Jejunal gastrointestinal stromal tumour masquerading as an ovarian cancer: A case report.

A 60-year-old lady presented with lower abdominal discomfort and a huge palpable intra-abdominal mass for 4 months, with significant weight loss over half a year. Transvaginal ultrasonography and computed tomography (CT) abdomen showed a large right solid cystic mass likely ovarian in origin. The CA-125 was raised. With the provisional diagnosis of ovarian cancer patient underwent laparotomy at Hospital Umum Sarawak, Malaysia. However intraoperative findings showed that uterus and both ovaries were normal. The tumour was arising from the jejunum and adherent to the dome of the urinary bladder and right broad ligament. The tumour was resected and final diagnosis was jejunal gastrointestinal stromal tumour (GIST). We described this case which was misinterpreted as an ovarian cancer.

Assessing and defining explicit processes in visuomotor adaptation.

The Process Dissociation Procedure (PDP) and Verbal Report Framework (VRF) reveal that both explicit (conscious) and implicit (unconscious) processes contribute to visuomotor adaptation. We looked to determine whether these two assessment methods establish similar processes underlying visuomotor adaptation by comparing the magnitude of explicit and implicit adaptation over time between the two assessments and to post-experiment assessments of awareness of the visuomotor distortion. Three groups of participants (PDP, VRF, VRF No-Cursor) completed three blocks of reach training in a virtual environment with a cursor rotated 40° clockwise relative to hand motion. Explicit and implicit adaptations were assessed immediately following each block, and again 5 min later. The VRF No-Cursor group completed the same assessment trials as the VRF group, but no visual feedback was presented during explicit and implicit assessment. Finally, participants completed a post-experiment questionnaire and a drawing task to assess their awareness of the visuomotor rotation and changes in reaches at the end of the experiment, respectively. We found that all groups adapted their reaches to the rotation. Averaged across participants, the magnitude and retention of explicit and implicit adaptations were similar between the PDP group and VRF group, with the VRF group demonstrating greater implicit adaptation than the VRF No-Cursor group. Furthermore, the magnitude of explicit adaptation established in the VRF group was not related to participant's post-experiment awareness of the visuomotor distortion nor how they had changed their reaches, as observed in the PDP group and VRF No-Cursor group. Together, these results indicate that, explicit adaptation established via typical VRF methods does not reflect one's awareness of the visuomotor distortion at the end of the experiment, and hence the established processes underlying visuomotor adaptation are dependent on method of assessment (i.e., PDP versus VRF).

Structural determinants of heparin-transforming growth factor-ß1 interactions and their effects on signaling.

Transforming growth factor-ß1 (TGF-ß1, Uniprot: P01137) is a heparin-binding protein that has been implicated in a number of physiological processes, including the initiation of chondrogenesis by human mesenchymal stem cells (hMSCs). Here, we identify the molecular features in the protein and in heparin required for binding and their effects on the potentiation of TGF-ß1's activity on hMSCs. Using a proteomics "Protect and Label" approach, lysines K291, K304, K309, K315, K338, K373, K375 and K388 were identified as being directly involved in binding heparin (Data are available via ProteomeXchange with identifier PXD002772). Competition assays in an optical biosensor demonstrated that TGF-ß1 does require N- and 6-O-sulfate groups for binding but that 2-O-sulfate groups are unlikely to underpin the interaction. Heparin-derived oligosaccharides as short as degree of polymerization (dp) 4 have a weak ability to compete for TGF-ß1 binding to heparin, which increases with the length of the oligosaccharide to reach a maximum between dp18 and dp24. In cell-based assays, heparin, 2-O-, 6-O- and N-desulfated re-N-acetylated heparin and oligosaccharides 14-24 saccharides (dp14-24) in length all increased the phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) after 6 h of stimulation with TGF-ß1. The results provide the structural basis for a model of heparin/heparan sulfate binding to TGF-ß1 and demonstrate that the features in the polysaccharide required for binding are not identical to those required for sustaining the signaling by TGF-ß1 in hMSCs.

First trial and StartReact effects induced by balance perturbations to upright stance.

