HOT CRT-The Effective Combination of Conventional Cardiac Resynchronization and His Bundle Pacing.

Background and Objectives: Cardiac Resynchronization Therapy (CRT) has, besides its benefits, various limitations. For instance, atrial fibrillation (AF) has a huge impact on the therapy efficacy. It usually reduces the overall BiV pacing percentage and leads, inevitably, to lack of fusion beats. In many patients with heart failure that could benefit from resynchronization, the QRS morphology is often IVCD and atypical, or non-LBBB, which further diminishes the CRT response. In those cases, we established His pacing combined with LV pacing as a feasible option to reduce the impact of AF on the CRT response and regain partially physiological ventricular activation to improve the electromechanical sequence. Materials and Methods: We implanted two patients with AF, HF, EF < 35%, NYHA II-III and QRS > 150 ms with CRT-D systems modified to HOT-CRT and observed their clinical, ECG and echocardiographic improvements over a follow-up period of three months. Results: In both patients we observed improvements of the initial parameters. We were able to shorten the QRS duration to approx. 120 ms, improve NYHA functional class, increase the EF by approximately 12% and distinctly reduce mitral regurgitation. Conclusion: Since the conventional CRT reaches its limits within this specific patient group, we need to consider alternative pacing sites and the effective combination of them. Our results and respectively other studies that are also mentioned in the current guidelines, support the feasibility of HOT-CRT in the above mentioned patient group.

The P wave dispersion-one pixel, one millisecond.

The electrophysiological activity of the heart is recorded and presented in form of electrocardiogram (ECG). In 1998 the concept of P wave dispersion as the risk factor for atrial fibrillation (AF) recurrence was introduced. It was calculated as the difference between the longest and the shortest P wave. The aim of our study is to prove that the P wave dispersion is an artifact of low accuracy in P wave measurement. The study included 186 patients (78M 108F) aged 59.7 ± 12.9 years, undergoing various electrophysiological procedures. The P wave was measured twice: first, at the paper speed of 50 mm/s, enhancement 8× (standard - imprecise) and the second time at 200 mm/s, 64-256× (precise). The imprecise measurement method resulted in different duration of all P wave parameters in comparison with precise measurement. The difference between Δ P max and Δ P min indicated a higher value for the latter parameter. It was indicated that the imprecise P wave dispersion value correlated most significantly with the maximal P wave duration, which was measured in a similar way. In contrast with the imprecise measurement method, the minimal and maximal durations of the P waves, being measured accurately, were almost identical. Using precise methodology, the P wave dispersion reaches negligible values and tends to zero. The measurements of the P wave have to be precise to assure the highest scientific and medical sincerity. The highest clinical value is related to the P wave duration.

Acurin A, a novel hybrid compound, biosynthesized by individually translated PKS- and NRPS-encoding genes in Aspergillus aculeatus.

This work presents the identification and proposed biosynthetic pathway for a compound of mixed polyketide-nonribosomal peptide origin that we named acurin A. The compound was isolated from an extract of the filamentous fungus Aspergillus aculeatus, and its core structure resemble that of the mycotoxin fusarin C produced by several Fusarium species. Based on bioinformatics in combination with RT-qPCR experiments and gene-deletion analysis, we identified a biosynthetic gene cluster (BGC) in A. aculeatus responsible for the biosynthesis of acurin A. Moreover, we were able to show that a polyketide synthase (PKS) and a nonribosomal peptide synthetase (NRPS) enzyme separately encoded by this BGC are responsible for the synthesis of the PK-NRP compound, acurin A, core structure. In comparison, the production of fusarin C is reported to be facilitated by a linked PKS-NRPS hybrid enzyme. Phylogenetic analyses suggest the PKS and NRPS in A. aculeatus resulted from a recent fission of an ancestral hybrid enzyme followed by gene duplication. In addition to the PKS- and NRPS-encoding genes of acurin A, we show that six other genes are influencing the biosynthesis including a regulatory transcription factor. Altogether, we have demonstrated the involvement of eight genes in the biosynthesis of acurin A, including an in-cluster transcription factor. This study highlights the biosynthetic capacity of A. aculeatus and serves as an example of how the CRISPR/Cas9 system can be exploited for the construction of fungal strains that can be readily engineered.

