Voltage-dependent block of NMDA responses by 5-HT agonists in ventral spinal cord neurones.
1. Modulation by 5-hydroxytryptamine receptor agonists of the NMDA responses of ventral spinal cord neurones was studied by use of the whole-cell patch-clamp technique. 2. In a Mg-free solution containing tetrodotoxin and glycine, 5-hydroxytryptamine (5-HT, 10-100 microM) reduced the NMDA response, the block increasing with hyperpolarization. Kainate responses were little affected. 3. Some classical agonists of 5-HT receptors induced similar blocking effects. At 10 microM, both a selective agonist of 5-HT2 receptors, (+/-)-2,5-dimethoxy-4 iodo amphetamine (DOI), and a selective agonist of some 5-HT1 receptors, (+/-)-8-hydroxy-2(n-dipropyl amino) tetralin (8-OH-DPAT), induced pronounced blocking effects, of 48% and 33% respectively at -100 mV, whereas another 5-HT1 agonist, 5-carboxamidotryptamine (5-CT) was ineffective. At 100 microM, 5-methoxytryptamine (5-MeOT) induced a complete block of the NMDA responses recorded at -100 mV. The order of potency was: 5-MeOT congruent to DOI > 8-OH-DPAT > 5-HT > 5-CT. 4. Neither spiperone nor ketanserin (1 microM) prevented the blocking effect of 5-HT or DOI. 5. Prolonged preincubations with 5-HT did not block the response if NMDA was applied without 5-HT. When 5-HT agonists were applied both by preincubation and with NMDA, the degree of block increased during the NMDA application. 6. Lowering the NMDA concentration (from 100 to 20 microM) slightly decreased the blocking effect of 5-MeOT. 7. External Mg2+ ions (1 mM) also reduced the blocking effects of 5-HT and 5-MeOT. 8. The blocking effects described appear to be independent of classical 5-HT receptors. Their voltage-dependence suggests a mechanism of open channel block consistent with all the results obtained.


Examining advocacy and comprehensive cancer control.
The effectiveness of advocacy has been well documented and its use established as a common practice in furthering sound public health policy and practices. Efforts are underway to explain how advocacy has supported, shaped and influenced public policy concerning -- and the growth and development of -- comprehensive cancer control initiatives. The objective of this paper is to assess the history, current role and future of advocacy as a means of articulating the value of, and furthering, comprehensive cancer control practices. Comprehensive cancer control is approaching a critical moment in its development, and a unified approach is necessary to achieve common goals. A call to action for supporting and contributing to the success of a comprehensive approach to cancer control is more important today than it was 11 years ago. Advocacy is an essential strategy in that call to action.


[Changes in fibrinogen values in children with acute articular rheumatism and streptococcal disease].
A study was made of changes in body fluid parameters of rheumatism following treatment with sulphoadenosine-methionine and classic forms of management. Particular attention is drawn to improvement of the serum electrophoretic picture (especially in the case of alpha 2 and gamma-globulins) with respect to untreated control group. Note is also taken of the drug's positive influence on liver function, particularly with regard to lactate hydrogenase, compared with the variations in such parameters in the control group.


Capacitative calcium entry in the nervous system.
Capacitative calcium entry is a process whereby the depletion of Ca(2+) from intracellular stores (likely endoplasmic or sarcoplasmic reticulum) activates plasma membrane Ca(2+) channels. Current research has focused on identification of capacitative calcium entry channels and the mechanism by which Ca(2+) store depletion activates the channels. Leading candidates for the channels are members of the transient receptor potential (TRP) superfamily, although no single gene or gene product has been definitively proven to mediate capacitative calcium entry. The mechanism for activation of the channels is not known; proposals fall into two general categories, either a diffusible signal released from the Ca(2+) stores when their Ca(2+) levels become depleted, or a more direct protein-protein interaction between constituents of the endoplasmic reticulum and the plasma membrane channels. Capacitative calcium entry is a major mechanism for regulated Ca(2+) influx in non-excitable cells, but recent research has indicated that this pathway plays an important role in the function of neuronal cells, and may be important in a number of neuropathological conditions. This review will summarize some of these more recent findings regarding the role of capacitative calcium entry in normal and pathological processes in the nervous system.


Impact of immediate post-reperfusion cooling on outcome in patients with acute stroke and substantial ischemic changes.
In patients with acute stroke and an extensive ischemic burden at baseline, the prognosis is usually poor despite timely reperfusion. To overcome universally poor outcomes in such patients, by applying immediate 'post-reperfusion cooling' in order to reduce reperfusion-related complications, and to describe the clinical and imaging characteristics. Patients having (1) an acute anterior large vessel occlusive stroke within 4.5 h since last known well, (2) Alberta Stroke Program Early CT Score (ASPECTS) ≤5 on baseline imaging, and (3) targeted temperature management with endovascular cooling after confirmed reperfusion were included in this study. Eighteen patients (mean±SD age 59.5±10.9 years, median National Institutes of Health Stroke Scale score of 17, and median ASPECTS of 3) were analyzed. Median lesion volumes at baseline and after treatment were 130.2 and 110.6 mL, respectively. Median time from onset to the start of hypothermia and hypothermia duration were 213 min and 51 h, respectively. Favorable outcome (modified Rankin Scale ≤2) at 3 months was observed in 10 (55.6%) patients. Symptomatic intracranial hemorrhage, malignant brain edema, and pneumonia were observed in 2, 6, and 8 patients, respectively. The use of post-reperfusion cooling as a rescue treatment in patients with substantial ischemia at baseline might improve clinical outcome.


[Myomas management, alternatives to hysterectomy and myomectomy: what can we propose?].
Second generation endometrial ablation techniques must be used preferably as they present less complications than first generation techniques. An efficient contraception is highly recommended after thermal ablation. Myolysis techniques are still investigational, focused ultrasound myolysis MR or ultrasound-guided is accessible to approximately 10% of uterine myomas with 70% of long-term symptom relief. Outcomes of laparoscopic uterine artery occlusion are similar to those of uterine artery embolization but with less long-term durability.


Measuring True Change in Individual Patients: Reliable Change Indices of Cardiac Rehabilitation Outcomes, and Implications for Quality Indicators.
Mediated by outcomes such as improved exercise capacity, cardiac rehabilitation (CR) reduces morbidity and mortality. For accuracy, an individual CR patient's change must be measured reliably, an issue not typically considered in practice. Drawing from psychometric theory, we calculated reliable change indices (RCIs), to measure individual CR patients' true clinical change, apart from that from error and test practice/exposure, in exercise capacity, anxiety, and depression. Indirectly calculated exercise capacity (peak metabolic equivalents [METs]) and psychological symptoms were each measured twice, 1 week apart, by administering treadmill tests or the Hospital Anxiety and Depression Scale (HADS) to separate samples of 35 (mean age: 59.0 years; 6 women) and 96 (mean age: 64.4 years; 32 women) CR patients, respectively. Using test-retest reliability and mean difference scores from these samples to estimate error and practice/exposure effects, we calculated RCIs for a separate cohort (n = 2066; mean age: 62.0 years; 533 women) who completed 6-month CR, and compared change distributions (worsened/unchanged/improved) based on critical RCIs, mean and percent changes, cut-off scores, and standard deviations. Practice/exposure effects were nonsignificant, except the mean HADS anxiety score decreased significantly (P ≤ 0.013; d = 0.17, small effect). Test-retest reliabilities were high (METs r = 0.934; HADS anxiety score r = 0.912; HADS depression score r = 0.90; P < 0.001). Among 2066 CR patients, RCI distributions differed (P < 0.001) from those of most other change criteria. Change ascertainment depends on criterion choice. A Canadian Cardiovascular Society CR quality indicator of increase by 0.5 MET may be too small to assess individuals' functional capacity change. RCIs offer a pragmatic approach to benchmarking reliable change frequency, and pending further validation, could be used for feedback to individual patients.


Synergistically-acting Enterocin LD3 and Plantaricin LD4 Against Gram-Positive and Gram-Negative Pathogenic Bacteria.
The efficacy of antimicrobials is an important aspect during their applications in food and therapeutics. In this study, combination of two bacteriocins, enterocin LD3 and plantaricin LD4, was studied against two pathogenic bacteria, Staphylococcus aureus subsp. aureus ATCC25923 and Salmonella enterica subsp. enterica serovar Typhimurium ATCC13311 for increasing their potency and bactericidal activity. The minimal inhibitory concentrations (MICs) of enterocin LD3 and plantaricin LD4 against Staph. aureus subsp. aureus ATCC25923 were 180 and 220 μg/mL, whereas in combination, reduced to 115 μg/mL, respectively. The MICs of enterocin LD3 and plantaricin LD4 against Salm. enterica subsp. enterica serovar Typhimurium ATCC13311 were 240 and 320 μg/mL, respectively, whereas in combination, these were found to be 130 μg/mL, respectively. The fractional inhibitory concentration (FIC) indices calculated as 0.50 against Staph. aureus subsp. aureus ATCC25923 and 0.43 against Salm. enterica subsp. enterica serovar Typhimurium ATCC13311 were found to be ≤ 0.5 indicating the synergy. The isobologram showed MIC of combined bacteriocins falls below the plotted straight line further signifies synergy. The growth response of Staph. aureus subsp. aureus ATCC25923 and Salm. enterica subsp. enterica serovar Typhimurium ATCC13311 was significantly reduced in the presence of combined bacteriocins in comparison with their individual effects. The number of dead cells was higher as a result of combined effect as compared with their independent effect evidenced by fluorescent microscopy. Transmission electron microscopy (TEM) revealed the higher disruption of cell membrane in the combined bacteriocin-treated cells as compared with alone effects. The FTIR spectra of enterocin LD3-treated cells showed alteration at ~ 1,451.82 and ~ 1,094.30/cm corresponding to nucleic acids and phospholipids suggesting its interaction with cell membrane and nucleic acids. In contrast, plantaricin LD4-treated cells did not show such alterations suggesting plantaricin LD4 may kill target cells using other mechanism. Our data suggest that different mode of action of both bacteriocins results in division of labour and may be responsible for their synergistic activity against target cells. Similarly, the synergistic effect of bacteriocins was also observed against other pathogenic bacteria such as Proteus mirabilis ATCC43071, Pseudomonas aeruginosa ATCC27853 and Escherichia coli ATCC25922. These bacteriocins, therefore, act synergistically against target pathogens and may be applied in appropriate combinations for food safety and medical applications.


