A class of antimicrobial peptides involved in host defense consists of sequences rich in Arg and Trp-R and -W. Analysis of the pharmacophore in these peptides revealed that chains as short as trimers of sequences such as WRW and RWR have antimicrobial activity (M. B. Strom, B. E. Haug, M. L. Skar, W. Stensen, T. Stiberg, and J. S. Svendsen, J. Med. Chem. 46:1567-1570, 2003). To evaluate the effect of chain length on antimicrobial activity, we synthesized a series of peptides containing simple sequence repeats, (RW)n-NH2 (where n equals 1, 2, 3, 4, or 5), and determined their antimicrobial and hemolytic activity. The antimicrobial activity of the peptides increases with chain length, as does the hemolysis of red blood cells. Within the experimental error, longer peptides (n equals 3, 4, or 5) show similar values for the ratio of hemolytic activity to antibacterial activity, or the hemolytic index. The (RW)3 represents the optimal chain length in terms of the efficacy of synthesis and selectivity as evaluated by the hemolytic index. Circular dichroism spectroscopy indicates that these short peptides appear to be unfolded in aqueous solution but acquire structure in the presence of phospholipids. Interaction of the peptides with model lipid vesicles was examined using tryptophan fluorescence. The (RW)n peptides preferentially interact with bilayers containing the negatively charged headgroup phosphatidylglycerol relative to those containing a zwitterionic headgroup, phosphatidylcholine.

Twenty-nine youth with autism spectrum disorders and 26 with typical development between 12 and 18 years of age were engaged in structured interviews (ADOS). The interviews were videotaped and rated for atypical conversational behaviors by trained raters, using the Pragmatic Rating Scale (Landa et al. Psychol Med 22:245-254, 1992). The ASD group was divided into AS and HFA/PDD-NOS subgroups. Significant differences were found among groups on approximately one-third of the PRS items. These items involved primarily the management of topics and information, reciprocity, intonation, and gaze management. The only differences to reach significance between the AS and HFA/PDD-NOS group were a greater tendency for overly formal speech on the part of the AS group, and more difficulty with gaze management on the part of the group with HFA/PDD-NOS. The implications of these findings for understanding and treating conversational deficits in ASD are discussed.

Anterior cruciate ligament (ACL) injuries are the most costly injuries in football at both professional and amateur levels (Orchard J, Seward H, McGivern J, Hood S. Intrinsic and extrinsic risk factors for anterior cruciate ligament injury in Australian footballers. Am J Sports Med 2001;29:196-200.). In this study video analysis of 34 ACL injuries in Australian football was performed to investigate the causes of these injuries. Factors that may have contributed to the cause of the injury were analysed, rated and reported. The factors analysed were: type of manoeuvre, direction the knee 'gave way', running speed, knee angle, cutting angle and if the player was accelerating or decelerating. The majority of the injuries analysed occurred in non-contact situations (56%). Of these 37% occurred during sidestepping manoeuvres, 32% in landing, 16% land and step, 10% stopping/slowing and 5% crossover cut manoeuvres. Ninety-two percent of the non-contact injuries occurred at extended knee angles of 30 degrees or less, which is also commonly known to place stress on the ACL and reduce the protective role of hamstrings. Over half (54%) of non-contact injuries occurred whilst decelerating. It would be expected that greater speed and angle cut too would increase the frequency of ACL injury. The results could not confirm this with most injuries occurring at running speeds of slow jogging to running and equal number of injuries occurred at cutting to angles of the ranges 15-45 degrees and 45-75 degrees. These results give greater understanding into potential causes or contributors of ACL injury and information to assist in the development of knee injury prevention programs.

Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication (Meds) have proved to be effective therapies for treating bradykinesia in Parkinson's disease. However, it is not currently known how or to what extent STN stimulation alters the control signals to agonist and antagonist muscles to change movement speed. Our objective was to investigate movement speed along with the amplitude and temporal features of EMG activity to determine how and to what extent these parameters are changed by DBS and medication. Nine patients with Parkinson's disease were studied following neurosurgery that implanted high-frequency stimulating electrodes in the STN. The experiments for the patients were performed in each of four treatment conditions: (i) OFF treatment; (ii) STN DBS; (iii) Meds; and (iv) Meds plus STN DBS. Also, a group of age- and gender-matched control subjects were examined. Medication and DBS had similar effects in that both treatments increased movement speed, increased the amplitude of the first agonist burst, increased burst duration, reduced the number of agonist bursts, reduced cocontraction, increased the size of the antagonist EMG, and reduced the centroid time of the antagonist EMG. When DBS and medication were combined, only temporal measures of burst duration and the number of agonist bursts were different from the medication alone condition. There was a positive association between the level of bradykinesia OFF treatment and the level of bradykinesia following DBS and medication. The movement speed of neurologically normal control subjects' was over 40% higher during both flexion and extension movements when compared with the patients during Meds plus STN DBS. The changes in the muscle activation patterns provide a mechanism of action for the pharmacological and surgical interventions used to treat bradykinesia in Parkinson's disease. However, despite the success of medication and DBS at improving bradykinesia in patients with Parkinson's disease, patients' movement speed was not restored to normal due to limitations in the amplitude and temporal scaling of the agonist and antagonist bursting pattern. These findings suggest a link between basal ganglia function in scaling both the amplitude and temporal parameters of the input to the motor neuron pool.

BACKGROUND

Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model.

RESULTS

In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65+/-5% at baseline, 17+/-3% at the end of stage 1, and 47+/-7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61+/-4% at baseline, 18+/-3% at the end of stage 1, and 34+/-4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64+/-5% at baseline, 19+/-5% at the end of stage 1, and 28+/-3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (P<0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27+/-17 and 27%, respectively; P<0.03) and MED (58+/-42 and 33%; P<0.05) versus CTRL (88+/-52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52+/-5%) and SCS+MEDS (46+/-4%) groups compared with the MEDS (38+/-2%) and CTRL (31+/-4%) groups.

CONCLUSIONS

SCS significantly improved cardiac contractile function and decreased ventricular arrhythmias in canine heart failure.

BACKGROUND

Previous studies have found that few chronically depressed patients remit with antidepressant medications alone.

OBJECTIVE

To determine the role of adjunctive psychotherapy in the treatment of chronically depressed patients with less than complete response to an initial medication trial.

METHODS

This trial compared 12 weeks of (1) continued pharmacotherapy and augmentation with cognitive behavioral analysis system of psychotherapy (CBASP), (2) continued pharmacotherapy and augmentation with brief supportive psychotherapy (BSP), and (3) continued optimized pharmacotherapy (MEDS) alone. We hypothesized that adding CBASP would produce higher rates of response and remission than adding BSP or continuing MEDS alone.

METHODS

Eight academic sites.

METHODS

Chronically depressed patients with a current DSM-IV-defined major depressive episode and persistent depressive symptoms for more than 2 years.

METHODS

Phase 1 consisted of open-label, algorithm-guided treatment for 12 weeks based on a history of antidepressant response. Patients not achieving remission received next-step pharmacotherapy options with or without adjunctive psychotherapy (phase 2). Individuals undergoing psychotherapy were randomized to receive either CBASP or BSP stratified by phase 1 response, ie, as nonresponders (NRs) or partial responders (PRs).

METHODS

Proportions of remitters, PRs, and NRs and change on Hamilton Scale for Depression (HAM-D) scores.

RESULTS

In all, 808 participants entered phase 1, of which 491 were classified as NRs or PRs and entered phase 2 (200 received CBASP and MEDS, 195 received BSP and MEDS, and 96 received MEDS only). Mean HAM-D scores dropped from 25.9 to 17.7 in NRs and from 15.2 to 9.9 in PRs. No statistically significant differences emerged among the 3 treatment groups in the proportions of phase 2 remission (15.0%), partial response (22.5%), and nonresponse (62.5%) or in changes on HAM-D scores.

CONCLUSIONS

Although 37.5% of the participants experienced partial response or remitted in phase 2, neither form of adjunctive psychotherapy significantly improved outcomes over that of a flexible, individualized pharmacotherapy regimen alone. A longitudinal assessment of later-emerging benefits is ongoing.

