluted with a 4% glycerol freezing medium, divided into two aliquots, and assigned to one of two cooling rates: fast or slow (0.7 or 0.16 degrees C/min, respectively). Sperm motility index (SMI) and percentage of sperm with an intact acrosome were assessed before freezing and after thawing, and the ability of sperm to bind to the zona pellucida of IVM domestic cat oocytes were assessed in a competitive in vitro sperm-binding assay. Regardless of the cooling rate, frozen-thawed sperm from both species exhibited a SMI of 50; approximately 20 and approximately 32% of post-thaw sperm had an intact acrosome in ocelots and tigrinas, respectively (P<0.05). The mean (+/-S.E.M.) number of sperm bound per oocyte was higher for fast-cooled (8.5+/-1.3) than slow-cooled (2.5+/-0.3; P<0.01) ocelot sperm. In contrast, more tigrina sperm bound to domestic cat oocytes when cooled slowly versus quickly (5.8+/-0.9 versus 2.7+/-0.4, P<0.05). In conclusion, cryopreservation decreased sperm function in both species, and the oocyte-binding assay was the most efficient method to detect functional differences in post-thaw sperm.     

Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI

The activation of adenosine 2A receptors before reperfusion following coronary artery occlusion reduces infarct size and improves ejection fraction (EF). In this study, we examined the effects of delaying treatment with the adenosine 2A receptor agonist ATL146e (ATL) until 1 h postreperfusion. The infarct size and EF were serially assessed by gadolinium-diethylenetriaminepentaacetic acid-enhanced MRI in C57BL/6 mice at 1 and 24 h postreperfusion. The infarct size was also assessed by 2,3,5-triphenyltetrazolium chloride staining at 24 h. Mice were treated with ATL (10 microg/kg ip) either 2 min before reperfusion (early ATL) or 1 h postreperfusion (late ATL) following the 45-min coronary occlusion. The two methods used to assess infarct size at 24 h postreperfusion (MRI and 2,3,5-triphenyltetrazolium chloride) showed an excellent correlation (R=0.96). The risk region, determined at 24 h postreperfusion, was comparable between the control and ATL-treated groups. The infarct size by MRI at 1 versus 24 h postreperfusion was 25+/-1 vs. 26+/-1% of left ventricular mass (means+/-SE) in control mice, 16+/-2 versus 17+/-2% in early-ATL mice, and 24+/-2 versus 25+/-2% in late-ATL mice (intragroup, P=not significant; and intergroup, early ATL vs. control or late ATL, P<0.05). EF was reduced in control mice but was largely preserved between 1 and 24 h in both early-ATL and late-ATL mice (P<0.05). In conclusion, after coronary occlusion in mice, the extent of myocellular death due to ischemia-reperfusion injury is 95% complete within 1 h of reperfusion. The infarct size was significantly reduced by ATL when given just before reperfusion, but not 1 h postreperfusion. Either treatment window helped preserve the EF between 1 and 24 h postreperfusion.     

Efficacy of anchoring the four-arm transvaginal mesh to the mid-urethra vs original surgery as a surgical correction for stress urine incontinence in coexisting anterior vaginal prolapse grades II and III: study protocol for a randomized controlled trial

Background

The prevalence of obesity with aging is escalating alarmingly; and pelvic organ prolapse (POP) and stress urinary incontinence (SUI) are now becoming a growing epidemic among the elderly. Synthetic transvaginal mesh has been employed with increasing popularity in the treatment of POP and is usually highly effective in controlling the principal symptoms of prolapse. However, studies have reported that mesh operations provide fairly unfavorable SUI cure rates. Therefore, additional anti-incontinence surgical strategies are increasingly being scrutinized to achieve better postoperative continence without any significant side-effects for patients with both POP and SUI. We hypothesize that the modification with the fixing of the mesh to the mid-urethra is superior to the original transvaginal mesh operation (TVM) with regard to anti-incontinence.

Methods

One hundred and thirty patients diagnosed with POP–Q II–III and concomitant SUI requiring surgical treatment will be included in this prospective, randomized, double-blind, controlled clinical trial. Patients will be randomly allocated to receive either original TVM (TVM group, n?=?65) or modified TVM surgery (mTVM group, n?=?65). As the primary outcome parameter, we will evaluate the objective SUI and POP cure rates. Secondary endpoints include postoperative morbidity as assessed with the International Urogynaecological Association classification and subjective prolapse and incontinence cure rates reported by questionnaires.

Discussion

Recognizing the importance of an additional surgical procedure for anti-incontinence management, we aim to investigate whether a stabilizing suturing of the mesh to the mid-urethra delivers superior SUI correction compared to the original prosthesis surgery.

Trial registration

ClinicalTrials.gov, NCT02935803. Registered on 20 May 2016.