Postural responses (PR) to a balance perturbation differ between the first and subsequent perturbations. One explanation for this first trial effect is that perturbations act as startling stimuli that initiate a generalized startle response (GSR) as well as the PR. Startling stimuli, such as startling acoustic stimuli (SAS), are known to elicit GSRs, as well as a StartReact effect, in which prepared movements are initiated earlier by a startling stimulus. In this study, a StartReact effect paradigm was used to determine if balance perturbations can also act as startle stimuli. Subjects completed two blocks of simple reaction time trials involving wrist extension to a visual imperative stimulus (IS). Each block included 15 CONTROL trials that involved a warning cue and subsequent IS, followed by 10 repeated TEST trials, where either a SAS (TESTSAS) or a toes-up support-surface rotation (TESTPERT) was presented coincident with the IS. StartReact effects were observed during the first trial in both TESTSAS and TESTPERT conditions as evidenced by significantly earlier wrist movement and muscle onsets compared with CONTROL. Likewise, StartReact effects were observed in all repeated TESTSAS and TESTPERT trials. In contrast, GSRs in sternocleidomastoid and PRs were large in the first trial, but significantly attenuated over repeated presentation of the TESTPERT trials. Results suggest that balance perturbations can act as startling stimuli. Thus first trial effects are likely PRs which are superimposed with a GSR that is initially large, but habituates over time with repeated exposure to the startling influence of the balance perturbation.

Startle induces early initiation of classically conditioned postural responses.

Startling acoustic stimuli (SAS) induce the early release of prepared motor responses. The current study used SAS, in conjunction with a classical conditioning paradigm, to examine advanced motor preparation of conditioned postural responses (PRs). After generalized startle responses were induced, standing posture was perturbed in 2 blocks of 15 Conditioning trials, where in each trial the onset of a nonstartling auditory cue [i.e., a conditioned stimulus (CS)] preceded a leftward support-surface translation. Upon completion of each block, a single trial was conducted. After block 1, a CS-Only trial was used to induce conditioned PRs in the absence of balance perturbations. After block 2, a post-Conditioning Startle trial that involved a CS subsequently followed by a SAS was used to examine motor preparation of conditioned PRs. PRs were quantified in terms of center of pressure displacements, ankle and hip kinematics, as well as surface electromyography of proximal and distal bilateral muscle pairs. Results indicated that repeated experience with cued balance perturbations led to PR conditioning and, more importantly, motor preparation of PRs. Conditioning was evidenced in biomechanical and electromyographic responses observed in CS-Only trials, as well as the progressive changes to evoked response parameters during repeated Conditioning trials. SAS presented in post-Conditioning Startle trials evoked early onsets of biomechanical and electromyographic responses, while preserving relative response parameters that were each distinct from generalized startle responses. These results provide important insight into both the consequences of using cues in dynamic postural control studies and the neural mechanisms governing PRs.

Assessing explicit processes does not influence the magnitude of implicit processes.

Implicit (unconscious) and explicit (strategy) processes have been shown to contribute to visuomotor adaptation. Current methods, such as the Process Dissociation Procedure (PDP) and the Verbal Report Framework (VRF), simultaneously evaluate both implicit and explicit contributions to visuomotor adaptation. It is unclear whether the act of assessing explicit adaptation leads to variations in the magnitude of implicit adaptation observed. To address this question, four groups of participants adapted their reaches to a 40° clockwise visuomotor rotation. Implicit and explicit adaptation were assessed in a PDP-IE group and a VRF-IE group following 3 blocks of rotated reach training trials. In contrast, only implicit adaptation was assessed at the same time points for a PDP-I group and VRF-I group. Results indicated a similar magnitude of implicit adaptation regardless of whether explicit adaptation was assessed or not. Thus, assessing explicit adaptation simultaneously with implicit adaptation following reach adaptation does not influence the magnitude of implicit adaptation established via the PDP and VRF methods.

Surgical site infection and development of antimicrobial sutures: a review.

Sutures are used to facilitate wound healing and play an important role in ensuring the success of surgical interventions in healthcare facilities. Suture-associated surgical site infection (SSI) may develop when bacterial contaminants colonize the suture surface and establish biofilms that are highly resistant to antibiotic treatment. The outcome of SSI affects postoperative care, leading to high rates of morbidity and mortality, prolonged hospitalization, and increased financial burden. Antimicrobial sutures coated with antiseptics such as triclosan and chlorhexidine have been used to minimize the occurrence of SSI. However, as the efficacy of antiseptic-based sutures may be affected due to the emergence of resistant strains, new approaches for the development of alternative antimicrobial sutures are necessary. This review provides an update and outlook of various approaches in the design and development of antimicrobial sutures. Attaining a zero SSI rate will be possible with the advancement in suturing technology and implementation of good infection control practice in clinical settings.

Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children.

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

The cysteine-rich regions of the regulatory domains of Raf and protein kinase C as retinoid receptors.

Vitamin A and its biologically active derivatives, the retinoids, are recognized as key regulators of vertebrate development, cell growth, and differentiation. Although nuclear receptors have held the attention since their discovery a decade ago, we report here on serine/threonine kinases as a new class of retinoid receptors. The conserved cysteine-rich domain of the NH(2)-terminal regulatory domains of cRaf-1, as well as several select domains of the mammalian protein kinase C (PKC) isoforms alpha, delta, zeta, and mu, the Drosophila and yeast PKCs, were found to bind retinol with nanomolar affinity. The biological significance was revealed in the alternate redox activation pathway of these kinases. Retinol served as a cofactor to augment the activation of both cRaf and PKC alpha by reactive oxygen, whereas the classical receptor-mediated pathway was unaffected by the presence or absence of retinol. We propose that bound retinol, owing to its electron transfer capacity, functions as a tag to enable the efficient and directed redox activation of the cRaf and PKC families of kinases.

Retro-retinoids in regulated cell growth and death.

Vitamin A serves as a prohormone from which three classes of active metabolites are derived: the aldehydes, the carboxylic acids, and the retro-retinoids. Although these three classes are united under the rubric of signal transduction, they act by different molecular mechanisms: the 11-cis-retinaldehydes combine with opsin to form the universal visual pigments and the retinoic acids form ligands for transcription factors, whereas the retro-retinoids, as shown here, intersect with signal transduction at a cytoplasmic or membrane site. The retro-retinoid, anhydroretinol (AR), has long been known to act as a growth inhibitor in lymphocytes, whereas 14-hydroxy-4,14-retro-retinol (14-HRR) is required for normal lymphocyte proliferation. A mutually reversible relationship exists between these two retro-retinoids as one can reverse the effects of the other when given in pharmacological doses. The common explanation for reversible inhibition is competition for a shared receptor. We now provide evidence that when AR is given to T cells unmitigated by 14-HRR, rapid cell death can occur. The circumstances are closely related to nonclassical forms of apoptosis: within 2 h of AR administration the T cells undergo widespread morphological changes, notably surface blebbing and ballooning and, inevitably, bursting. In contrast, nuclear changes are comparatively mild, as indicated by absence of chromatin condensation and overt DNA cleavage to discrete nucleosomal fragments, although DNA nicks are readily discernible by terminal deoxynucleotidyl transferase assay. What further distinguishes the AR-induced form of apoptosis from classical ones is a lack of requirements of messenger RNA and protein synthesis, suggesting that the events leading to cell death are primarily initiated and play themselves out in the cytoplasm. This view is further reinforced by the finding that herbimycin A can prevent the onset of programmed cell death. The importance of our findings is that they strongly suggest a second messenger role for vitamin A metabolites in the cytoplasmic realm that has not been seen previously. These findings are entirely compatible with a general notion that in a cell requiring multiple coordinated signals for survival, the provision of an unbalanced signal can initiate programmed cell death. Collectively, our data also challenge the paradigm that retinoids (outside vision) solely mediate their function via the steroid/ retinoic acid receptor family of nuclear transcription factors. Instead, a mode of action in the cytoplasmic realm akin to one attributed to other small lipophilic second messenger molecules, such as diacyl glycerol or ceramide, may apply to retro-retinoids.

Molecular patterns in melanoma and therapeutic targets.

Malignant melanoma is one of the most lethal cancers whose treatment options are limited once it has metastasized. Recent advances in molecular technology have improved our understanding of the underlying mechanisms of melanoma pathogenesis. In this article, we highlight several pathways that have been implicated in melanoma-genesis. While a cure is not yet within grasp, the picture on the horizon is less hazy and the next decade promises to yield exciting new therapeutic discoveries.

Retention of the Structure and Function of Heparan Sulfate Biomaterials After Gamma Irradiation.