Chronic human exposure to low levels of inorganic arsenic increases the incidence of vascular diseases and specific cancers. Exposure of endothelial cells to environmentally relevant concentrations of arsenic trioxide (arsenite) induces oxidant formation, activates the transcription factor NF-kappaB, and increases DNA synthesis (Barchowsky et al., Free Radic. Biol. Med. 21, 783-790, 1996). We show, in the current study, that arsenite induces concentration-dependent cell proliferation or death in primary porcine aortic endothelial cells. Low concentrations caused cell proliferation and were associated with increased superoxide and H(2)O(2) accumulation, cSrc activity, H(2)O(2)-dependent tyrosine phosphorylation, and NF-kappaB-dependent transcription. These concentrations were insufficient to activate MAP kinases. However, the MAP kinases, extracellular signal-regulated kinase and p38, were activated in response to levels of arsenite that caused cell death. These data suggest that arsenite-induced oxidant accumulation and subsequent activation of tyrosine phosphorylation represent a MAPK-independent pathway for phenotypic change and proliferation in vascular cells.

OBJECTIVE

To explore the application of the original Charles et al. model of shared treatment decision-making [Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: what does it mean? (or it takes at least two to tango). Soc Sci Med 1997;44:681-92; Charles C, Gafni A, Whelan T. Decision-making in the physician-patient encounter: revisiting the shared treatment decision-making model. Soc Sci Med 1999;49:651-61] in the context of general practice, and to determine whether the model needs tailoring for use in this clinical context.

METHODS

Conceptual paper, presenting the defining characteristics of general practice compared to the original clinical context for which the model was developed (i.e. life threatening disease with different treatment options), and exploring how the model can be tailored for use in the context of general practice.

RESULTS

We identify two areas where the original model requires tailoring: sharing the decision-making around agreeing on an agenda for each consultation; and adapting the information transfer component of the model to acknowledge that doctors may not be the only, or even the main, source of technical information for patients. Finally, we explore the importance of shared decision-making in the context of chronic disease.

CONCLUSIONS

The Charles et al. model can be tailored for use in general practice.

CONCLUSIONS

Tailoring the model for use in general practice has implications for research, in terms of identifying the additional physician competencies needed for implementation. Policy makers who wish to promote shared decision-making need to ensure that incentives which prioritize access and health outcomes do not militate against shared decision-making in general practice.

GATE (Geant4 Application for Emission Tomography) is a Monte Carlo simulation platform developed by the OpenGATE collaboration since 2001 and first publicly released in 2004. Dedicated to the modelling of planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET) acquisitions, this platform is widely used to assist PET and SPECT research. A recent extension of this platform, released by the OpenGATE collaboration as GATE V6, now also enables modelling of x-ray computed tomography and radiation therapy experiments. This paper presents an overview of the main additions and improvements implemented in GATE since the publication of the initial GATE paper (Jan et al 2004 Phys. Med. Biol. 49 4543-61). This includes new models available in GATE to simulate optical and hadronic processes, novelties in modelling tracer, organ or detector motion, new options for speeding up GATE simulations, examples illustrating the use of GATE V6 in radiotherapy applications and CT simulations, and preliminary results regarding the validation of GATE V6 for radiation therapy applications. Upon completion of extensive validation studies, GATE is expected to become a valuable tool for simulations involving both radiotherapy and imaging.

A potential relationship between structural compartments in neural tissue and NMR parameters may increase the specificity of MRI in diagnosing diseases. Nevertheless, our understanding of MR of nerves and white matter is limited, particularly the influence of various water compartments on the MR signal is not known. In this study, components of the (1)H transverse relaxation decay curve in frog peripheral nerve were correlated with the diffusion characteristics of the water in the nerve. Three T(2) values were identified with nerve. Water mobility was found to be unrestricted on the timescale of 100 msec in the component of the signal with the intermediate T(2) time, suggesting some contribution from the interstitial space to this T(2) component. Restricted diffusion was observed in the component with the longest T(2) time, supporting the assignment of at least part of the spins contributing to this component to an intracellular compartment. The observed nonexponential behavior of the diffusion attenuation curves was investigated and shown to be potentially caused by the wide range of axon sizes in the nerve. Magn Reson Med 42:911-918, 1999.

OBJECTIVE

To compare the audiologic results of geriatric patients receiving cochlear implants with younger age groups and to evaluate the quality of life after cochlear implantation in the geriatric population by means of validated quality-of-life questionnaires.

METHODS

Cross-sectional study involving 89 postlingually deafened cochlear implant subjects.

METHODS

Tertiary referral center.

METHODS

A total of 89 postlingually deafened patients were included in the study, among which were 25 patients who were aged 70 years or older.

METHODS

All patients received a cochlear implant. Subjects were implanted with either the Laura, Nucleus 24, or Med-el Combi 40+ cochlear implant systems implementing the SPEAK, ACE, CIS, or CIS+ coding strategies.

