Bilingualism is a long-term cognitively challenging experience that modulates metabolite concentrations in the healthy brain.

Cognitively demanding experiences, including complex skill acquisition and processing, have been shown to induce brain adaptations, at least at the macroscopic level, e.g. on brain volume and/or functional connectivity. However, the neurobiological bases of these adaptations, including at the cellular level, are unclear and understudied. Here we use bilingualism as a case study to investigate the metabolic correlates of experience-based brain adaptations. We employ Magnetic Resonance Spectroscopy to measure metabolite concentrations in the basal ganglia, a region critical to language control which is reshaped by bilingualism. Our results show increased myo-Inositol and decreased N-acetyl aspartate concentrations in bilinguals compared to monolinguals. Both metabolites are linked to synaptic pruning, a process underlying experience-based brain restructuring. Interestingly, both concentrations correlate with relative amount of bilingual engagement. This suggests that degree of long-term cognitive experiences matters at the level of metabolic concentrations, which might accompany, if not drive, macroscopic brain adaptations.

High complication rates during and after repeated Lichtenstein or laparoscopic inguinal hernia repairs in the same groin: a cohort study based on medical records.

PURPOSE: Performing two anterior or two posterior inguinal hernia repairs in the same groin contradict guidelines. Nevertheless, there can be indications for using the same approach at reoperation, and information on complications other than the risk of a third repair and chronic pain is lacking in the literature. The aim was to assess intraoperative events and postoperative complications after two Lichtenstein repairs or laparoscopic inguinal hernia repairs in the same groin. METHODS: This nationwide cohort study included patients that had received two Lichtenstein repairs (Lichtenstein-Lichtenstein) or two laparoscopic (Laparoscopy-Laparoscopy) inguinal hernia repairs in the same groin. Patients were identified in the Danish Hernia Database and outcomes were identified in medical records during a period of 6 years. Outcomes were intraoperative events that deviated from a standard repair and 1-year postoperative complications classified according to the Clavien-Dindo classification. Outcomes were reported separately for the two cohorts. RESULTS: Among the included 102 Lichtenstein reoperations, 27% of the repairs had intraoperative events, with drain placement being most common (10%). Half of the reoperations resulted in complications where infection (15%) and hematoma (12%) were most frequent. Among the 58 laparoscopic reoperations, 16% had an intraoperative event where bleeding requiring clips was most common (10%). Half of the reoperations resulted in a complication with surgery in general anesthesia in the same groin area being the most frequent complication (9%). CONCLUSIONS: Intraoperative events and 1-year postoperative complications were high for both Lichtenstein-Lichtenstein and Laparoscopy-Laparoscopy, and the results therefore support guidelines that recommend another approach at reoperation.

Optimal Timing for Laparoscopic Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography: A Systematic Review.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy is often used as definitive treatment for common bile duct stones. The aim of this study was to investigate the optimal time interval between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. MATERIALS AND METHODS: PubMed and Embase were searched for studies comparing different time delays between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. Observational studies and randomized controlled trials were included. Primary outcome was conversion rate from laparoscopic to open cholecystectomy and secondary outcomes were complications, mortality, operating time, and length of stay. RESULTS: A total of 14 studies with a total of 1930 patients were included. The pooled estimate revealed an increase from a 4.2% conversion rate when laparoscopic cholecystectomy was performed within 24 h of endoscopic retrograde cholangiopancreatography to 7.6% for 24-72 h delay to 12.3% when performed within 2 weeks, to 12.3% for 2-6 weeks, and to a 14% conversion rate when operation was delayed more than 6 weeks. CONCLUSION: According to this systematic review, it is preferable to perform cholecystectomy within 24 h of endoscopic retrograde cholangiopancreatography to reduce conversion rate. Early laparoscopic cholecystectomy does not increase mortality, perioperative complications, or length of stay and on the contrary it reduces the risk of reoccurrence and progression of disease in the delay between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy.

Obstruction of BRAFV600E transcription by complementary PNA oligomers as a means to inhibit BRAF-mutant melanoma growth.