Modified anchoring maneuver using pilot puncture needle to facilitate internal jugular vein puncture for small children.
Internal jugular vein (IJV) cannulation in infants has been reported with varied success using surface landmark. The aim is to share authors experience of modified anchoring technique used in infants. Anchoring maneuver using pilot needle (PN) has been recently described in adults. We have found that if the PN is left in IJV and then i.v. cannula (22G or 24G) is passed just posterior to the puncture point of PN to track down the PN path at 10-20 degree angles from skin, a natural tumbling movement of the PN helped to anchor anterior wall of IJV and facilitated its puncture. The results of 128 punctures performed in infants (<1 years) were analyzed in two groups of <6 months (n = 52) and >6 months to 1 year (n = 76). In infants weighing 3.5-14 kg, all cannulations were performed successfully. IJV puncture was detected at the entry of i.v. cannula more often in both the groups (81% in <6 months baby and 84% in >6 months baby) than withdrawing it. In 12 (10%) patients, the puncture site was changed to left IJV as carotid artery was punctured in three and failure to localize right IJV in nine patients by surface landmark. In authors experience, the described technique detected IJV cannulation at its entry in majority of infants and so the method is less prone to complications related to overshooting of the needle in lack of IJV puncture detection.


Passenger and heavy vehicle collisions with pedestrians: Assessment of injury mechanisms and risk.
Automated Driving System (ADS) fleets are currently being deployed in several dense-urban operational design domains within the United States. In these dense-urban areas, pedestrians have historically comprised a significant portion, and sometimes the majority, of injury and fatal collisions. An expanded understanding of the injury risk in collision events involving pedestrians and human-driven vehicles can inform continued ADS development and safety benefits evaluation. There is no current systematic investigation of United States pedestrian collisions, so this study used reconstruction data from the German In-Depth Accident Study (GIDAS) to develop mechanistic injury risk models for pedestrians involved in collisions with vehicles. The study queried the GIDAS database for cases from 1999 to 2021 involving passenger vehicle or heavy vehicle collisions with pedestrians. We describe the injury patterns and frequencies for passenger vehicle-to-pedestrian and heavy vehicle-to-pedestrian collisions, where heavy vehicles included heavy trucks and buses. Injury risk functions were developed at the AIS2+, 3+, 4+ and 5+ levels for pedestrians involved in frontal collisions with passenger vehicles and separately for frontal collisions with heavy vehicles. Model predictors included mechanistic factors of collision speed, pedestrian age, sex, pedestrian height relative to vehicle bumper height, and vehicle acceleration before impact. Children (≤17 y.o.) and elderly (≥65 y.o.) pedestrians were included. We further conducted weighted and imputed analyses to understand the effects of missing data elements and of weighting towards the overall population of German pedestrian crashes. We identified 3,112 pedestrians involved in collisions with passenger vehicles, where 2,524 of those collisions were frontal vehicle strikes. Furthermore, we determined 154 pedestrians involved in collisions with heavy vehicles, where 87 of those identified collisions were frontal vehicle strikes. Children were found to be at higher risk of injury compared to young adults, and the highest risk of serious injuries (AIS 3+) existed for the oldest pedestrians in the dataset. Collisions with heavy vehicles were more likely to produce serious (AIS 3+) injuries at low speeds than collisions with passenger vehicles. Injury mechanisms differed between collisions with passenger vehicles and with heavy vehicles. The initial engagement caused 36% of pedestrians' most-severe injuries in passenger vehicle collisions, compared with 23% in heavy vehicles collisions. Conversely, the vehicle underside caused 6% of the most-severe injuries in passenger vehicle collisions and 20% in heavy vehicles collisions. U.S. pedestrian fatalities have risen 59% since their recent recorded low in 2009. It is imperative that we understand and describe injury risk so that we can target effective strategies for injury and fatality reduction. This study builds on previous analyses by including the most modern vehicles, including children and elderly pedestrians, incorporating additional mechanistic predictors, broadening the scope of included crashes, and using multiple imputation and weighting to better estimate these effects relative to the entire population of German pedestrian collisions. This study is the first to investigate the risk of injury to pedestrians in collisions with heavy vehicles based on field data.


A simple method to improve the energy value of bank human milk.
Drip milk can be collected in large amounts, hence its potential value for human milk banks. This advantage is however offset by its low energy value. For those milk banks which depend mostly on drip milk, the energy value of its donor milk can be improved to a more acceptable level, and total volumes of donations increased, by encouraging mothers to combine collections of both drip and expressed milk.


Genomic characterization of two new viruses infecting Ageratum conyzoides in China.
Two new RNA viruses were identified in Ageratum conyzoides in China using high-throughput sequencing, and their genome sequences were determined using PCR and rapid amplification of cDNA ends. The new viruses, which have positive-sense, single-stranded RNA genomes, were provisionally named "ageratum virus 1" (AgV1) and "ageratum virus 2" (AgV2). AgV1 has a genome of 3,526 nucleotides with three open reading frames (ORFs) and shares 49.9% nucleotide sequence identity with the complete genome of Ethiopian tobacco bushy top virus (genus Umbravirus, family Tombusviridae). The genome of AgV2 consists of 5,523 nucleotides and contains five ORFs that are commonly observed in members of the genus Enamovirus of the family Solemoviridae. Proteins encoded by AgV2 exhibited the highest amino acid sequence similarity (31.7-75.0% identity) to the corresponding proteins of pepper enamovirus R1 (an unclassified enamovirus) and citrus vein enation virus (genus Enamovirus). Based on their genome organization, sequence, and phylogenetic relationships, AgV1 is proposed to be a new umbra-like virus of the family Tombusviridae, and AgV2 is proposed to be a new member of the genus Enamovirus of the family Solemoviridae.


Comparative evaluation of four trityl-type amidomethyl polystyrene resins in Fmoc solid phase peptide synthesis.
Four trityl-type (i.e. non-substituted trityl-, o-Cl-trityl-, o-F-trityl- and p-CN-trityl-) amidomethyl polystyrene resins were evaluated comparatively, in terms of the stability of the trityl-ester bond in slightly acidic dichloromethane solutions, and the p-CN-trityl-amidomethyl polystyrene resin was found to be the most stable of them. The above resins were applied, in parallel with Wang benzyl-type resin, well known for its stability in mild acidic conditions, to the Fmoc solid phase synthesis of the 43-amino acid residue long bioactive peptide thymosin beta-4. Independent of their differences in acid sensitivity, the resins seemed to function equally well under the conditions used, since pure thymosin beta-4 was obtained with a final yield of approximately 30% from each resin. The trityl-type amidomethyl polystyrene resins were also applied, in parallel with the Wang resin, to the Fmoc solid phase synthesis of a bioactive peptide containing proline at its C-terminus, i.e. the N-terminal tetrapeptide of thymosin beta-4, AcSDKP. In this case, the best yield (87%) was obtained with the o-Cl-trityl-amidomethyl polystyrene resin, which may be the resin of choice, of those studied, for the Fmoc solid phase peptide synthesis.


Production of antibodies to recombinant antigens from Lucilia cuprina following cutaneous immunisation of sheep.
Immunological control of cutaneous myiasis of sheep caused by Lucilia cuprina larvae has been an elusive goal. Antibody to antigens derived from the peritrophic membrane can stunt or kill larvae in a dose dependent fashion. Thus efficacy of vaccines employing these antigens may be limited by the amount of antibody in skin available for ingestion by larvae. The potential for elevating antibody concentrations in skin by intradermal immunisation with the recombinant peritrophic membrane antigens peritrophin-44, peritrophin-48 and peritrophin-95 was therefore examined. Using within-animal comparisons, specific antibody was significantly higher in skin transudates from locally immunised sites than from adjacent adjuvant control sites. It was concluded that cutaneous immunisation may assist immunological control of blowfly larvae.


Iris color as a predictive factor for intraoperative floppy iris syndrome.
To assess the influence of iris color on the predisposition for intraoperative floppy iris syndrome (IFIS) during cataract surgery. Medical records of patients who underwent cataract surgery in two medical centers between July 2019 and February 2020 were reviewed. Patients younger than 50 years, with preexisting ocular conditions affecting pupillary size or anterior chamber depth (ACD), and combined procedures were excluded. The remaining patients were questioned via telephone regarding their iris color. The association of IFIS occurrence and severity with iris color was tested using univariant and multivariant analyses. Overall, 155 eyes of 155 patients were included, 74 with documented IFIS and 81 without. The mean age was 74.03 ± 7.09 years, and 35.5% were female. The most common iris color among study eyes was brown (110/155, 70.97%), followed by blue (25/155, 16.13%) and green (20/155, 12.90%). Compared to brown-colored eyes, blue irises exhibited a 4.50-fold risk for IFIS (OR = 4.50, 95% CI: 1.73-11.70, p = 0.002), and green irises 7.00-fold risk (OR = 7.00, 95% CI: 2.19-22.39, p = 0.001). After adjusting for possible confounders, the results remained statistically significant (p < 0.01). Light-colored irises tended to exhibit a more severe IFIS compared to the brown iris group (p < 0.001). IFIS bilaterality was also affected by iris color (p < 0.001), with a 10.43-fold risk for fellow eye IFIS in the green iris group compared to eyes with brown irises (OR = 10.43, 95% CI: 3.35-32.54, p < 0.001). Light iris color was associated with a significantly increased risk of IFIS occurrence, severity, and bilaterality on univariate and multivariate analysis in this study.