METHODS

Speech recognition was determined by means of phonetically balanced monosyllabic word lists. The Hearing Handicap Inventory for Adults, the Glasgow Benefit Inventory, and the scale for the prediction of hearing disability in sensorineural hearing loss were used to quantify the quality of life.

RESULTS

Mean audiologic performance for the three groups increased significantly after implantation (p < 0.001). Postoperative audiologic performance of the geriatric population led to useful hearing, but these scores were significantly lower than for the younger age groups (p = 0.002). However, the quality-of-life outcomes for the geriatric group were similar to those of the younger age groups (p = 0.411 for the Hearing Handicap Inventory for Adults; p = 0.886 for the Glasgow Benefit Inventory).

CONCLUSIONS

The results of this study prove that cochlear implantation in the elderly provides improvements in quality of life and speech understanding, similar to those for younger adult cochlear implant recipients.

The discovery that cancer cells generate large membrane-enclosed packets of epigenetic information, known as microvesicles (MVs), that can be transferred to other cells and influence their behavior (Antonyak et al., Small GTPases 3:219-224, 2012; Cocucci et al., Trends Cell Biol 19:43-51, 2009; Rak, Semin Thromb Hemost 36:888-906, 2010; Skog et al., Nat Cell Biol 10:1470-1476, 2008) has added a unique perspective to the classical paracrine signaling paradigm. This is largely because, in addition to growth factors and cytokines, MVs contain a variety of components that are not usually thought to be released into the extracellular environment by viable cells including plasma membrane-associated proteins, cytosolic- and nuclear-localized proteins, as well as nucleic acids, particularly RNA transcripts and micro-RNAs (Skog et al., Nat Cell Biol 10:1470-1476, 2008; Al-Nedawi et al., Nat Cell Biol 10:619-624, 2008; Antonyak et al., Proc Natl Acad Sci U S A 108:4852-4857, 2011; Balaj et al., Nat Commun 2:180, 2011; Choi et al., J Proteome Res 6:4646-4655, 2007; Del Conde et al., Blood 106:1604-1611, 2005; Gallo et al., PLoS One 7:e30679, 2012; Graner et al., FASEB J 23:1541-1557, 2009; Grange et al., Cancer Res 71:5346-5356, 2011; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863-885, 2012; Martins et al., Curr Opin Oncol 25:66-75, 2013; Noerholm et al., BMC Cancer 12:22, 2012; Zhuang et al., EMBO J 31:3513-3523, 2012). When transferred between cancer cells, MVs have been shown to stimulate signaling events that promote cell growth and survival (Al-Nedawi et al., Nat Cell Biol 10:619-624, 2008). Cancer cell-derived MVs can also be taken up by normal cell types that surround the tumor, an outcome that helps shape the tumor microenvironment, trigger tumor vascularization, and even confer upon normal recipient cells the transformed characteristics of a cancer cell (Antonyak et al., Proc Natl Acad Sci U S A 108:4852-4857, 2011; Martins et al., Curr Opin Oncol 25:66-75, 2013; Al-Nedawi et al., Proc Natl Acad Sci U S A 106:3794-3799, 2009; Ge et al., Cancer Microenviron 5:323-332, 2012). Thus, the production of MVs by cancer cells plays crucial roles in driving the expansion of the primary tumor. However, it is now becoming increasingly clear that MVs are also stable in the circulation of cancer patients, where they can mediate long-range effects and contribute to the formation of the pre-metastatic niche, an essential step in metastasis (Skog et al., Nat Cell Biol 10:1470-1476, 2008; Noerholm et al., BMC Cancer 12:22, 2012; Peinado et al., Nat Med 18:883-891, 2012; Piccin et al., Blood Rev 21:157-171, 2007; van der Vos et al., Cell Mol Neurobiol 31:949-959, 2011). These findings, when taken together with the fact that MVs are being aggressively pursued as diagnostic markers, as well as being considered as potential targets for intervention against cancer (Antonyak et al., Small GTPases 3:219-224, 2012; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863-885, 2012; Martins et al., Curr Opin Oncol 25:66-75, 2013; Ge et al., Cancer Microenviron 5:323-332, 2012; Peinado et al., Nat Med 18:883-891, 2012; Piccin et al., Blood Rev 21:157-171, 2007; Al-Nedawi et al., Cell Cycle 8:2014-2018, 2009; Cocucci and Meldolesi, Curr Biol 21:R940-R941, 2011; D'Souza-Schorey and Clancy, Genes Dev 26:1287-1299, 2012; Shao et al., Nat Med 18:1835-1840, 2012), point to critically important roles for MVs in human cancer progression that can potentially be exploited to develop new targeted approaches for treating this disease.