Peptide nucleic acid (PNA) oligomers are DNA mimics, which are capable of binding gene sequences 1000-fold more avidly than complementary native DNA by strand invasion and effectively obstruct transcription. Irreversibly obstructing the transcription or replication of a gene sequence, such as BRAFV600E, offers a potential route to specifically target the cancer cell itself. We have employed PNA oligomers to target BRAFV600E in a sequence-specific complementary manner. These PNAs have been modified by appending configurationally stabilizing cationic peptides in order to improve their cellular delivery and target avidity. Our results indicate that exposure of the melanoma cell lines to a modified PNA-peptide conjugate complementary to BRAFV600E mutation sequence results in a concentration-dependent and time-dependent inhibition of cell growth that is specific for the BRAFV600E-mutant melanoma cell lines with inhibition of mRNA and protein expression. Xenograft mouse trials show increased tumor growth delay and necrosis with the BRAFV600E-complementary PNA-peptide conjugates as compared with the saline and scrambled PNA sequence controls. Similarly, quantitative measurement shows a 2.5-fold decrease in Ki67 and a 3-fold increase in terminal deoxynucleotidyl transferase dUTP nick end labeling expression with this approach. PNA-delivery peptide conjugates represent a novel way to target BRAFV600E and represent a new approach in targeting selective oncogenes that induce tumor growth.

Short-term outcome after Onstep versus Lichtenstein technique for inguinal hernia repair: results from a randomized clinical trial.

PURPOSE: Because of the high number of patients with chronic pain following inguinal hernia repair, a new, simple and safe method of repair is needed. Onstep is a new type of inguinal hernia repair that might be able to reduce postoperative acute and chronic pain. The aim of this study was to investigate if there were differences in early postoperative pain during the first 10 days between the Onstep and the Lichtenstein technique. METHODS: This was a double-blinded, randomized clinical trial conducted in five surgical departments in Denmark, from April 2013 to June 2014. Eligible participants for this study were male patients, >18 years, with a primary inguinal hernia. Experimental treatment in this study was the Onstep technique, which was compared with the Lichtenstein repair. Primary outcome was postoperative pain during the first 10 days following surgery. Secondary outcomes included duration of surgery, period for return to normal daily activities (days), and recurrence. Randomization was done in blocks and stratified on centers. Participants and study personnel handling questionnaires and analysis were blinded to the allocation. RESULTS: In total, 290 participants were randomized. We found no significant differences between the groups regarding early postoperative pain or minor postoperative complications. Four patients had a recurrence within the first 10 days of follow-up, one patient in the Lichtenstein group and three patients in the Onstep group, p = 0.30. CONCLUSION: The Onstep technique for inguinal hernia repair was safe and had comparable results to the Lichtenstein repair regarding short-term pain and postoperative complications. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01753219).

Sexual activity and functioning in female scleroderma patients.

OBJECTIVE: Few studies exist on sexual activity and functioning in female patients with systemic sclerosis (SSc, scleroderma). We studied the patient-reported impact of SSc on sexual functioning among female patients. METHODS: 101 SSc patients completed the Short Form-36 (SF-36), the Female Sexual Functioning Index (FSFI) and the Female Sexual Function in Scleroderma (FSFS) questionnaires. RESULTS: Sixty patients reported being sexually active (59.4%). Reasons for sexual inactivity included lack of a partner (36.6%), personal choice (31.7%), and health status of the respondent's partner (19.5%). Only 7 subjects (17%) listed scleroderma as the primary reason for sexual inactivity. The mean FSFI score in the sexually active population was 24.9 (SD=6.7, range = 4.5-34.8) which is significantly lower than the mean score of 30.5 reported for the general population. Sexual functioning was significantly correlated with the Mental Component Score of the SF-36 (r=0.54, p<0.001) but surprisingly not with the Physical Component Score of the SF-36, age, and disease classification or duration. Several scleroderma-related problems including fatigue, body pain, vaginal dryness, and vaginal discomfort were cited as contributing to sexual difficulties. CONCLUSION: Women with scleroderma do remain sexually active overall in spite of several disease-related physical and psychological difficulties. Many of their problems are amenable to health interventions and should be addressed during health care visits.

Therapeutic cancer vaccines in cervical cancer: phase I study of Lovaxin-C.

Producing effective therapeutic vaccines has proved much more difficult and challenging than developing cancer preventive vaccines. Despite huge research in the area of cancer immunology, FDA/EMEA have not approved any type of cancer treatment vaccine so far. More than 99% of cervical cancers have detectable amounts of human papillomavirus (HPV) DNA. Integration of high-risk HPV into the host cell genome is followed by continual expression of HPV E6 and E7 oncoproteins, making them excellent targets for developing vaccines which could be used in high grade precancerous (CIN) lesions or invasive cancer or in the prevention of cancer recurrence. Therapeutic cervical cancer vaccines have been extensively studied. Strategies used were vaccination with HPV peptides or proteins, alone or in pulsed dendritic cells, DNA vaccines, virus-like particles or viral and bacterial vectors. Lovaxin-C is a recombinant live-attenuated Listeria monocytogenes (Lm) that secretes the antigen HPV-16 E7 fused to a non-hemolytic listeriolysin O protein. In a phase I study Lovaxin-C was administered to advanced cervical cancer patients refractory to existing therapies. The dose-limiting toxicity was hypotension and flue-like syndrome. There were no serious adverse events. Specific T-cell response was detected as well as clinical response to Lovaxin-C. Several other therapeutic HPV vaccines are in clinical development and in most of the studies specific immunological and clinical responses were seen. Efficacious therapeutic vaccine for the treatment of cervical cancer should be expected in the near future.

Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome- and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP.

The effects of multifocal refractive lenses on occipital extension and forward head posture during a visual task.

The purpose of this study was to determine if a change in forward head posture and occipital extension occurred in participants who wore multifocal lenses vs. those persons with non-multifocal lenses while performing an 8-min visual reading task on a visual display unit (VDU). Forty-two healthy human participants were recruited for this study. Thirty-three participants completed the study. Fourteen participants wore multifocal lenses and 19 wore frames with non-multifocal lenses. To evaluate the degree of change of forward head posture and occipital extension digital photographs of cervical posture were taken at four different time intervals: prior to performing the reading task and at 3, 5 and 8 min during the reading task. The digital photographs were analysed utilizing a computer program. Two one-way ANOVA were utilized to determine the degree of change of forward head posture and occipital extension between groups. A significant difference was identified between groups for changes in degrees of forward head posture while performing a visual reading task on a VDU. However, no significant difference between groups was found for occipital extension while performing the same task. Multifocal wearers exhibit greater degrees of change in forward head posture and occipital extension than non-multifocal wearers. These postural changes may place them at a greater risk for musculoskeletal disorders and headaches.

Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network.

Caenorhabditis elegans CEP-1 activates germline apoptosis in response to genotoxic stress, similar to its mammalian counterpart, tumor suppressor p53. In mammals, there are three p53 family members (p53, p63, and p73) that activate and repress many distinct and overlapping sets of genes, revealing a complex transcriptional regulatory network. Because CEP-1 is the sole p53 family member in C. elegans, analysis of this network is greatly simplified in this organism. We found that CEP-1 functions during normal development in the absence of stress to repress many (331) genes and activate only a few (28) genes. In response to genotoxic stress, 1394 genes are activated and 942 are repressed, many of which contain p53-binding sites. Comparison of the CEP-1 transcriptional network with transcriptional targets of the human p53 family reveals considerable overlap between CEP-1-regulated genes and homologues regulated by human p63 and p53, suggesting a composite p53/p63 action for CEP-1. We found that phg-1, the C. elegans Gas1 (growth arrest-specific 1) homologue, is activated by CEP-1 and is a negative regulator of cell proliferation in the germline in response to genotoxic stress. Further, we find that CEP-1 and PHG-1 mediate the decreased developmental rate and embryonic viability of mutations in the clk-2/TEL2 gene, which regulates lifespan and checkpoint responses.

Emergency department visits for concern regarding anthrax--New Jersey, 2001.

INTRODUCTION: In October of 2001, after letters processed in Trenton, New Jersey, resulted in multiple cases of anthrax, emergency departments (EDs) in New Jersey experienced an increase in visits from patients concerned about possible exposure to agents of biologic terrorism. Information about the effect of an actual biologic terrorism attack on the emergency department population might be useful in the design of biosurveillance systems, particularly with regard to their performance during the mitigation phase that occurs after an attack. In addition, such information might help identify issues that arise regarding the public health response in the ED setting. OBJECTIVES: The objectives of this report were to identify and characterize ED visits, by patients concerned with exposure to biologic terrorism agents, in selected New Jersey hospitals after the anthrax attack in fall 2001. METHODS: A retrospective cohort design was used in this study. The setting was 15 New Jersey EDs within a 55-mile radius of Trenton. Participants were consecutive patients evaluated by ED physicians for the following four periods in 2001: 1 month before September 11; 1 month after September 11; 1 month after October 11; and for the second month after October 11. Percentages of visits were calculated with a concern for exposure (CE) visits by using International Classification of Diseases, Ninth Revision (ICD-9) descriptors: Feared Complaint-No Diagnosis (ICD-9 code v65.6) and Screening for Infectious Disease (ICD-9 code v75.9) for all hospitals and for Trenton versus non-Trenton hospitals as a percentage of ED visits. Charts were reviewed by using a structured data form. RESULTS: A total of 225,403 ED visits occurred during the 4 months, of which 698 were CE visits. The percentages of CE visits for the four periods were 0.06%, 0.06%, 0.92%, and 0.10%, respectively. For the peak third period, the percentage was increased for the two Trenton hospitals, 1.81%, versus 0.82% for the 13 non-Trenton hospitals. This report is a summary of the 508 visits associated with concern for anthrax exposure during the peak third period: 47% reported exposure to powder, 13% were postal workers, 4% received chest radiographs, 65% had a nasal swab for anthrax, 13% had ED decontamination, and 32% received antibiotics. CONCLUSION: An increase in CE visits occurred during the 1-month period after October 11, 2001. During the peak month, a higher increase occurred in Trenton EDs. Considering the substantial variation in diagnostic evaluation and treatment, readily available guidelines are needed.