Atomistic Molecular Dynamics Simulations of DNA Minicircle Topoisomers: A Practical Guide to Setup, Performance, and Analysis.
While DNA supercoiling is ubiquitous in vivo, the structure of supercoiled DNA is more challenging to study experimentally than simple linear sequences because the DNA must have a closed topology in order to sustain superhelical stress. DNA minicircles, which are closed circular double-stranded DNA sequences typically containing between 60 and 500 base pairs, have proven to be useful biochemical tools for the study of supercoiled DNA mechanics. We present detailed protocols for constructing models of DNA minicircles in silico, for performing atomistic molecular dynamics (MD) simulations of supercoiled minicircle DNA, and for analyzing the results of the calculations. These simulations are computationally challenging due to the large system sizes. However, improvements in parallel computing software and hardware promise access to improve conformational sampling and simulation timescales. Given the concurrent improvements in the resolution of experimental techniques such as atomic force microscopy (AFM) and cryo-electron microscopy, the study of DNA minicircles will provide a more complete understanding of both the structure and the mechanics of supercoiled DNA.


Prevalence of restless legs syndrome and quality of sleep in type 2 diabetics.
Restless legs syndrome (RLS) is characterized by an irresistible urge to move, with or without paraesthesia occurring or worsening at rest and relieved by activity. Only a few reports of prevalence of RLS with type 2 diabetes are available in India. To estimate the occurrence and risk factors of RLS among Indian patients with type 2 diabetes mellitus. This cross-sectional study was done in consecutive adult patients with type 2 diabetes. Demographic and comorbidity profile were collected. RLS diagnosis was made based on revised international RLS study group (IRLSSG) criteria. Two hundred and ten diabetic patients were interviewed. Mean age was 56 ± 13.5 years. Male-female ratio was 139: 71. Mean duration of diabetes was 8.3 years. Treatment received for diabetes included oral hypoglycaemic agents (153 patients) and insulin (85 patients). Forty-five patients had polyneuropathy, 18 had retinopathy and 22 had nephropathy. Majority (103) of subjects reported their bedtime as 9-10 pm. Average sleep duration was 8.4 h per night. RLS was diagnosed in 17 (8%) subjects. Mean sleep onset in subjects with RLS was 56 min versus 29 min in diabetics without RLS (p-0.01). The mean Pittsburgh Sleep Quality Index score was 5 in RLS and 3.3 in non-RLS patients (p-0.01). RLS resulted in poor sleep quality and affected overall quality of life in diabetics. As poor sleep is a known risk factor for uncontrolled diabetes, early identification and treatment of RLS would help improve glycaemic control and quality of life in these patients.


Cu(I)/Chiral Vanadium Complex Cooperatively Catalyzed Asymmetric Sulfonation/Rearrangement of Alkenylfurans.
The asymmetric three-component rearrangement of alkenylfurans with various sulfonyl chlorides and anilines is developed via copper(I) and chiral vanadium cooperative catalysis, providing a facile access to a broad spectrum of sulfonyl-functionalized 4-aminocyclopentenones in high yields with excellent enantio- and diastereoselectivities.


[Induction of T-cell producers of the macrophage migration inhibitory factor by the products of the K-, I- and D-regions of the H-2 complex in mice].
It has been demonstrated with the help of intravenous in-vivo immunization with irradiated splenocytes of A.AL anti-A.TL (difference at the K-region of H-2), A. TH anti-A. TL and A. TL anti-A. TH (difference at the I-region of H-2), C57BL/10Sn anti-B10.D2(R107) and B10.D2 (R107) anti-C57BL/10Sn (difference at the D-region of H-2) mice that T cells--MIF producers, induced at different times after induction of the alloimmune response, react to the products of the K- and I- but not to those of the D-region of the H-2 complex.


Evaluation of sexual function and sexual quality of life in women during the COVID-19 Pandemic: the Turkish case.
Sexual health is an important component of general health. To evaluate sexual function and sexual quality of life (SQOL) in women during the COVID-19 pandemic. This descriptive, cross-sectional study was conducted in Turkey. Data were collected via a Visual Analog Scale (VAS), Female Sexual Function Index (FSFI), and Sexual Quality of Life-Female (SQOL-F) questionnaire. The mean FSFI score was 26.91±5.62, and 39.1% of the women had an FSFI score of 26.55 or lower. The mean SQOL-F score was 79.08±20.90. FSFI score was significantly associated with employment status (β=-0.661), partner education (β=1.698), sexual compatibility between partners (β=0.518), sexual satisfaction (β=0.230), fatigue level (β= -0.120), and frequency of sexual intercourse (β=0.160). In addition, SQOL-F score was significantly associated with sexual desire (β=2.625), satisfaction (β=1.338), pain or discomfort (β=1.274), age (β= -0.356), sexual compatibility between partners (β=1.984), and fatigue level (β=-0.981) (p<0.05). Less than half of the women participating in this study had sexual dysfunction, and overall SQOL was moderate to high. These results were associated with some descriptive characteristics of the women and were similar to those reported in pre-pandemic studies conducted in Turkey.


Phase II Study of Third-Line Panitumumab Rechallenge in Patients with Metastatic Wild-Type KRAS Colorectal Cancer Who Obtained Clinical Benefit from First-Line Panitumumab-Based Chemotherapy: JACCRO CC-09.
Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0-70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. UMIN000015916.


Global left-ventricular function assessment using dual-source multidetector CT: effect of improved temporal resolution on ventricular volume measurement.
The purpose was to compare global left-ventricular (LV) function parameters measured with cine MRI with results from multiphase dual-source CT (DSCT) using 10 and 20 reconstruction phases. Twenty-eight patients with suspected or known CAD underwent DSCT coronary angiography. LV end-diastolic (EDV), end-systolic (ESV) and stroke volumes (SV), and ejection fraction (EF) were determined using LV segmentation and selection of specific phases from DSCT image sets reconstructed either at 5% or 10% steps through the R-R interval. Cine MRI served as the reference investigation. Threshold-based 3D-segmentation was feasible in all DSCT data sets. EDV and ESV were underestimated by DSCT, but showed excellent correlation (Pearson's correlation coefficient 0.95/0.97) to values obtained with MRI. Using data from 5% DSCT image reconstructions instead of 10% phase reconstructions, the position of the ED and ES phase was changed in 16 of 28 patients; ESVs were to found to be slightly smaller, whereas EDV were slightly larger, resulting in a systematic overestimation of LV EF by 1.9% (p=0.56). Threshold-based 3D segmentation enables accurate and reliable DSCT determination of global LV function with excellent correlation to cine MRI. Minor differences in LV EF indicate that both modalities are virtually interchangeable, even if the number of reconstructed phases is limited to 10% phase reconstructions.


Enhanced UV-Irradiated Photocatalytic Degradation of Malachite Green by Porous WO3 Decorated on 2D Graphene Sheet.
High efficient and environment friendly one-pot in situ microwave irradiation method was implemented towards the preparation of porous reduced graphene oxide/WO3 (rGOW) nanocomposites for the first time. Here, 3D porous WO3 nanoparticles were evenly decorated on 2D rGO sheets. The crystal phase purity and the functional group characterizations of the as-synthesized nanomaterials were examined by powder XRD and Raman spectral analyses. The morphological studies from the SEM, TEM, and BET measurements clearly revealed the highly porous nature of nano-sized WO3 and its distribution on the surface of rigid 2D graphene sheet. The UV along with visible light-driven degradation mechanism of malachite green (MG) dye in the rGOW nanocomposites was well illustrated with the schematic diagram and discussed in detail through the kinetics of the degradation process upon calculating the rate constant and half-life time. The rGO/WO3 photocatalyst delivered high MG degradation efficiency of 97% under UV irradiation.


Assessing visualization in robotic-assisted surgery: demystifying a misty lens.
Despite major technological advancements in robotic-assisted laparoscopic surgery (RAS), there remain shortcomings yet to be addressed. This study assesses the prevalence of suboptimal vision in minimally invasive RAS and corresponding factors regarding related surgical conditions. 45 minimally invasive robotic surgeries, performed using Da Vinci XI, were observed across three surgical subspecialties: general, urology, and OB/GYN. Lens occlusion events were monitored and defined as the presence of a visual distortion caused by debris deposition on the scope lens. Lens occlusions and cleanings, and "active instrumentation" were recorded. Descriptive statistics summarized duration-based variables, and one-factor ANOVA compared the presence of active instrumentation. Cases averaged 127 ± 76 min. Active instrumentation ANOVA during lens occlusions demonstrated significant variation between categories (F7, 256 = 11.63, p = 2.558e-13). Post hoc Tukey HSD found electrocautery devices were active significantly more during occlusion events (37.9%) than other instruments. On average, lens cleaning occurred every 36.5 ± 39.8 min despite lens occlusion occurring every 24.5 ± 15.7 min. Of the operative time observed, 41.4% ± 28.1% was conducted with visual distortion. 1.16% ± 0.97% of time observed was spent cleaning. Although only 1.16% of operative time was spent cleaning, surgeons experienced suboptimal conditions for nearly 35× the time it would take the clear lens, potentially indicating a tendency to avoid cleaning the lens to disrupt surgery. Future research may examine the impact of occluded visualization and lens cleaning on other aspects of surgery.


"Leave your smartphone out of bed": quantitative analysis of smartphone use effect on sleep quality.
Smartphones have become an integral part of people's everyday lives. Smartphones are used across all household locations, including in the bed at night. Smartphone screens and other displays emit blue light, and exposure to blue light can affect one's sleep quality. Thus, smartphone use prior to bedtime could disrupt the quality of one's sleep, but research lacks quantitative studies on how smartphone use can influence sleep. This study combines smartphone application use data from 75 participants with sleep data collected by a wearable ring. On average, the participants used their smartphones in bed for 322.8 s (5 min and 22.8 s), with an IQR of 43.7-456. Participants spent an average of 42% of their time in bed using their smartphones (IQR of 5.87-55.5%). Our findings indicate that smartphone use in bed has significant adverse effects on sleep latency, awake time, average heart rate, and HR variability. We also find that smartphone use does not decrease sleep quality when used outside of bed. Our results indicate that intense smartphone use alone does not negatively affect well-being. Since all smartphone users do not use their phones in the same way, extending the investigation to different smartphone use types might yield more information than general smartphone use. In conclusion, this paper presents the first investigation of the association between smartphone application use logs and detailed sleep metrics. Our work also validates previous research results and highlights emerging future work.