A greater adherence to the traditional Mediterranean (MED) diet is associated with a reduced risk of developing chronic diseases. This dietary pattern is based on higher consumption of plant products that are rich in flavonoids. We compared the total flavonoid dietary intakes, their food sources and various lifestyle factors between MED and non-MED countries participating in the EPIC study. Flavonoid intakes and their food sources for 35,628 subjects, aged 35-74 years and recruited between 1992 and 2000, in twenty-six study centres were estimated using standardised 24 h dietary recall software (EPIC-Soft®). An ad hoc food composition database on flavonoids was compiled using analytical data from the United States Department of Agriculture and Phenol-Explorer databases. Moreover, it was expanded to include using recipes, estimations of missing values and flavonoid retention factors. No significant differences in total flavonoid mean intake between non-MED countries (373·7 mg/d) and MED countries (370·2 mg/d) were observed. In the non-MED region, the main contributors were proanthocyanidins (48·2%) and flavan-3-ol monomers (24·9%) and the principal food sources were tea (25·7%) and fruits (32·8%). In the MED region, proanthocyanidins (59·0%) were by far the most abundant contributor and fruits (55·1%), wines (16·7%) and tea (6·8%) were the main food sources. The present study shows similar results for total dietary flavonoid intakes, but significant differences in flavonoid class intakes, food sources and some characteristics between MED and non-MED countries. These differences should be considered in studies about the relationships between flavonoid intake and chronic diseases.

The unique nature of the intensive care unit (ICU) environment makes this part of the hospital a focus for the emergence and spread of many antimicrobial-resistant pathogens. There are ample opportunities for the cross-transmission of resistant bacteria from patient to patient, and patients are commonly exposed to broad-spectrum antimicrobial agents. Rates of resistance have increased for most pathogens associated with hospital-acquired infections among ICU patients, and rates are almost universally higher among ICU patients than non-ICU patients. Likewise, ICU patients hospitalized longer (i.e., >7 days) are two- to three-fold more likely to be infected with a pathogen possessing an antimicrobial-resistant phenotype of concern. However, there are many opportunities to prevent the emergence and spread of these resistant pathogens through improved use of established infection control measures (patient isolation, handwashing, glove use, and appropriate gown use) and implementation of a systematic review of antimicrobial use. (Crit Care Med 2001; 29[Suppl.]: N64-N68)

The healthy intestinal mucosa is home to one of the largest populations of macrophages (mvarphi) in the body [Lee SH, Starkey PM, Gordon S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 1985;161:475-89], yet little is known about their function. Resident mvarphi in the large and small intestine are distinct from other mvarphi populations in the body, with regards to both their functional properties and surface phenotype. They respond in an unconventional manner to inflammatory stimuli, with little upregulation of proteins involved in antigen presentation and T cell co-stimulation, and no production of pro-inflammatory cytokines. This suggests that under resting conditions, intestinal mvarphi may be conditioned to be anti-inflammatory in response to local stimuli such as commensal bacteria. In contrast, during inflammation, intestinal mvarphi exhibit increased bactericidal and inflammatory abilities, promote protective immunity and/or mediate pathology. Thus the status of this cell may be the key to understanding how the intestine maintains a balance between being able to generate protective immunity against pathogens, but still prevent pathological inflammation under normal conditions. In this review, we discuss the current knowledge of intestinal mvarphi biology, and highlight the different levels of immunoregulation which influence these cells, with particular focus on innate pathogen recognition receptor (PRR) function and responsiveness to microbial stimuli.