Neuronal conduction studies of the median nerve in non-impaired humans: a comparison of accepted techniques.

BACKGROUND AND PURPOSE: There are two commonly accepted techniques used for distal electro-stimulation placement when performing median motor nerve conduction studies. The purpose of this study was to compare latency using two commonly accepted sites of distal stimulation of the median nerve when performing motor nerve conduction studies on non-impaired adult humans. PARTICIPANTS: The sample consisted of 36 non-impaired participants (15 female, 21 male) aged 20 to 40 years. METHODS: Participants were randomly assigned to two groups and tested bilaterally for the median motor nerve. For distal stimulation of the median motor nerve, in the first group, 8 cm was measured from the center of the muscle diagonally to arrive at a point between the flexor carpi radialis and plamaris longus tendons. In the second group, 3.5 cm was measured from the distal wrist crease proximally along the median nerve for the distal stimulation of the median motor nerve. Distal latency of both techniques was obtained. Surface skin temperature of the palm was recorded throughout the procedures. RESULTS: No significant differences were found between the 8 cm and 3.5 cm techniques at p < or = 0. 05 level. COMMENT: Even though no differences were found between the two techniques, the 3.5-cm technique is recommended because of its consistency as an anatomical landmark reducing the potential for measurement error.

The relationship between temperature and neuronal characteristics.

The purpose of this study was to determine a relationship between surface temperature of the limb and neuronal characteristics of the median and ulnar nerves in non-impaired individuals. Previous literature demonstrates that there is a negative correlation between distal latency and amplitude and temperature while a positive correlation exists between nerve conduction velocity and temperature. It is a common clinical practice to externally manipulate the temperature of a cold limb. Thirty-six participants (21 male, 15 female,) with an age range between 20-38 years old (mean age = 26.6) completed the study. Temperature of the limb was not manipulated by the researchers prior to testing and was measured at the distal wrist crease using a surface probe. Relationship was determined using a Pearson product-moment coefficient of correlation. A significant negative correlation existed for median distal sensory latency (DSL), ulnar DSL, ulnar motor amplitude (CMAP), and ulnar sensory amplitude (SNAP). The investigators conclude that temperature is a factor to consider when performing nerve conduction studies. The researchers suggest using mathematical correction factors to compensate for a cool limb rather than external heating.

Domain wall pinning in narrow ferromagnetic ring structures probed by magnetoresistance measurements.

We present a magnetoresistance study of magnetization reversal and domain wall pinning effects in a mesoscopic narrow ferromagnetic Permalloy ring structure containing notches. The size and strength of the attractive pinning potential created by a notch is measured and the resistance minimum at remanence is found to occur when a single transverse domain wall is pinned at the notch, in agreement with the results of numerical simulations of the anisotropic magnetoresistance. When a field is applied in the direction corresponding to a potential well edge, a novel magnetic state with a very wide domain wall is stabilized, giving rise to a characteristic signature in the magnetoresistance at such angles.

Role of oral anti-diabetic agents in modifying cardiovascular risk factors.

Patients with type 2 diabetes have an increased risk for cardiovascular disease (CVD) and it accounts for up to 80% of excess deaths in these patients. It has been recognized that type 2 diabetes is associated with an increased prevalence of CVD risk factors, including hypertension, dyslipidemia, microalbuminuria, and altered hemostasis. The benefit of cardiovascular protection can only be partially explained by controlling hyperglycemia. Some of the oral agents used to treat hyperglycemia significantly modify other cardiovascular risk factors. This article will review oral agents used to treat type 2 diabetes and their effects on modifying CVD risk factors.

A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis.