The mitochondrial tricarboxylate carrier.
The tricarboxylate carrier has recently been purified from rat liver mitochondria by three distinct scientific groups using different methods. A 37-38-kDa protein has been prepared by silca gel 60 chromatography by our group (Claeys and Azzi, 1989; Glerum et al., 1990). The specific citrate transport activity of this preparation is not significantly different from that measured in mitochondria and it is inhibitable by 1,2,3-benzenetricarboxylic acid. Bisaccia et al. (1990) have reported the isolation of a 30-kDa protein by Celite 535 chromatography, and Kaplan's group (Kaplan et al., 1990) have isolated a 32.5-kDa protein by Matrex Orange, Matrex Blue, and Affi-Gel chromatography. Peptide mapping has failed to support any structural homologies between the 37-38-kDa and the 30-32.5-kD proteins. The 38-kD protein is N-terminally blocked. The peptides obtained by several cleavage procedures have been partially sequenced. Their sequence information has been used to obtain different cDNA clones by a dual approach, the polymerase chain reaction and screening of a lambda ZAP cDNA library. The largest cDNA which could be isolated is 2,986 bp in length and contains a 1071-bp-long open reading frame and an unusually long 3' untranslated region, both of which have been completely sequenced. The protein sequence of the carrier from the first in-frame methionine is 322 amino acids in length and exhibits a molecular mass of 35,546. Comparison of the protein sequence to the sequences of the four members of the mitochondrial carrier protein family (ADP/ATP carrier, phosphate carrier, 2-oxoglutarate/malate carrier, and uncoupling protein) does not reveal significant similarity (cf. Walker et al., 1987). A tripartite internal homology, which is a characteristic of these proteins, is not present in the sequence of the tricarboxylate carrier protein. The mRNA for the tricarboxylate carrier is expressed in rat liver and brain, but not in rat heart.


Near-membrane ensemble elongation in the proline-rich LRP6 intracellular domain may explain the mysterious initiation of the Wnt signaling pathway.
LRP6 is a membrane protein crucial in the initiation of canonical Wnt/β-catenin signalling. Its function is dependent on its proline-serine rich intracellular domain. LRP6 has five PPP(S/T)P motifs that are phosphorylated during activation, starting with the site closest to the membrane. Like all long proline rich regions, there is no stable 3D structure for this isolated, contiguous region. In our study, we use a computational simulation tool to sample the conformational space of the LRP6 intracellular domain, under the spatial constraints imposed by (a) the membrane and (b) the close approach of the neighboring intracellular molecular complex, which is assembled on Frizzled when Wnt binds to both LRP6 and Frizzled on the opposite side of the membrane. We observe that an elongated form dominates in the LRP6 intracellular domain structure ensemble. This elongation could relieve conformational auto-inhibition of the PPP(S/T)PX(S/T) motif binding sites and allow GSK3 and CK1 to approach their phosphorylation sites, thereby activating LRP6 and the downstream pathway. We propose a model in which the conformation of the LRP6 intracellular domain is elongated before activation. This is based on the intrusion of the Frizzled complex into the ensemble space of the proline rich region of LRP6, which alters the shape of its available ensemble space. To test whether this observed ensemble conformational change is sequence dependent, we did a control simulation with a hypothetical sequence with 50% proline and 50% serine in alternating residues. We confirm that this ensemble neighbourhood-based conformational change is independent of sequence and conclude that it is likely found in all proline rich sequences. These observations help us understand the nature of proline rich regions which are both unstructured and which seem to evolve at a higher rate of mutation, while maintaining sequence composition.


An exploratory study of the informational and psychosocial needs of patients with human papillomavirus-associated oropharyngeal cancer.
Although the incidence of oropharyngeal squamous cell carcinoma (OPSCC) attributable to human papillomavirus (HPV) is rapidly increasing, patients' informational and psychosocial needs related to the sexual transmission of HPV remain unexplored. The goal of this exploratory study was to assess informational and psychosocial needs of HPV+ OPSCC patients and identify psychosocial challenges associated with having an HPV+ cancer. Patients (N=62; 87% male; mean age=56years) with HPV+ OPSCC and in cohabitating relationships completed paper-pencil questionnaires assessing their HPV-related knowledge (e.g., cancer etiology), information needs (e.g., communicability), psychosocial concerns (e.g., relational consequences, self-blame) and measures of distress and health behaviors. Medical information was obtained from patients' electronic medical records. Sixty-six percent of patients correctly identified their HPV status but only 35% of them recognized HPV as their putative cancer cause. The majority of patients disclosed their HPV status to their partner, 41% discussed transmission of the virus, and only 23% felt informed regarding potential transmission risks and precautions. Thirty-nine percent want their oncologist to discuss more about HPV-related issues and 58% sought this from other sources. Over one-third said they would be interested in more HPV-related information. Patients reported moderate levels of distress (mean=3.52, SD=2.54, possible range 0-10) and relatively low levels of self-blame (mean=2.27, SD=1.23, possible range 1-4) with distress and self-blame being significantly correlated (r=.38, p=.005). Significant knowledge gaps exist regarding patients' understanding of the link between HPV and OPSCC and the implications of infectious etiology. Future research is encouraged to establish best practice guidelines.


Optimal feature selection using a modified differential evolution algorithm and its effectiveness for prediction of heart disease.
Enormous data growth in multiple domains has posed a great challenge for data processing and analysis techniques. In particular, the traditional record maintenance strategy has been replaced in the healthcare system. It is vital to develop a model that is able to handle the huge amount of e-healthcare data efficiently. In this paper, the challenging tasks of selecting critical features from the enormous set of available features and diagnosing heart disease are carried out. Feature selection is one of the most widely used pre-processing steps in classification problems. A modified differential evolution (DE) algorithm is used to perform feature selection for cardiovascular disease and optimization of selected features. Of the 10 available strategies for the traditional DE algorithm, the seventh strategy, which is represented by DE/rand/2/exp, is considered for comparative study. The performance analysis of the developed modified DE strategy is given in this paper. With the selected critical features, prediction of heart disease is carried out using fuzzy AHP and a feed-forward neural network. Various performance measures of integrating the modified differential evolution algorithm with fuzzy AHP and a feed-forward neural network in the prediction of heart disease are evaluated in this paper. The accuracy of the proposed hybrid model is 83%, which is higher than that of some other existing models. In addition, the prediction time of the proposed hybrid model is also evaluated and has shown promising results.


The axosomatic contacts on the bursting neuron of the snail Helix pomatia. II. Ultrastructural localization of adenylate cyclase.
Fluoride and peptide-stimulated adenylate cyclase activity was investigated by electron histochemistry on serial sections of the RPAI neuron of the snail Helix pomatia. Fluoride-stimulated adenylate cyclase was detected in the surface membrane of the RPAI neuron, the postsynaptic membrane of axosomatic contacts, and the surface of glial cells forming a multilayer capsule around the neuron. Peptide-stimulated adenylate cyclase was located in the membrane of glial cells surrounding the neuron, their processes (trophospongia) invaginating deeply in the neuronal soma, and the membrane of somatic protrusions forming the system of lacoons in the region of the axosomatic contact. No peptide-stimulated adenylate cyclase was revealed in the remaining part of the surface of the somatic membrane. The localization of adenylate cyclase activity in the postsynaptic membrane in the region of the axosomatic contact is in accordance with the hypothesis based on electrophysiological experiments that the cyclase system participates in the genesis and regulation of the bursting activity of the RPAI neuron.


The effect of molecular weight, compositions and lectin type on the properties of hyperbranched glycopolymers as non-viral gene delivery systems.
The architectures of gene delivery vectors, in addition to their molecular weights and compositions, can play a critical role in DNA condensation and hence on their gene expression. In general, branched polymers are superior gene delivery vectors as compared to their linear analogs. This study reports the efficacy of cationic hyperbranched glycopolymers for DNA condensation and gene expression. Hyperbranched glycopolymers of varying molecular weights and compositions are synthesized via reversible addition fragmentation chain transfer (RAFT) process and are further explored for their gene expression in vitro. Galactose-based hyperbranched polymers are compared to glucose-derived hyperbranched polymers for their cellular uptake, toxicity and gene expression. It is found that molecular weight of hyperbranched polymers, and carbohydrate content of copolymers are critical factors in determining the gene expression as well as in imparting the specificity to these novel gene delivery vectors. The galactose-based hyperbranched glycopolymer of ~30 kDa or lower show improved gene expression at varying polymer/plasmid ratios. The incubation of hyperbranched polyplexes in the presence of serum protein show the presence of stable particles and gene expression of these hyperbranched polyplexes is unaffected in the presence of serum proteins. Furthermore, the cellular uptake and gene expression are studied in two different cell lines in the presence of lectins. It is found that polyplexes-lectin conjugates show enhanced cellular uptake in vitro, however their gene expression is cell line and lectin type dependent.


Optimization of a cultivation procedure to selectively isolate lactic acid bacteria from insects.
Natural niches and transmission routes of lactic acid bacteria (LAB) are highly versatile. Proposed routes of transmission to food fermentations are from plant material via insects or vice versa. This study aimed to establish a method for the selective isolation of LAB from insects. Varied parameters that influence growth and selectivity are temperature, type of carbohydrate and atmosphere. Additionally, the effects of antibiotics to suppress non-LAB species were evaluated. A model consortium consisting of 12 species representing different lifestyles was inoculated in a growth medium to identify conditions for the highest diversity and recovery rate. The method was applied to isolate LAB from Drosophila melanogaster, Sitotroga cerealella, Tribolium castaneum and Tenebrio molitor. Isolated species were Leuconostoc mesenteroides, Paucilactobacillus vaccinostercus and Lactiplantibacillus plantarum from D. melanogaster and L. mesenteroides, Pediococcus pentosaceus and Latilactobacillus curvatus from T. molitor. No LAB could be isolated from T. castaneum and S. cerealella. 16S rDNA amplicon sequencing of DNA obtained from insects corroborated part of our results. A combination of different enrichment conditions ensures a high probability to isolate LAB species from insects and can be helpful above already known non-cultivation methods. The novel method allows to selectively isolate LAB from insects and the strategy of the method is of interest to study other niches.