This report provides evidence from a number of different approaches (i.e., comparison of cell shape in 1-microm sections of photodamaged versus healthy skin at the light microscopic level; comparison of cell shape and apposition to collagen fibrils in ultrathin sections of the same tissues examined by transmission electron microscopy, and fluorescence staining for adhesion site protein expression and actin filament architecture in frozen tissue sections) that dermal cells in healthy skin are attached to collagen fibrils over a large part of the cell border, have a flattened/spread (two-dimensional) appearance and have abundant actin in their cytoplasm. In contrast, cells in photodamaged skin are often in contact with fragmented collagen or amorphous debris rather than intact collagen, have a collapsed/elongated shape, and have a lower amount of actin. Collagen synthesis is reduced in severely photodamaged skin relative to collagen synthesis in corresponding sun-protected skin (N Engl J Med 329:530, 1993). We hypothesize that fibroblasts in severely damaged skin have less interaction with intact collagen and as a result experience a reduction in mechanical tension. Decreased collagen synthesis is (presumed to be) the result.

BACKGROUND

Zika virus (ZIKV) is transmitted to humans primarily by Aedes mosquito bites. However, circumstantial evidence points to a sexual transmission route.

OBJECTIVE

To assess the sexually acquired ZIKV cases and to investigate the shedding of ZIKV in genital fluids.

METHODS

PubMed, Scopus, Pro-MED-mail and WHO ZIKV notification databases from inception to December 2016.

METHODS

Reports describing ZIKV acquisition through sex and studies reporting the detection or isolation of ZIKV in the genital fluids were included.

UNASSIGNED

The risk of bias was assessed using the National Institute of Health Tool.

RESULTS

Eighteen studies reporting on sex-acquired ZIKV and 21 describing the presence of ZIKV in genital fluids were included. The overall risk of bias was moderate. Sexual transmission was male-female (92.5%), female-male (3.7%) and male-male (3.7%). Modes of sexual transmission were unprotected vaginal (96.2%), oral (18.5%) and anal (7.4%) intercourse. The median time between onset of symptoms in the index partner and presumed sexual transmission was 13 days (range 4-44 days). ZIKV RNA was detected in semen as late as 188 days (range 3-188 days) following symptom onset, and infectious virus was isolated in semen up to 69 days after symptom onset. No study reported ZIKV isolation from female genital samples, but detection did occur up to 13 days after symptom onset.

CONCLUSIONS

ZIKV is potentially sexually transmitted and persists in male genital secretions for a prolonged period after symptom onset. PROSPERO systematic review registration number CRD42016041475.

The HIV-1-encoded Tat protein controls transcription elongation by increasing processivity of RNA polymerase II (Pol II). Here, we have identified a Tat stimulatory activity (Tat-SF) as a novel RNA Pol II-containing complex. Remarkably, Tat-SF contains the previously identified Tat cofactors Tat-SF1, P-TEFb and hSPT5/Tat-CT1, in addition to RNA Pol II and other unidentified polypeptides, but none of the SRB/MED proteins or other factors found associated with the previously described RNA Pol II holoenzyme complex. Tat-SF supports basal, Sp1-activated and Tat-activated transcription in a reconstituted system, and a Tat-SF-derived fraction lacking RNA Pol II can complement non-responsive RNA Pol II complexes for Tat-enhanced HIV-1 transcription, indicating that Tat-SF contains factors that are critical for Tat function. Both Tat-SF and RNA Pol II holoenzyme are present in HeLa nuclear extracts and each can be recruited to the HIV-1 promoter. Our results indicate that Tat-SF is a Tat cofactor-containing RNA Pol II complex whose recruitment to the promoter provides elongation factors important for Tat-enhanced HIV-1 transcription following TAR RNA synthesis.

OBJECTIVE

Homonymous visual field defects (HVFDs) are among the most common disorders that occur in the elderly after vascular brain damage and can have a major impact on quality of life (QOL). Aims of this study were to describe the vision-targeted, health-related QOL in patients with HVFDs after cerebrovascular lesion, and to determine the relationship between patients' self-reported difficulties and the characteristics of HVFDs in the binocular visual field.

METHODS

The German version of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) was used. NEI-VFQ-25 scores for patients were compared to reference values of healthy German subjects from Franke (Z Med Psychol 7:178-184, 1999). Extent and location of absolute HVFDs were assessed by binocular semi-automated kinetic perimetry (SKP) within the 90 degrees visual field. Correlations of the NEI-VFQ-25 scores of patients with the area of sparing within the affected hemifield (A-SPAR) were estimated by Spearman's r (s).

RESULTS

The mean NEI-VFQ-25 composite score for 33 patients (time span after brain injury at least 6 months) was 77.1, which was significantly lower (p < 0.0001) than the reference value for 360 healthy subjects (composite score = 90.6), and this was also the case for general vision, near activities, vision specific mental health, driving, colour, and peripheral vision. The score for general health was also significantly lower in patients than in reference subjects (p < 0.0001). A weak correlation of the composite score with A-SPAR (r (s) = 0.38) was observed.