In Caenorhabditis elegans, histone acetyltransferase CBP-1 counteracts the repressive activity of the histone deacetylase HDA-1 to allow endoderm differentiation, which is specified by the E cell. In the sister MS cell, the endoderm fate is prevented by the action of an HMG box-containing protein, POP-1, through an unknown mechanism. In this study, we show that CBP-1, HDA-1 and POP-1 converge on end-1, an initial endoderm-determining gene. In the E lineage, an essential function of CBP-1 appears to be the activation of end-1 transcription. We further identify a molecular mechanism for the endoderm-suppressive effect of POP-1 in the MS lineage by demonstrating that POP-1 functions as a transcriptional repressor that inhibits inappropriate end-1 transcription. We provide evidence that POP-1 represses transcription via the recruitment of HDA-1 and UNC-37, the C.elegans homolog of the co-repressor Groucho. These findings demonstrate the importance of the interplay between acetyltransferases and deacetylases in the regulation of a critical cell fate-determining gene during development. Furthermore, they identify a strategy by which concerted actions of histone deacetylases and other co-repressors ensure maximal repression of inappropriate cell type-specific gene transcription.

A t-SNARE of the endocytic pathway must be activated for fusion.

The t-SNARE in a late Golgi compartment (Tlg2p) syntaxin is required for endocytosis and localization of cycling proteins to the late Golgi compartment in yeast. We show here that Tlg2p assembles with two light chains, Tlg1p and Vti1p, to form a functional t-SNARE that mediates fusion, specifically with the v-SNAREs Snc1p and Snc2p. In vitro, this t-SNARE is inert, locked in a nonfunctional state, unless it is activated for fusion. Activation can be mediated by a peptide derived from the v-SNARE, which likely bypasses additional regulatory proteins in the cell. Locking t-SNAREs creates the potential for spatial and temporal regulation of fusion by signaling processes that unleash their fusion capacity.

ELT-5 and ELT-6 are required continuously to regulate epidermal seam cell differentiation and cell fusion in C. elegans.

The C. elegans epidermis is a simple epithelium comprised of three major cell types, the seam, syncytial and P cells. While specification of all major epidermal cells is known to require the ELT-1 GATA transcription factor, little is known about how the individual epidermal cell types are specified. We report that elt-5 and -6, adjacent genes encoding GATA factors, are essential for the development of the lateral epidermal cells, the seam cells. Inhibition of elt-5 and -6 function by RNA-mediated interference results in penetrant late embryonic and early larval lethality. Seam cells in affected animals do not differentiate properly: the alae, seam-specific cuticular structures, are generally absent and expression of several seam-specific markers is blocked. In addition, elt-3, which encodes another GATA factor normally expressed in non-seam epidermis, is often ectopically expressed in the seam cells of affected animals, demonstrating that ELT-5 and -6 repress elt-3 expression in wild-type seam cells. Seam cells in affected animals often undergo inappropriate fusion with the epidermal syncytia. Interference of elt-5 and -6 function during larval development can cause fusion of all seam cells with the surrounding syncytia and pronounced defects in molting. elt-5 and -6 are both expressed in seam cells and many other cells, and are apparently functionally interchangeable. Their expression is controlled by separable tissue-specific regulatory elements and the apportionment of monocistronic versus dicistronic transcription of both genes appears to be subject to cell-type-specific regulation. Collectively, these findings indicate that elt-5 and -6 function continuously throughout C. elegans development to regulate seam cell differentiation and cell fusion.

Distinct requirements for C.elegans TAF(II)s in early embryonic transcription.

TAF(II)s are conserved components of the TFIID, TFTC and SAGA-related mRNA transcription complexes. In yeast (y), yTAF(II)17 is required broadly for transcription, but various other TAF(II)s appear to have more specialized functions. It is important to determine how TAF(II)s contribute to transcription in metazoans, which have larger and more diverse genomes. We have examined TAF(II) functions in early Caenorhabditis elegans embryos, which can survive without transcription for several cell generations. We show that taf-10 (yTAF(II)17) and taf-11 (yTAF(II)25) are required for a significant fraction of transcription, but apparently are not needed for expression of multiple developmental and other metazoan-specific genes. In contrast, taf-5 (yTAF(II)48; human TAF(II)130) seems to be required for essentially all early embryonic mRNA transcription. We conclude that TAF-10 and TAF-11 have modular functions in metazoans, and can be bypassed at many metazoan-specific genes. The broad involvement of TAF-5 in mRNA transcription in vivo suggests a requirement for either TFIID or a TFTC-like complex.