Non-thiol farnesyltransferase inhibitors: FTase-inhibition and cellular activity of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors.
Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue farnesyltransferase inhibitors. These compounds turned out to be only weakly active against farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.


The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max.
The c-Myc protein (Myc) is involved in cellular transformation and mitogenesis, but is also a potent inducer of programmed cell death, or apoptosis. Whether these apparently opposite functions are mediated through common or distinct molecular mechanisms remains unclear. Myc and its partner protein, Max, dimerize and bind DNA in vitro and in vivo through basic/helix-loop-helix/leucine zipper motifs (bHLH-LZ). By using complementary leucine zipper mutants (termed MycEG and MaxEG), which dimerize efficiently with each other but not with their wild-type partners, we demonstrate that both cell cycle progression and apoptosis in nontransformed rodent fibroblasts are induced by Myc-Max dimers. MycEG or MaxEG alone are inactive, but co-expression restores ability to prevent withdrawal from the cell cycle and to induce cell death upon removal of growth factors. Thus, Myc can control two alternative cell fates through dimerization with a single partner, Max.


Enhancement of differentiation efficiency of hESCs into vascular lineage cells in hypoxia via a paracrine mechanism.
Hypoxia is one way of inducing differentiation due to the activation of the key regulatory factor, Hypoxia-inducible factor 1 alpha (HIF-1α). However, the action of HIF-1α on the differentiation of hESCs was unclear until now. To investigate the effect of hypoxia on the differentiation of hESCs, we compared the differentiation efficacy into vascular lineage cells under normoxic and hypoxic conditions. We observed HIF-1α expression and the related expression of pro-angiogenic factors VEGF, bFGF, Ang-1 and PDGF in hEBs cultured under hypoxic conditions. Along with this, differentiation efficacy into vascular lineage cells was improved under hypoxic conditions. When HIF-1α was blocked by echinomycin, both angiogenic factors and the differentiation efficacy were down-regulated, suggesting that the enhancement of differentiation efficacy was caused by intrinsic up-regulation of HIF-1α and these pro-angiogenic factors under hypoxic condition. This response might be primarily regulated by the HIF-1α signal pathway, and hypoxia might be the key to improving the differentiation of hESCs into vascular lineage cells. Therefore, this study demonstrated that microenvironmental changes (i.e., hypoxia) can improve differentiation efficacy of hESCs into a vascular lineage without exogenous factors via cell-intrinsic up-regulation of angiogenic factors. These facts will contribute to the regulation of stem cell fate.


Scanning electron microscopy of abomasium and intestine of gnotoxenic calves infected either with rotavirus, coronarivus or enteropathogenic Escherichia coli or with rotavirus and E. coli.
Neonatal calf diarrhoea induced with several agents of infection was studied by scanning electron microscopy. In a gnotoxenic calf infected with E. coli K99+ Ent+, slight lesions of the small intestine were observed and desquamation or puffiness of microvilli occurred. In rotavirus-infected calves, the abomasum was covered with abudant mucous film and appeared to be desquamated. In the small intestine, no desquamation of epithelium was observed. Inoculation of the rotavirus and E. coli induced severe diarrhoea. The whole digestive tract, even the abomasum and colon, was eroded. Coronavirus induced marked lesions in all levels of the intestine. These results demonstrate unequivocally the pathogenic properties of the three infectious agnets, the synergistic effect of E. coli and rotavirus. Furthermore, the importance of the abomasum in neonatal diarrhoea is emphasized.


Triglycerides are more important in atherosclerosis than epidemiology has suggested.
Epidemiology call be a useful guide to risk prediction. If, for example, the value of serum cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides as predictors of future CHD events is considered, then generally the triglyceride level measured on a single occasion will add little to the prognostic information contained in cholesterol and HDL cholesterol. The serum triglyceride concentration is, however, often more strongly correlated with future CHD incidence in univariate analysis than is serum cholesterol. However, in multiple logistic regression analysis, particularly when HDL cholesterol is included, the strength of the apparent independent relationship between triglycerides and CHD incidence is weakened often to the point of insignificance in individual trials, although it is still evident on meta-analysis of all the epidemiological trials in which both HDL cholesterol and triglyceride levels were measured. The erosion of the relationship between triglycerides and CHD incidence when HDL is included in multiple logistic regression analysis is to some extent is an artefact of the greater biological variation of triglyceride concentrations compared with HDL cholesterol. When allowance is made for this triglycerides can have more predictive power than HDL. Important clinical decisions are generally not based on single measurements, but on a series which reduces the effect of biological variation. However, even more importantly epidemiology cannot tell us that lowering cholesterol or raising HDL cholesterol levels will have more therapeutic benefit than decreasing triglyceride levels. That can only be established in clinical trials. An overview of trials involving drugs, which have as their principal action triglyceride-lowering, revealed them to decrease CHD incidence as much as statins. In the trials the drugs, which principally lowered triglycerides, also produced small decreases in serum cholesterol. The decrease in CHD incidence was, however, more than would be predicted from a similar reduction in cholesterol achieved with statins. Epidemiology can thus be a poor guide to clinical decisions. Furthermore the epidemiological relationship between cholesterol, triglycerides, HDL and CHD gives us only limited insight into the mechanisms by which these lipids and lipoproteins are involved in atherogenesis and their relative importance in this process. Thus evidence from clinical studies linking hypertriglyceridaemia with potentially important atherogenic factors such as intermediate density lipoproteins, small dense LDL and increased cholesteryl ester exchange may provide a greater understanding of atherogenesis and potential sites of therapeutic intervention than epidemiology. There is thus evidence for the therapeutic value of lowering triglycerides and an emerging view that triglyceride-rich lipoproteins are frequently crucial in atherogenesis.


Tyrosine-hydroxylase immunoreactivity in the mouse transparent brain and adrenal glands.
Working on catecholamine systems for years, the neuropharmacologist Arvid Carlsson has made a number of important and pioneering discoveries, which have highlighted the key role of these neuronal and peripheral neurotransmitters in brain functions and adrenal regulations. Since then, major advances have been made concerning the distribution of the catecholaminergic systems in particular by studying their rate-limiting enzyme, tyrosine hydroxylase (TH). Recently new methods of tissue transparency coupled with in toto immununostaining and three-dimensional (3D) imaging technologies allow to precisely map TH immunoreactive pathways in the mouse brain and adrenal glands. High magnification images and movies obtained with combined technologies (iDISCO+ and light-sheet microscopy) are presented in this review dedicated to the pioneer work of Arvid Carlsson and his collaborators.


Accuracy and Survival Outcomes after National Implementation of Sentinel Lymph Node Biopsy in Early Stage Endometrial Cancer.
Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endometrial cancer at early stage, which is key to tailoring adjuvant treatments. Our aim was to evaluate the national implementation of SLN biopsy in terms of accuracy to detect nodal disease in a clinical setting and oncologic outcomes according to the volume of nodal disease. A total of 29 Spanish centers participated in this retrospective, multicenter registry including patients with endometrial adenocarcinoma at preoperative early stage who had undergone SLN biopsy between 2015 and 2021. Each center collected data regarding demographic, clinical, histologic, therapeutic, and survival characteristics. A total of 892 patients were enrolled. After the surgery, 12.9% were suprastaged to FIGO 2009 stages III-IV and 108 patients (12.1%) had nodal involvement: 54.6% macrometastasis, 22.2% micrometastases, and 23.1% isolated tumor cells (ITC). Sensitivity of SLN biopsy was 93.7% and false negative rate was 6.2%. After a median follow up of 1.81 years, overall surivial and disease-free survival were significantly lower in patients who had macrometastases when compared with patients with negative nodes, micrometastases or ITC. In our nationwide cohort we obtained high sensitivity of SLN biopsy to detect nodal disease. The oncologic outcomes of patients with negative nodes and low-volume disease were similar after tailoring adjuvant treatments. In total, 22% of patients with macrometastasis and 50% of patients with micrometastasis were at low risk of nodal metastasis according to their preoperative risk factors, revealing the importance of SLN biopsy in the surgical management of patients with early stage EC.


The Corona mortis is similar in size to the regular obturator artery, but is highly variable at the level of origin: an anatomical study.
An enlarged anastomosis connecting the vascular territory of the external iliac and the obturator artery may replace most or all of the latter. This relatively common vascular variation, known as Corona mortis, can lead to death in the worst-case scenario if injured. Despite being well-known, exact anthropometric data are lacking. The purpose of this study was to determine diameters of the regular obturator artery, the Corona mortis and the inferior epigastric artery. In addition, the level of origin of the Corona mortis was quantified. The obturator artery and its norm variants were dissected bilaterally in 75 specimens (37 females, 38 males) and measured using two different methods. The Corona mortis was present in 36 of the 150 hemipelves (24%), presenting in one third of all cases bilaterally. Its level of origin measured from the commencement of the inferior epigastric artery was subject to high variability (4.4-28.3 mm). The mean diameters of the Corona mortis (mean 2.5 and 2.1 mm, respectively) and the regular obturator artery (mean 2.4 and 2.0 mm, respectively) were similar for both methods. There were no significant sex nor side differences. The diameter of the inferior epigastric artery was significantly smaller distal to the origin of the Corona mortis. The high incidence, non-predictable level of origin of the Corona mortis and its size similar to the regular obturator artery support its clinical relevance even to date. Clinicians should always be aware of an additional arterial vessel close to the pelvic brim.