CONCLUSIONS

Our findings indicate that detectable decrements in vision-targeted, health-related QOL are observed in patients with homonymous visual field loss. A relationship of the perceived visual functioning with objective parameters is by definition difficult; however, understanding what components of visual function affect certain visual tasks, would help in developing more efficient, clinical assessment strategies. The results reveal a tendency for increasing QOL with advancing size of the area of sparing within the affected hemifield (A-SPAR). The lack of a strong correlation between NEI-VFQ-25 subscales and A-SPAR suggests that an assessment of the visual field may not accurately reflect patients' perceived difficulty in visual tasks. Additional consideration of visual exploration via eye and head movements may improve the correlation between visual function and its perception.

The N-terminal sequence of the major human serum mannose-binding protein (MBP1) was shown to be identical at all positions determined with the amino acid sequence predicted from a cDNA clone of a human liver MBP mRNA. An oligonucleotide corresponding to part of the sequence of this cDNA clone was used to isolate a cosmid genomic clone containing a homologous gene. The intron/exon structure of this gene was found to closely resemble that of the gene encoding a rat liver MBP (MBP A). The nucleotide sequence of the exons differed in several places from that of the human cDNA clone published by Ezekowitz, Day & Herman [(1988) J. Exp. Med. 167, 1034-1046]. The MBP molecule comprises a signal peptide, a cysteine-rich domain, a collagen-like domain, a 'neck' region and a carbohydrate-binding domain. Each domain is encoded by a separate exon. This genomic organization lends support to the hypothesis that the gene arose during evolution by a process of exon shuffling. Several consensus sequences that may be involved in controlling the expression of human serum MBP have been identified in the promoter region of the gene. The consensus sequences are consistent with the suggestion that this mammalian serum lectin is regulated as an acute-phase protein synthesized by the liver.

OBJECTIVE

A systematic review and meta-analysis of studies of the association between secondhand tobacco smoke (SHTS) and middle ear disease (MED) in children.

METHODS

MEDLINE, EMBASE, and CAB abstracts (through December 2010) and reference lists.

METHODS

Sixty-one epidemiological studies of children assessing the effect of SHTS on outcomes of MED. Articles were reviewed, and the data were extracted and synthesized by 2 researchers. MAIN OUTCOME EXPOSURES: Children's SHTS exposure.

METHODS

Middle ear disease in children.

RESULTS

Living with a smoker was associated with an increased risk of MED in children by an odds ratio (OR) of 1.62 (95% CI, 1.33-1.97) for maternal postnatal smoking and by 1.37 (95% CI, 1.25-1.50) for any household member smoking. Prenatal maternal smoking (OR, 1.11; 95% CI, 0.93-1.31) and paternal smoking (OR, 1.24; 95% CI, 0.98-1.57) were associated with a nonsignificant increase in the risk of MED. The strongest effect was on the risk of surgery for MED, where maternal postnatal smoking increased the risk by an OR of 1.86 (95% CI, 1.31-2.63) and paternal smoking by 1.83 (95% CI, 1.61-2.07).

CONCLUSIONS

Exposure to SHTS, particularly to smoking by the mother, significantly increases the risk of MED in childhood; this risk is particularly strong for MED requiring surgery. We have shown that per year 130 200 of child MED episodes in the United Kingdom and 292 950 of child frequent ear infections in the United States are directly attributable to SHTS exposure in the home.

Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.

We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.

Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.

Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.

IκB kinase α (IKKα) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKKα and its activator, NF-κB-inducing kinase (NIK), support the expansion of tumor-initiating cells (TICs) that copurify with a CD24(med)CD49f(hi) population from premalignant ErbB2-expressing mammary glands. Upon activation, IKKα enters the nucleus, phosphorylates the cyclin-dependent kinase (CDK) inhibitor p27/Kip1, and stimulates its nuclear export or exclusion. Reduced p27 expression rescues mammary tumorigenesis in mice deficient in IKKα kinase activity and restores TIC self-renewal. IKKα is also likely to be involved in human breast cancer, where its expression shows an inverse correlation with metastasis-free survival, and its presence in the nucleus of invasive ductal carcinomas (IDCs) is associated with decreased nuclear p27 abundance.