Could home sexually transmitted infection specimen collection with e-prescription be a cost-effective strategy for clinical trials and clinical care?

BACKGROUND: Results of a recent demonstration project evaluating feasibility, acceptability, and cost of a Web-based sexually transmitted infection (STI) testing and e-prescription treatment program (eSTI) suggest that this approach could be a feasible alternative to clinic-based testing and treatment, but the results need to be confirmed by a randomized comparative effectiveness trial. METHODS: We modeled a decision tree comparing (1) cost of eSTI screening using a home collection kit and an e-prescription for uncomplicated treatment versus (2) hypothetical costs derived from the literature for referral to standard clinic-based STI screening and treatment. Primary outcome was number of STIs detected. Analyses were conducted from the clinical trial perspective and the health care system perspective. RESULTS: The eSTI strategy detected 75 infections, and the clinic referral strategy detected 45 infections. Total cost of eSTI was $94,938 ($1266/STI detected) from the clinical trial perspective and $96,088 ($1281/STI detected) from the health care system perspective. Total cost of clinic referral was $87,367 ($1941/STI detected) from the clinical trial perspective and $71,668 ($1593/STI detected) from the health care system perspective. CONCLUSIONS: Results indicate that eSTI will likely be more cost-effective (lower cost/STI detected) than clinic-based STI screening, both in the context of clinical trials and in routine clinical care. Although our results are promising, they are based on a demonstration project and estimates from other small studies. A comparative effectiveness research trial is needed to determine actual cost and impact of the eSTI system on identification and treatment of new infections and prevention of their sequelae.

Fully integrated e-services for prevention, diagnosis, and treatment of sexually transmitted infections: results of a 4-county study in California.

OBJECTIVES: We examined the acceptability, feasibility, and cost of a fully integrated online system (eSTI) for sexually transmitted infection (STI) testing, treatment, and linkage to care with 4 Northern California health departments. METHODS: In April 2012, we implemented the eSTI system, which provided education; testing of self-collected vaginal swabs for chlamydia, gonorrhea, and trichomoniasis; e-prescriptions; e-partner notification; and data integration with clinic electronic health records. We analyzed feasibility, acceptability, and cost measures. RESULTS: During a 3-month period, 217 women aged 18 to 30 years enrolled; 67% returned the kit. Of these, 92% viewed their results online. STI prevalence was 5.6% (chlamydia and trichomoniasis). All participants with STIs received treatment either the same day at a pharmacy (62%) or within 7 days at a clinic (38%). Among participants completing follow-up surveys, 99% would recommend the online eSTI system to a friend, and 95% preferred it over clinic-based testing within a study. CONCLUSIONS: The fully integrated eSTI system has the potential to increase diagnosis and treatment of STIs with higher patient satisfaction at a potentially lower cost.

HSV-1 and HSV-2 seroprevalence in the united states among asymptomatic women unaware of any herpes simplex virus infection (Herpevac Trial for Women).

OBJECTIVES: Recent evidence suggests that the epidemiology of herpes simplex viruses (HSVs) is changing because fewer HSV-1 infections are acquired in childhood and increased sexual transmission of HSV-1 is reported. The objective of the study was to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. METHODS: We used the Western blot antibody screening data from a large phase III vaccine efficacy trial (Herpevac Trial for Women) to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. RESULTS: The antibody status of 29,022 women (>31,000 women interviewed and then had their blood drawn for the HSV testing [29,022 women]) between the ages of 18 and 30 years in the United States revealed that increasing age was associated with increasing seroprevalence to HSV. Overall, in asymptomatic women unaware of any HSV infection, HSV-1/-2 status was positive/negative in 45%, negative/positive in 5%, positive/positive in 7%, negative/negative in 38%, and indeterminate in 5%. HSV-1 infections were more common in Hispanic and non-Hispanic black women and in the US northeast and in individuals living in urban areas. HSV-2 was more common in non-Hispanic black women, the US south, and in urban areas. CONCLUSIONS: Seronegative status for both HSV-1 and HSV-2 was the second most common finding after positive antibody to HSV-1 but negative antibody to HSV-2. Despite recent changes in genital herpes epidemiology, most women acquired HSV-1 but not HSV-2 infections before 18 years of age. Among participants screened for study participation and who were unaware of any HSV infection, progressively higher prevalence of the HSV-1 or HSV-2 antibody was observed in older subjects. Many women who test positive for HSV-1 and/or HSV-2 are unaware of their status.

Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women.

BACKGROUND: Herpes simplex virus infections type 1 (HSV-1) and type 2 (HSV-2) are common, but the epidemiology of HSV disease is changing. METHODS: HSV-seronegative women, aged 18-30 years, who were in the control arm of the HERPEVAC Trial for Women were followed for 20 months for primary HSV infections. RESULTS: Of the 3438 evaluable participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. The rate of infection for HSV-1 (2.5 per 100 person-years) was more than twice that for HSV-2 (1.1 per 100 person-years). Most infections (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease. The HSV-2 infection rate was 2.6 times higher in non-Hispanic black participants than in Hispanics and 5.5 times higher than in non-Hispanic whites (P < .001), while the HSV-1 infection rate was 1.7 times higher in non-Hispanic whites than non-Hispanic blacks. Younger participants (18-22 years) were more likely to acquire HSV-1 infections and less likely to develop recognized disease than older participants. Overall, 84% of recognized disease cases were genital. No differences were noted in the clinical manifestations of genital HSV-1 vs genital HSV-2 disease. The clinicians' assessment that cases were caused by HSV was good when they assessed cases as clinically confirmed or unlikely (validated in 83% and 100% of cases, respectively). CONCLUSIONS: HSV-1 is now more common than HSV-2 as a cause of oral and genital mucosal infections in young women, but there are important age and race differences.

P wave duration in paroxysmal and persistent atrial fibrillation.

BACKGROUND: Functional and structural changes in the atrial muscle constitute a substrate for atrial fibrillation (AF). The pathological changes in the left atrium decrease the conduction velocity and result in prolongation of the P wave duration. OBJECTIVES: To assess the duration of the P wave in patients with AF in different clinical presentations of arrhythmia. MATERIAL AND METHODS: The study group consisted of 119 patients diagnosed with AF: 57 women and 62 men, aged 65.3 ±9.4 years. There were 65 patients with paroxysmal AF and 54 with persistent AF. In this group, electrical cardioversion was performed. The P wave duration was measured using an electrophysiological system in all leads at a paper speed of 200 mm/s. RESULTS: The patients did not differ in terms of age, gender or comorbidities. The patients with persistent AF had longer P wave duration (159.9 ±22.3 ms compared to 144.6 ±17.2 ms; p < 0.001) and higher glucose concentration (119.4 ±33.4 mg/dL compared to 108.0 ±24.6 mg/dL; p = 0.015). These results were not influenced by the anti-arrhythmic treatment. CONCLUSIONS: Persistent AF shows a longer P wave duration than the paroxysmal AF, independent of age, gender and anti-arrhythmic medication. The prolongation of the P wave related to persistent arrhythmia should force physicians to restore the sinus rhythm earlier in order to more successfully maintain it in the long term.

Structure determination and ligand interactions of the PDZ2b domain of PTP-Bas (hPTP1E): splicing-induced modulation of ligand specificity.

Two versions of the PDZ2 domain of the protein tyrosine phosphatase PTP-Bas/human PTP-BL are generated by alternative splicing. The domains differ by the insertion of five amino acid residues and their affinity to the tumour suppressor protein APC. Whereas PDZ2a is able to bind APC in the nanomolar range, PDZ2b shows no apparent interaction with APC. Here the solution structure of the splicing variant of PDZ2 with the insertion has been determined using 2D and 3D heteronuclear NMR experiments. The structural reason for the changed binding specificity is the reorientation of the loop with extra five amino acid residues, which folds back onto beta-strands two and three. In addition the side-chain of Lys32 closes the binding site of the APC binding protein and the two helices, especially alpha-helix 2, change their relative position to the protein core. Consecutively, the binding site is sterically no longer fully accessible. From the NMR-titration studies with a C-terminal APC-peptide the affinity of the peptide with the protein can be estimated as 540(+/-40)microM. The binding site encompasses part of the analogous binding site of PDZ2a as already described previously, yet specific interaction sites are abolished by the insertion of amino acids in PDZ2b. As shown by high-affinity chromatography, GST-PDZ2b and GST-PDZ2a bind to phosphatidylinositol 4,5-bisphosphate (PIP(2)) micelles with a dissociation constant K(D) of 21 microM and 55 microM, respectively. In line with these data PDZ2b binds isolated, dissolved PIP(2) and PIP(3) (phosphatidylinositol 3,4,5-trisphosphate) molecules specifically with a lower K(D) of 230(+/-20)microM as detected by NMR spectroscopy. The binding site could be located by our studies and involves the residues Ile24, Val26, Val70, Asn71, Gly77, Ala78, Glu85, Arg88, Gly91 and Gln92. PIP(2) and PIP(3) binding takes place in the groove of the PDZ domain that is normally part of the APC binding site.

Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families.

BACKGROUND: Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication. METHODS: In this study, we conducted a second-stage genome-wide scan with 408 microsatellite markers on 201 asthma-affected sib pair families and defined clinical subgroups to identify phenotype-genotype relations. RESULTS: The lowest P value for asthma in the total sample was 0.003 on chromosome 11, while several of the clinical subsets reached lower significance levels than in the overall sample. Suggestive evidence for linkage (p = 0.0007) was found for total IgE on chromosomes 1, 7 and again on chromosome 11, as well as for HDM asthma on chromosome 12. Weaker linkage signals could be found on chromosomes 4 and 5 for early onset and HDM, and, newly described, on chromosome 2 for severe asthma and on chromosome 9 for hay fever. CONCLUSIONS: This phenotypic dissection underlines the importance of detailed clinical characterisations and the extreme genetic heterogeneity of asthma.

The orphans of Eritrea: what are the choices?

The authors examined the emotional well-being, adaptability, and emotional distress of 10-13 year-old Eritrean war orphans cared for in 3 different social environments and 1 group of home-reared children using 2 scales of the Behavioral Assessment System for Children and informal interviews with the children. Orphans reunified with extended families had greater adaptive skills than institutional orphans but as many signs and symptoms of emotional distress as orphanage children. Group-home orphans had fewer signs and symptoms of emotional distress and greater adaptive skills than either reunified or institutional orphans, and they had fewer symptoms of emotional distress than home-reared children. However, placing orphans in small group homes was far more expensive than reunifying them with extended families. The public policy implications of the findings for the protection of unaccompanied children in impoverished developing countries are discussed.

The Orphans of Eritrea: A Comparison Study.

The social-emotional state and cognitive development was compared between a group of 74 4-7-year-old Eritrean orphans and refugee children living in families. Both groups had been exposed to the chronic stresses of war and drought and the orphans had, in addition, lost both parents to the violence of war, and were living in an overcrowded orphanage- Contrary to expectations, there were relatively few clinically significant differences between comparison groups. The orphans showed more behavioral symptoms of emotional distress, but performed at a more advanced level on cognitive and language performance measures. The findings suggest that when group care is child-centered, it can under some circumstances be a viable solution for unaccompanied children in countries where adoption and foster care are not realistic alternatives.

A functional magnetic resonance imaging study of paced finger tapping in children.

Fourteen typically developing children from 7.9-11.3 years in age were studied with functional magnetic resonance imaging to identify the cerebral loci involved in performance of paced finger tapping by children. Each child performed two bimanual alternating paced finger-tapping tasks. In the first, paced finger tapping was conducted to external 3-Hz pacing provided by a metronome. In the second, the metronome was turned off and finger tapping continued while each child tried to maintain the 3-Hz rhythm by self pacing. Individual and group data were analyzed with statistical parametric mapping techniques that resulted in activation maps for the two tasks. Metronome tapping produced activation of the posterior regions of both superior temporal gyri, both primary sensorimotor cortices, anterodorsomedial cerebellum and supplementary motor area. Self-tapping resulted in recruitment of pre-supplementary motor area and cerebellum in addition to bilateral supplementary motor area and primary sensorimotor cortical activation. Bimanual alternating paced finger tapping performed by children activates a neural network involving primary motor cortex, supplementary motor area, and cerebellum. Posterior superior temporal gyrus may be important for encoding auditory information, and presupplementary motor area and midline cerebellum play an important role in self-paced finger tapping.

Neurodevelopmental characteristics of children with learning impairments classified according to the double-deficit hypothesis.