Energy expenditure in children aged 1.5 to 4.5 years: a comparison with current recommendations for energy intake.
To compare measurements of total energy expenditure in children aged 1.5-4.5 years with current recommendations for energy intake. Total energy expenditure was measured using the doubly labelled water technique and compared with 1991 UK recommendations for energy intake. Community-based study in East Anglia and South East England. Ninety-three children aged 1.5-4.5 years recruited. Results available on 81 children. Mean values for total energy expenditure for the boys were 359, 341 and 327 kJ/kg in the age groups 1.5-2.5, 2.5-3.5 and 3.5-4.5 years respectively. In the girls, mean values for total energy expenditure were 347, 317 and 310 kJ/kg in the age groups 1.5-2.5, 2.5-3.5 and 3.5-4.5 respectively. These values were approximately 12% and 10% below current recommendations for energy intake in girls and boys respectively. These data add to the growing literature that indicate that energy expenditure in young children is significantly below previous estimates. Secular changes in habitual levels of physical activity might be responsible for reduced levels of physical activity.


Diazepam and Ro 15-1788 increase absence epilepsy in WAG/Rij rats chronically exposed to diazepam.
The mechanisms underlying tolerance to benzodiazepines were investigated by injecting diazepam (5 mg/kg) twice daily for 23 days in WAG/Rij rats (an animal model for non-convulsive absence epilepsy). After this the rats received either the agonist, diazepam, or the antagonist, flumazenil (Ro 15-1788). EEG analyses showed that both compounds increased the amount of absence epilepsy-like phenomena. This suggests that repeated administration of diazepam moves the benzodiazepine receptor spectrum towards the inverse agonist end.


Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial.
The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons. Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O2 30 %/60 %) or a group breathing control gas (N2/O2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure. The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [±0.368]; p = 0.008), peaking at 24 h compared to the baseline values (1.45 [±0.498]; p = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels (p = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure (p = 0.080). The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at ClinicalTrials.gov (NCT number: 02129400).


Temporal profiles of vasoactive intestinal polypeptide precursor mRNA and its receptor mRNA in the rat suprachiasmatic nucleus.
Many vasoactive intestinal polypeptide (VIP) neurons are distributed in the suprachiasmatic nucleus (SCN) and most of them arborize throughout the nuclei. We determined temporal patterns of VIP receptor (VPAC2 receptor) mRNA in the rat SCN in constant darkness and light-dark cycles, by means of in situ hybridization histochemistry. Amounts of VIP precursor mRNA in the SCN were also quantified in adjacent sections to compare its temporal profile with that of VPAC2 receptor mRNA. In constant darkness no circadian rhythms in VIP precursor mRNA or VPAC2 receptor mRNA in the SCN were detected. In light-dark cycles VIP precursor mRNA and VPAC2 receptor mRNA in the SCN showed robust but different daily rhythms. VPAC2 receptor mRNA decreased over the course of the light period and then gradually recovered during the dark period. VIP precursor mRNA was also reduced in response to light but the reduction was transient. This difference in the nature of light responsiveness between VIP mRNA and VPAC2 receptor mRNA suggests that pre- and postsynaptic events of the VIP transduction system represent different stages of light information processing in the SCN.


Considering Questions Before Methods in Dementia Research With Competing Events and Causal Goals.
Studying causal exposure effects on dementia is challenging when death is a competing event. Researchers often interpret death as a potential source of bias, although bias cannot be defined or assessed if the causal question is not explicitly specified. Here we discuss 2 possible notions of a causal effect on dementia risk: the "controlled direct effect" and the "total effect." We provide definitions and discuss the "censoring" assumptions needed for identification in either case and their link to familiar statistical methods. We illustrate concepts in a hypothetical randomized trial on smoking cessation in late midlife, and emulate such a trial using observational data from the Rotterdam Study, the Netherlands, 1990-2015. We estimated a total effect of smoking cessation (compared with continued smoking) on 20-year dementia risk of 2.1 (95% confidence interval: -0.1, 4.2) percentage points and a controlled direct effect of smoking cessation on 20-year dementia risk had death been prevented of -2.7 (95% confidence interval: -6.1, 0.8) percentage points. Our study highlights how analyses corresponding to different causal questions can have different results, here with point estimates on opposite sides of the null. Having a clear causal question in view of the competing event and transparent and explicit assumptions are essential to interpreting results and potential bias.


Species variations amongst proteinases in liver lysosomes.
Cathepsin B, H, L and D activities in liver lysosomes were compared between species. Although cathepsin B and D were detected in bovine, pig, chicken and rat liver, striking species differences were evident for cathepsin H and L. Cathepsin L activity was particularly high in chicken lysosomal extracts, but could not be detected in bovine and pig extracts. Whereas there was no significant cathepsin H activity in bovine extracts, rat liver lysosomal extracts contained large amounts of cathepsin H activity.


[Peritonsillar abscess treated with puncture and aspiration--a prospective 3-year follow-up].
Forty-one selected patients were treated with needle aspiration for peritonsillar abscess in our department in 1988. Two patients were treated with quinsy tonsillectomy secondary to needle aspiration, because of failure of treatment. The follow-up group consisted of 39 patients and the median follow-up time was 38 months (range 36-44 months). There were three recurrences of the abscess, and one patient had recurrent tonsillitis subsequent to discharge. The rate of recurrent tonsillitis/abscess among patients younger than 30 and 40 years was respectively 21% (4/19) and 14% (4/28). The rate in the corresponding older age groups was 0%. The overall recurrence rate was 10% (4/39). Needle aspiration is suggested as part of a selected strategy of treatment.


Author Correction: Evaluation of cell metabolic adaptation in wound and tumour by Fluorescence Lifetime Imaging Microscopy.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Harassment: it's not (all) about sex! Part II: plaintiffs, supervisors, and preventive protocols.
Policies prohibiting sexual harassment, although a good start, are not enough to protect health care employers from the risk of significant liability to an employee who suffers unlawful workplace harassment. The purpose of the second part of this 2-part article was to help health care managers introduce new policies, procedures, and protocols to ensure that their organizations are adequately protected from the threat of charges of unlawful harassment.


Molecular components of the Mammalian circadian clock.
Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.


Analytical estimation of beamforming speed-of-sound using transmission geometry.
Most ultrasound imaging techniques necessitate the fundamental step of converting temporal signals received from transducer elements into a spatial echogenecity map. This beamforming (BF) step requires the knowledge of speed-of-sound (SoS) value in the imaged medium. An incorrect assumption of BF SoS leads to aberration artifacts, not only deteriorating the quality and resolution of conventional brightness mode (B-mode) images, hence limiting their clinical usability, but also impairing other ultrasound modalities such as elastography and spatial SoS reconstructions, which rely on faithfully beamformed images as their input. In this work, we propose an analytical method for estimating BF SoS. We show that pixel-wise relative shifts between frames beamformed with an assumed SoS is a function of geometric disparities of the transmission paths and the error in such SoS assumption. Using this relation, we devise an analytical model, the closed form solution of which yields the difference between the assumed and the true SoS in the medium. Based on this, we correct the BF SoS, which can also be applied iteratively. Both in simulations and experiments, lateral B-mode resolution is shown to be improved by ≈25% compared to that with an initial SoS assumption error of 3.3% (50m/s), while localization artifacts from beamforming are also corrected. After 5 iterations, our method achieves BF SoS errors of under 0.6m/s in simulations. Residual time-delay errors in beamforming 32 numerical phantoms are shown to reduce down to 0.07μs, with average improvements of up to 21 folds compared to initial inaccurate assumptions. We additionally show the utility of the proposed method in imaging local SoS maps, where using our correction method reduces reconstruction root-mean-square errors substantially, down to their lower-bound with actual BF SoS.


Disturbance and organisms on boulders : I. Patterns in the environment and the community.
Several aspects of disturbance by waves to intertidal boulders were monitored for one year high and low on the shore on two rock platforms on the east coast of Australia. These boulders were also subjected to burial by sand, and this disturbance was monitored in the same places for two years. The mobile and sessile organisms on the tops and bottoms of the rocks were sampled six times during the same period in order to determine patterns in community structure and assess the role of disturbance. Small rocks were overturned more often and buried to a greater extent than large rocks, but rocks of all sizes were moved similar distances with similar frequency. These contrasting results were probably caused by the fact that small rocks were rounder than large rocks. Rocks were buried in sand much more at Long Reef than at Cape Banks, but differences among places in disturbance by waves were not great.Patterns in community structure were complex but suggested that disturbance was only important for sessile organisms on the undersides of boulders. The number of sessile species present was always related to the size of the rock but the total cover of algae on the tops of rocks never was. Some particular species were most abundant on large rocks but others showed the reverse pattern, covering more space on the smaller boulders. This latter pattern may have been due to the shorter period of exposure during low tide in this situation, though grazers were also abundant on these rocks in some places. In contrast, nearly all species on the undersides of rocks reached greatest abundance on the medium to large rocks, consistent with effects of disturbance. Space was in short supply low on the shore and overgrowth apparently reduced diversity but this was not the case elsewhere. Overall, the results indicate that disturbance was frequent and important, but not for all species nor in all places.


Carbon nanoparticles induce endoplasmic reticulum stress around blood vessels with accumulation of misfolded proteins in the developing brain of offspring.
Nano-particulate air pollution threatens developing brains and is epidemiologically related to neurodegenerative diseases involving deposition of misfolded proteins. However, the mechanism underlying developmental neurotoxicity by nanoparticles remains unknown. Here, we report that maternal exposure to low doses of carbon black nanoparticle (CB-NP) induces endoplasmic reticulum (ER) stress associated with accumulation of misfolded proteins. Notably, offspring specifically showed high induction of ER stress in perivascular macrophages and reactive astrocytes only around brain blood vessels, along with accumulation of β-sheet-rich proteins regarded as misfolded proteins. Our results suggest that maternal CB-NP exposure induced ER stress in PVMs and reactive astrocytes around blood vessels in the brain of offspring in mice. The induction of ER stress accompanied by the perivascular accumulation of misfolded proteins is likely to be associated with perivascular abnormalities and neurodegeneration, and development of neurodegenerative diseases related to particulate air pollution.