     

Implication for using heme methyl hyperfine shifts as indicators of heme seating as related to stereoselectivity in the catabolism of heme by heme oxygenase: in-plane heme versus axial his rotation

The triple mutant of the solubilized, 265-residue construct of human heme oxygenase, K18E/E29K/R183E-hHO, has been shown to redirect the exclusive alpha-regioselectivity of wild-type hHO to primarily beta,delta-selectivity in the cleavage of heme (Wang, J., Evans, J. P., Ogura, H., La Mar, G. N., and Ortiz de Montellano, P. R. (2006) Biochemistry 45, 61-73). The 1H NMR hyperfine shift pattern for the substrate and axial His CbetaH's and the substrate-protein contacts of the cyanide-inhibited protohemin and 2,4-dimethyldeuterohemin complexes of the triple mutant have been analyzed in detail and compared to data for the WT complex. It is shown that protein contacts for the major solution isomers for both substrates in the mutant dictate approximately 90 degrees in-plane clockwise rotation relative to that in the WT. The conventional interpretation of the pattern of substrate methyl hyperfine shifts, however, indicates substrate rotations of only approximately 50 degrees . This paradox is resolved by demonstrating that the axial His25 imidazole ring also rotates counterclockwise with respect to the protein matrix in the mutant relative to that in the WT. The axial His25 CbetaH hyperfine shifts are shown to serve as independent probes of the imidazole plane orientation relative to the protein matrix. The analysis indicates that the pattern of heme methyl hyperfine shifts cannot be used alone to determine the in-plane orientation of the substrate as it relates to the stereospecificity of heme cleavage, without explicit consideration of the orientation of the axial His imidazole plane relative to the protein matrix.     

Influence of environmental stress on distributions of times to first division in Escherichia coli populations, as determined by digital-image analysis of individual cells

The distributions of times to first cell division were determined for populations of Escherichia coli stationary-phase cells inoculated onto agar media. This was accomplished by using automated analysis of digital images of individual cells growing on agar and calculation of the "box area ratio." Using approximately 300 cells per experiment, the mean time to first division and standard deviation for cells grown in liquid medium at 37 degrees C and inoculated on agar and incubated at 20 degrees C were determined as 3.0 h and 0.7 h, respectively. Distributions were observed to tail toward the higher values, but no definitive model distribution was identified. Both preinoculation stress by heating cultures at 50 degrees C and postinoculation stress by growth in the presence of higher concentrations of NaCl increased mean times to first division. Both stresses also resulted in an increase in the spread of the distributions that was proportional to the mean division time, the coefficient of variation being constant at approximately 0.2 in all cases. The "relative division time," which is the time to first division for individual cells expressed in terms of the cell size doubling time, was used as measure of the "work to be done" to prepare for cell division. Relative division times were greater for heat-stressed cells than for those growing under osmotic stress.     

Cellular markers based on DNA repair (BER,MMR) expression of MLH1, MSH2, FasR and death of lymphocytes as predictive parameters for clinical response to chemotherapy of melanoma patients

Melanoma is a highly aggressive tumor of melanocytes. The efficacy of different cytotoxic chemotherapy regimens does not exceed 20%. The search for markers for patient sensitivity to chemotherapy provides a rational basis for the development of cytotoxic chemotherapy. In this study, we evaluated six blood lymphocyte parameters (the efficacy of BER and MMR; the expression of MLH1, MSH2, FasR; and cell death) as prognostic markers for melanoma chemotherapy. We found that chemotherapy induced AP sites and ssDNA breaks in lymphocytes repaired through the BER pathway. However, ssDNA breaks were completely repaired after chemotherapy and, therefore, did not contribute to the toxic effect of chemotherapy. dsDNA breaks produced by a functioning MMR system appeared downstream of methylation adducts, which was confirmed by the linear correlation of these parameters in various patients. The number of dsDNA breaks, but not MMR, MLH1, and MSH2 expression, correlated to the efficacy of chemotherapy. A positive correlation was observed between lymphocyte death induced by chemotherapy and the patient’s clinical response, which may show that the nucleotide excision repair (NER) mechanism is implicated in the generation of double-strand breaks and the cytotoxic effect of chemotherapy.     

New perspectives on taste and primate evolution: the dichotomy in gustatory coding for perception of beneficent versus noxious substances as supported by correlations among human thresholds

In various environments where primates are presently observed, as well as in forests and savannas which have been inhabited by australopithecines and early hominids, there are (or there have been presumably) categories of substances eliciting taste signals associated with stereotyped responses. Such is the case for various soluble sugars of fruits and nectars, attracting consumers, and for several plant compounds in which bitter or strongly astringent properties have a repulsive effect. The occurrence of such classes of tasty substances among natural products appears to be related to the evolutionary trends that shaped primate sensory perception (for detecting either beneficent or potentially noxious substances) in the context of a long history of coevolution between animals and plants. Here, we present original psychophysical data on humans (412 individuals aged 17-59 years) as an analogy with which to test recent evidence from electrophysiology in nonhuman primates (Hellekant et al. [1997] J. Neurophysiol. 77:978-993; Danilova et al. [1998] Ann. N.Y. Acad. Sci. 855:160-164) that taste fibers can be grouped into clusters of "best-responding fibers" with two more specific clusters, one for sugars and one for quinine and tannins. The collinearity found between human taste responses (recognition thresholds) for fructose and sucrose, as well as for quinine and tannins, is presented and discussed as another evidence of the two-direction evolutionary trend determining taste sensitivity. Salt perception appears to be totally independent of these trends. Accordingly, the appreciation of a salty taste seems to be a recent culturally learned response, and not a primary taste perception. The very existence of primary tastes is discussed in the context of evolutionary trends, past and present.