The double-deficit model has been examined primarily in relation to reading. We investigated whether children classified according to the double-deficit model would exhibit differences in other neuropsychological domains. Children referred for learning problems (N = 188), ages 7 to 11, were classified by double-deficit subtype. Only three of the four groups predicted by the model could be identified. There were no group differences in IQ or attention problems. The three groups showed different neuropsychological profiles, involving functional domains other than reading and language. Differences also emerged in nonverbal low-level information processing. The double-deficit group was generally most severely affected. The double-deficit groupings identify children with different neuropsychological profiles and variation in the efficiency of basic online information processing, extending beyond the oral and written language domain.

Spirometric reference values in urban children in Madagascar: poverty is a risk factor for low lung function.

BACKGROUND: Studies about children with respiratory diseases in Africa are impeded by the dearth of reliable data for the vast majority of countries on the continent. This study was conducted to establish representative reference values, therefore allowing a more accurate evaluation of lung function in Malagasy children. METHODS: One thousand two hundred thirty-six students from three public and five private schools aged 8-12 years were recruited. A total of 1,093 children were healthy, had a valid lung function measurement and were thus deemed evaluable for this study. Lung function data were collected on consecutive days in Antananarivo, Madagascar's capital, using spirometry and a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. RESULTS: The lung volumes found were substantially lower compared to Caucasian and African equations. The mean Z-score (Stanojevic) for the forced vital capacity (FVC) found was -1.45 and -0.93 for the forced expiratory volume in 1 sec (FEV1) with significant differences between private and public schools (FVC: P = 0.0023, FEV1: P = 0.0004). CONCLUSIONS: The equations established for school children in Madagascar's capital Antananarivo showed lung function values were lower than reference values for the same age group seen not only in European, but also in African American and African children. The unique ethnicity of the Malagasy people, which combines Southeast-Asian with substantial African influences, the heavy burden of pollution and poverty may explain these differences.

Premature infant swallowing: patterns of tongue-soft palate coordination based upon videofluoroscopy.

Coordination between movements of individual tongue points, and between soft palate elevation and tongue movements, were examined in 12 prematurely born infants referred from hospital NICUs for videofluoroscopic swallow study (VFSS) due to poor oral feeding and suspicion of aspiration. Detailed post-evaluation kinematic analysis was conducted by digitizing images of a lateral view of digitally superimposed points on the tongue and soft palate. The primary measure of coordination was continuous relative phase of the time series created by movements of points on the tongue and soft palate over successive frames. Three points on the tongue (anterior, medial, and posterior) were organized around a stable in-phase pattern, with a phase lag that implied an anterior to posterior direction of motion. Coordination between a tongue point and a point on the soft palate during lowering and elevation was close to anti-phase at initiation of the pharyngeal swallow. These findings suggest that anti-phase coordination between tongue and soft palate may reflect the process by which the tongue is timed to pump liquid by moving it into an enclosed space, compressing it, and allowing it to leave by a specific route through the pharynx.

Growth of the genetically engineered strain Cupriavidus necator RW112 with chlorobenzoates and technical chlorobiphenyls.

Cupriavidus necator (formerly Ralstonia eutropha) strain H850 is known to grow on biphenyl, and to co-oxidize congeners of polychlorinated biphenyls (PCBs). Using a Tn5-based minitransposon shuttle system and the TOL plasmid, the rational construction of hybrids of H850 was achieved by subsequent introduction of three distinct elements carrying 11 catabolic loci from three other biodegrading bacteria into the parent strain, finally yielding C. necator RW112. The new genetic elements introduced into H850 and its derivatives were tcbRCDEF, which encode the catabolic enzymes needed for chlorocatechol biodegradation under the control of a transcriptional regulator, followed by cbdABC, encoding a 2-halobenzoate dioxygenase, and xylXYZ, encoding a broad-spectrum toluate dioxygenase. The expression of the introduced genes was demonstrated by measuring the corresponding enzymic activities. The engineered strain RW112 gained the ability to grow on all isomeric monochlorobenzoates and 3,5-dichlorobenzoate, all monochlorobiphenyls, and 3,5-dichloro-, 2,3'-dichloro- and 2,4'-dichlorobiphenyl, without accumulation of chlorobenzoates. It also grew and utilized two commercial PCB formulations, Aroclor 1221 and Aroclor 1232, as sole carbon and energy sources for growth. This is the first report on the aerobic growth of a genetically improved bacterial strain at the expense of technical Aroclor mixtures.