Application of the extractive alkylation technique to the pentafluorobenzylation of morphine (a heroin metabolite) and surrogates, with special reference to the quantitative determination of plasma morphine levels using mass fragmentography.
The pentafluorobenzylation of morphine and related phenolic alkaloids by extractive alkylation is described. The alkylation is performed using tetrabutylammonium as counter ion and ethyl acetate as solvent. Optimum reaction conditions are presented together with the gas chromatographic properties of the derivatives formed. The technique is applied to the quantitation of plasma morphine levels. Using morphine-d3 as internal standard mass fragmentographic analysis of morphine as its pentafluorobenzyl- and pentafluorobenzyl, mono-trifluoroacetyl derivatives is demonstrated, and a case report is presented. Quantitation to a plasma morphine level of 5 ng/ml is readily attainable.


More tornadoes in the most extreme U.S. tornado outbreaks.
Tornadoes and severe thunderstorms kill people and damage property every year. Estimated U.S. insured losses due to severe thunderstorms in the first half of 2016 were $8.5 billion (US). The largest U.S. effects of tornadoes result from tornado outbreaks, which are sequences of tornadoes that occur in close succession. Here, using extreme value analysis, we find that the frequency of U.S. outbreaks with many tornadoes is increasing and that it is increasing faster for more extreme outbreaks. We model this behavior by extreme value distributions with parameters that are linear functions of time or of some indicators of multidecadal climatic variability. Extreme meteorological environments associated with severe thunderstorms show consistent upward trends, but the trends do not resemble those currently expected to result from global warming.


Hypocholesterolaemia in the rat after p-chlorophenoxyisobutyric acid (CPIB) administration as a synthetic triglyceride, 1,3-dipalmitoyl 2(p-chlorophenoxyisobutyroyl)-rac-glycerol.
A synthetic triglyceride analogue, 1,3-dipalmitoyl 2(p-chlorophenoxyisobutyroyl)-rac-glycerol, was fed to rats and its effect compared to that of clofibrate. Both compounds significantly lowered plasma cholesterol concentration and the decreases essentially paralleled each other, even when the dose of drug or the period of administration was varied. No consistent effect was noted on the plasma triglyceride concentration. The results suggest that synthetic lipids are potentially suitable carriers for the oral administration of pharmacologically active agents.


Astrocyte elevated gene 1 (AEG-1) promotes anoikis resistance and metastasis by inducing autophagy in hepatocellular carcinoma.
Astrocyte elevated gene 1 (AEG-1) is overexpressed in hepatocellular carcinoma (HCC) and is strongly associated with tumor metastasis. Anoikis resistance and autophagy may play an important role in the survival of circulating tumor cells. However, the relationship among AEG-1, anoikis resistance, autophagy, and metastasis in HCC is still not clear. The results of this study indicate that AEG-1 expression is increased in HCC cell lines grown in suspension culture. AEG-1 could enhance anoikis resistance to promote the survival of detached HCC cells. Moreover, the anoikis resistance appears to be partly dependent on autophagy. Regulating AEG-1 expression changed the autophagy levels to modulate anoikis resistance, likely acting via the protein kinase RNA-like ER kinase (PERK)-eIF2α-ATF4-CHOP signaling axis. Finally, inhibiting autophagy by RNA interference prevented the AEG-1-promoted metastasis of HCC xenografts to the liver and lungs of nude mice. Taken together, AEG-1 is a key contributor to anoikis resistance and metastasis by inducing autophagy in vitro and in vivo, and it may be a potential target for therapeutic intervention in HCC.


Photocoagulation for choroidal neovascularization.
Nearly 90% of severe visual loss among patients with senile macular degeneration can be ascribed to the neovascular form of the disease. The Senile Macular Degeneration Study demonstrated that argon laser photocoagulation can reduce the risk of severe visual loss by more than 60% among patients with choroidal new vessel membranes 200 microns or greater from the center of the foveal avascular zone (FAZ). The Krypton Photocoagulation Study, also supported by the National Eye Institute, is evaluating whether krypton red laser photocoagulation can reduce the risk of visual loss in SMD patients with new vessels within 200 microns of the center of the FAZ.


A longer total duration of rapid ventricular pacing does not increase the risk of postprocedural myocardial injury in patients who undergo transcatheter aortic valve implantation.
Rapid ventricular pacing (RVP) is used during transcatheter aortic valve implantation (TAVI). RVP disturbs myocardial oxygen balance, and when prolonged, it may cause procedure-related myocardial injury (PMI). This study investigated whether a longer duration of RVP increased the occurrence of PMI or worsened long-term mortality after TAVI. We retrospectively analyzed data from 188 patients who underwent TAVI in our institute from January 2013 to July 2015. Myocardial injury was represented by the peak value of creatine kinase-myocardial band (CK-MB) within 72 h after the procedure; an increase greater than 5 times the upper reference limit was regarded as PMI. There was no difference in RVP time (RVPT) between patients with and without PMI (median [range]: 57 [9-189] s vs. 54 [0-159] s, p = 0.9). A higher peak CK-MB was significantly correlated with the apical approach for the procedure (p < 0.001) but not with total RVPT (p = 0.22). A subanalysis of 133 patients whose troponin I was tested within 72 h postprocedurally showed no correlation between the peak value and RVPT (p = 0.40). Shortening RVPT did not result in myocardial protection; thus, RVPT during TAVI should be sufficient to optimize valve placement.


Combined toxicity of microplastic and lead on submerged macrophytes.
Microplastic pollution has become ubiquitous due to industrialization and wide use of plastic products. The continuous discharge of microplastics into aquatic ecosystems, combined with different toxic chemicals can create serious environmental pollution. Lead is an extremely toxic metal which can strongly adsorb to microplastics, however, little is known about their combined toxicity on submerged macrophytes. To test our hypothesis that microplastic can aggravate lead toxicity on submerged macrophytes, we designed a five-day hydroponic experiment to explore the toxic effects of microplastic and lead alone, and in combination, on Potamogeton crispus and Vallisneria denseserrulata. Photosynthetic pigment, chlorophyll fluorescence (Fv/Fm and ETRmax), soluble sugar, protein and malondialdehyde (MDA) declined with increasing lead concentration alone and in the combined treatment. In both submerged macrophytes, the level of superoxide dismutase (SOD) and lead bioaccumulation increased with increasing lead concentration. However, microplastic aggravated lead toxicity on chlorophyll a and SOD activity in P. crispus only under the highest lead concentration. In conclusion, lead alone and combined exposure caused a series of toxic effects on physio-biochemical traits of submerged macrophytes that appeared to be synergistic and species-specific. Our comprehensive results have important implications for appropriate management of microplastics and lead alone, or in combination, for submerged macrophytes.


Impact of Malnutrition on Hospitalization Outcomes for Older Adults Admitted for Sepsis.
Malnutrition is a major determinant of health outcomes among the older adult population. Our goal was to evaluate the impact of malnutrition on hospitalization outcomes for older adults who were admitted with a diagnosis of sepsis. The National Inpatient Sample was queried for all patients who were admitted with a primary diagnosis of sepsis from January to December 2016. These patients were identified using the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code A419. Patients who were diagnosed with malnutrition were identified using ICD-10 codes E43, E440, E441, E45, and E46. Outcomes of hospitalization were modeled using logistic regression for binary outcomes and generalized linear models for continuous outcomes. Overall, a total of 808,030 patients were admitted for sepsis. Those diagnosed with malnutrition were 15.6% (126,335) of the total. The mean age (standard error of the mean) was 78 years (0.03). On multivariate analysis, malnutrition correlated with increased odds for mortality: adjusted OR (aOR) 1.20; 95% confidence interval [CI], 1.15-1.26; P < .001; septic shock: aOR 1.50; 95% CI, 1.44-1.57; P < .001; and intubation: aOR 1.45; 95% CI, 1.38-1.52; P < .001. It was also associated with higher odds for acute kidney injury and stroke. Malnutrition correlated with a 53% increase in the length of stay, with mean ratio 1.53; 95% CI, 1.51-1.56; P < .01; and a 54% increase in cost, with mean cost ratio 1.54; 95% CI, 1.51-1.58; P < .001. Among the geriatric population diagnosed with sepsis, malnutrition is an independent predictor for poor hospitalization outcomes.


Sequence-dependent antitumour efficacy of combination chemotherapy of nedaplatin, a novel platinum complex, with 5-fluorouracil in an in vivo murine tumour model.
The antitumour efficacy of a sequential combination of nedaplatin (NDP) and 5-fluorouracil (5-FU) was evaluated using Lewis lung carcinoma in vivo. NDP was developed as a second generation platinum complex. Because it has greater antitumour activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumour activity of NDP plus 5-FU with that of CDDP plus 5-FU. A fixed 5-FU dose was injected daily for 5 days and increasing doses of either NDP or CDDP were injected once via the tail vein into the Lewis lung carcinoma-implanted mice. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) resulted in severe body weight loss followed by the death of the tumour-bearing mice when the high-dose of NDP or CDDP was administered. In contrast, the sequential administration of 5-FU prior to NDP or CDDP (FN or FC therapy) resulted in synergistically enhanced inhibition of tumour growth and prolonged survival in comparison with NDP, CDDP or 5-FU monotherapy. At the high-dose of NDP in FN therapy, a reduction of tumour size and long-term tumour-free survival were frequently observed. The survival effect of the combinations of NDP with 5-FU was superior to those of the combination of CDDP with 5-FU. In conclusion, the sequence-dependent antitumour efficacy and toxicity of the combination of NDP or CDDP with 5-FU was demonstrated in this study, and FN therapy appeared to be the most efficient regimen as a clinical therapy.


Intramuscular electroporation with the pro-opiomelanocortin gene in rat adjuvant arthritis.
Endogenous opioid peptides have an essential role in the intrinsic modulation and control of inflammatory pain, which could be therapeutically useful. In this study, we established a muscular electroporation method for the gene transfer of pro-opiomelanocortin (POMC) in vivo and investigated its effect on inflammatory pain in a rat model of rheumatoid arthritis. The gene encoding human POMC was inserted into a modified pCMV plasmid, and 0-200 microg of the plasmid-POMC DNA construct was transferred into the tibialis anterior muscle of rats treated with complete Freund's adjuvant (CFA) with or without POMC gene transfer by the electroporation method. The safety and efficiency of the gene transfer was assessed with the following parameters: thermal hyperalgesia, serum adrenocorticotropic hormone (ACTH) and endorphin levels, paw swelling and muscle endorphin levels at 1, 2 and 3 weeks after electroporation. Serum ACTH and endorphin levels of the group into which the gene encoding POMC had been transferred were increased to about 13-14-fold those of the normal control. These levels peaked 1 week after electroporation and significantly decreased 2 weeks after electroporation. Rats that had received the gene encoding POMC had less thermal hypersensitivity and paw swelling than the non-gene-transferred group at days 3, 5 and 7 after injection with CFA. Our promising results showed that transfer of the gene encoding POMC by electroporation is a new and effective method for its expression in vivo, and the analgesic effects of POMC cDNA with electroporation in a rat model of rheumatoid arthritis are reversed by naloxone.


The effect of oestrogen on mandibular condylar cartilage via hypoxia-inducible factor-2α during osteoarthritis development.
Oestrogen and hypoxia inducible factor-2α (HIF2α) are key regulators in the pathogenesis of osteoarthritis (OA). However, the cellular interaction between oestrogen and HIF2α in articular cartilage during OA process remains unknown. Our previous study has revealed that high-physiological level of oestrogen aggravates the degradation of condylar cartilage in the early stage of temporomandibular joint osteoarthritis (TMJ OA). Here, we hypothesize that HIF2α involves the effect of oestrogen on mandibular condylar cartilage in the progression of TMJ OA. Our experiment in vivo found that the degeneration of condylar cartilage caused by unilateral anterior crossbite (UAC) model, characterized by obvious degenerative morphology, loss of cartilage extracellular matrix, up-regulation of TNF-α, HIF2α and its' down-stream OA-related cytokines (MMP-13, VEGF and Col X), could be alleviated by lack of oestrogen while aggravated by high level of oestrogen in rats. Meanwhile, our in vitro study found that 17β-estradiol stimulation resulted in the loss of extracellular matrix, increased expression of TNF-α, IL-1, HIF2α and its' down-stream OA-related cytokines (MMP-13, VEGF and Col X) in primary condylar chondrocytes via oestrogen receptor beta (ERβ), which could be reversed by ER antagonist, selective estrogen receptor modulators (SERMs) and HIF2α translation inhibitor. Our results reveal that high level of oestrogen can aggravate the degenerative changes of mandibular condylar cartilage, while lack of oestrogen can alleviate it via oestrogen-ERβ-HIF2α pathway during TMJ OA progression.


Thrombus associated with mitral valve calcification. A possible mechanism for embolic stroke.
Several studies have demonstrated an association between mitral annular calcification and stroke; however, the pathophysiological explanation remains speculative. We describe two patients with cerebral embolism in whom mitral valve calcification was demonstrated by transthoracic echocardiography. In both patients, transesophageal echocardiography identified a mass that appeared to be thrombus on the calcified portion of the mitral apparatus. There was no evidence of a hypercoagulable state or endocarditis in either case. Repeated transesophageal echocardiography after anticoagulation demonstrated resolution of the masses in both patients. These cases support the hypothesis that thrombus formation may be a pathophysiological link between ischemic cerebral events and mitral annular calcification in some patients.


Neoadjuvant immunotherapy for dMMR/MSI-H locally advanced rectal cancer: The future new standard approach?
This is a review of the evidence from studies of the efficacy and tolerability of neoadjuvant immunotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) Locally Advanced Rectal Cancer (LARC). For this review, we searched EMBASE and MEDLINE until 22 September 2022. The terms used in the search included mismatch repair-deficient, microsatellite instability, rectal cancer, neoadjuvant and immunotherapy. A total of 92 studies were obtained but only 9 were selected for the final analysis (one prospective and eight retrospective studies), including less than 20 patients per study. Neoadjuvant immunotherapy provides overall response rates of 100% (with and completed clinical response between 40 and 100%). Our review discusses completed prospective and retrospective studies, ongoing clinical trials, and the clinical practice of using neoadjuvant immunotherapy for MSI-H/dMMR LARC. The promising results obtained, would open the door to exploring other alternatives for these patients, offering the possibility of avoiding chemoradiation therapy and surgery in the future.


Vertebral artery loop--a cause of cervical radiculopathy.
To report a case of cervical radiculopathy caused by an anomalous vertebral artery (VA) and illustrate the efficacy of microvascular decompression by the anterolateral approach. A 50-year-old woman was referred because of an 8-year history of progressive left C6 radiculopathy refractory to other forms of treatment, including C5-6 anterior cervical discectomy. Clinical and radiologic evaluation showed an abnormally tortuous loop of V2 causing direct neurovascular compression. A left cervical anterolateral approach was used to expose the anomalous loop. After a generous bony decompression, the loop was identified, and the artery was mobilized and ultimately separated from the C6 nerve root removing the direct pulsatile compression. Cervical root compression by an aberrant or anomalous extracranial VA is a rare cause of radiculopathy. The best management of such lesions is the anterolateral approach with bony and direct microvascular decompression.


[Chemical constituents from Rehmannia glutinosa].
To study the chemical constituents from the roots of Rehmannia glutinosa. The compounds were isolated by various chromatographic methods and identified by spectroscopic analysis. Twelve compounds were isolated and their structures were identified as 5-hydroxymethyl-pyrrole-2-carbaldehyde (1), 5-hydroxymethyl furfural (2), tyrosol (3), 5,6-dihydroxy-beta-ionone (4), 6-O-E-feruloyl ajugol (5), acteoside (6), leucosceptoside A (7), martynoside (8), isomartynoside (9), purpureaside C (10), jionoside A1 (11), and jionoside B1 (12). Compounds 1, 3 and 9 were isolated from the genus Rehmannia for the first time.


Intelligence and Brain Efficiency: Investigating the Association between Working Memory Performance, Glutamate, and GABA.
Intelligence is a measure of general cognitive functioning capturing a wide variety of different cognitive functions. It has been hypothesized that the brain works to minimize the resources allocated toward higher cognitive functioning. Thus, for the intelligent brain, it may be that not simply more is better, but rather, more efficient is better. Energy metabolism supports both inhibitory and excitatory neurotransmission processes. Indeed, in glutamatergic and GABAergic neurons, the primary energetic costs are associated with neurotransmission. We tested the hypothesis that minimizing resources through the excitation-inhibition balance encompassing gamma-aminobutyric acid (GABA) and glutamate may be beneficial to general cognitive functioning using 7 T 1H-MRS in 23 healthy individuals (male/female = 16/7, 27.7 ± 5.3 years). We find that a higher working memory index is significantly correlated with a lower GABA to glutamate ratio in the frontal cortex and with a lower glutamate level in the occipital cortex. Thus, it seems that working memory performance is associated with the excitation-inhibition balance in the brain.


Practice-based study of the cost-effectiveness of fissure sealants in Finland.
To retrospectively analyze the cost-effectiveness of sealant treatment in two health centers with different caries preventive strategies in Finland using a practice-based research protocol. The data of digital dental records were data-mined and analyzed retrospectively in the health center in Kemi where the preventive strategy was sealing selectively only high-caries risk patients, and in Vantaa where all patients were routinely sealed. Risk group determination in Kemi was based on the presence of Streptococcus mutans in dental plaque. Supervised use of xylitol was an additional caries preventive measure in Kemi. The subjects were divided into all-sealed and non-sealed groups in the beginning of the follow-up according to the sealant treatment status of their first permanent molars. The mean cumulative cost of restorations and sealing treatment was counted in children at 12 years of age. Sealing of risk children in Kemi resulted in a total cost of 185euro per child whereas the respective cost of routinely sealed children in Vantaa was 235euro. The cost of restorations was 76euro in Kemi and 150euro in 5 years in Vantaa. Risk determination and the use of xylitol did not affect significantly the total treatment cost in Kemi. The significant reduction in the cost of dental treatment can be achieved by leaving non-risk subjects unsealed and sealing only high-caries risk individuals.


Successful treatment of testicular pain with peripheral nerve stimulation of the cutaneous branch of the ilioinguinal and genital branch of the genitofemoral nerves.
To assess the effect of peripheral nerve stimulation on neuropathic testicular pain. A 30-year-old man with a four-year history of chronic testicular pain following scrotal hydrocele surgery had two percutaneous leads implanted in his groin and low-frequency stimulation of the cutaneous branch of the ilioinguinal and genital branch of the genitofemoral nerves. At seven-month follow-up, the pain intensity had declined from 9/10 to 2/10 on the numeric rating scale. We report the successful implantation of an ilioinguinal and genitofemoral nerve stimulator for sustained suppression of intractable neuropathic testicular pain.


Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy in the pre-lapatinib era.
Patients with HER2-positive breast cancer whose disease has become resistant to the anti-HER2 monoclonal antibody trastuzumab can benefit from lapatinib, a dual epidermal growth factor receptor/HER2 tyrosine kinase (TK) inhibitor. Before the availability of this compound, trastuzumab was often continued beyond disease progression, usually in addition to further chemotherapy, an approach which was not based on randomized studies. We sought to retrospectively compare the clinical outcomes of patients who, upon progression during an initial trastuzumab-based regimen, stopped or continued trastuzumab in addition to further chemotherapy. From the clinical records of 407 patients with HER2-positive advanced breast cancer, we identified 279 patients progressing during an initial trastuzumab-based treatment. Of these patients, 83 continued trastuzumab in addition to chemotherapy, and 112 received chemotherapy alone. We found no difference in response rate (28% vs. 30%; P = .5), median time to second tumor progression (8.4 months vs. 7 months; P = .24), or median postprogression survival (20.6 months and 15.4 months; P = .29) according to whether patients continued or stopped trastuzumab. At multivariate analysis, continuation of trastuzumab was associated with a statistically insignificant trend toward reduced risk of second progression (hazard ratio, 0.753; P = .08). Patients with HER2-positive advanced breast cancer developing tumor progression during an initial trastuzumab-based regimen did not seem to benefit significantly from the continuation of trastuzumab in addition to chemotherapy. For these patients, there is evidence from a large randomized trial that effective HER2 targeting can be accomplished by inhibiting the HER2 TK activity with lapatinib.