Heparan sulfate (HS) is a highly heterogeneous polysaccharide implicated in many important biological processes. Our previous work has demonstrated that a particular affinity-selected HS (referred to henceforth as "HS3") is capable of enhancing the osteogenic effects of bone morphogenetic protein 2 (BMP2). Here, we gamma-irradiated HS with 26 kGy of ionizing radiation to determine how this affected the structure, composition, and function. Initial structural studies were performed on a commercial preparation of HS as a proof-of-concept. Gamma irradiation of this HS preparation did not significantly alter its structure or composition compared to nonirradiated material, as demonstrated by proton nuclear magnetic resonance spectroscopy, molecular weight analysis using size exclusion chromatography, and disaccharide compositional analysis. When HS3 was gamma irradiated, no significant effect on binding affinity toward BMP2 was observed, based on competitive surface plasmon resonance and differential scanning fluorimetry assays. Furthermore, irradiation did not significantly affect HS3's ability to synergistically enhance the osteogenic effects of BMP2 in vitro; as measured by the relative abundance of osteogenic transcripts in transdifferentiating C2C12 murine myoblasts. Additionally, no significant differences were observed in the levels of alkaline phosphatase (ALP) or calcium deposition in C2C12s treated with BMP2, together with the irradiated, or nonirradiated HS3. Irradiation of HS3 incorporated into collagen type I sponges did not affect its ability to enhance BMP2-mediated ALP expression in C2C12 cells. Our data confirm that gamma irradiation is a cost-effective and viable solution for the sterilization of HS species that allows the retention of its structure and biological function. The work suggests an effective way to incorporate clinically compatible HS species into orthotic implants, scaffolds, and other medical devices for use in the treatment of a range of diseases and disorders.

An in-vitro urinary catheterization model that approximates clinical conditions for evaluation of innovations to prevent catheter-associated urinary tract infections.

BACKGROUND: Catheter-associated urinary tract infections (CAUTI) account for approximately 25% of nosocomial infections globally, and often result in increased morbidity and healthcare costs. An additional concern is the presence of microbial biofilms which are major reservoirs of bacteria, especially antibiotic-resistant bacteria, in catheters. Since introduction of the use of closed drainage systems, innovations to combat CAUTI have not led to significant improvements in clinical outcomes. The lack of a robust laboratory platform to test new CAUTI preventive strategies may impede development of novel technologies. AIM: To establish an in-vitro catheterization model (IVCM) for testing of technological innovations to prevent CAUTI. METHODS: The IVCM consists of a continuous supply of urine medium flowing into a receptacle (bladder) where the urine is drained through a urinary catheter connected to an effluent collection vessel (drainage bag). Test organism(s) can be introduced conveniently into the bladder via a rubber septa port. Development of bacteriuria and microbial biofilm on the catheter can be determined subsequently. FINDINGS: With an initial inoculum of Escherichia coli [∼5×105 colony-forming units (cfu)/mL] into the bladder, a 100% silicone catheter and a commercially available silver-hydrogel catheter showed heavy biofilm colonization (∼108 cfu/cm and ∼107 cfu/cm, respectively) with similar bacterial populations in the urine (bacteriuria) (∼108 cfu/mL and ∼107 cfu/mL, respectively) within three days. Interestingly, an antimicrobial peptide (CP11-6A)-coated catheter showed negligible biofilm colonization and no detectable bacteriuria. CONCLUSION: The IVCM is a useful preclinical approach to evaluate new strategies for the prevention of CAUTI.

Comparison and validation of three measures of quality of life in patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension, when advanced, markedly limits exercise capacity, activities of daily living and quality of life (QoL). No measure of QoL has yet been validated for the assessment of pulmonary hypertension. The aim of the study was to compare the validity of the Minnesota Living with Heart Failure (MLwHF) questionnaire, the Short Form-36 (SF-36) questionnaire and the Australian Quality of Life (AQoL) measure for assessing pulmonary hypertension treatment. METHODS: Eighty-three patients were enrolled in three studies of pulmonary hypertension treatment (treprostinil, bosentan and sildenafil). They were assessed at baseline and 3 months with the MLwHF questionnaire. Treprostinil and bosentan groups also had 6 and 12 months' data. Twenty-one patients in the sildenafil trial completed concurrently, the SF-36 and AQoL measures at baseline and 3 months. QoL scores were correlated with the 6-min walk test distance, New York Heart Association functional class and right heart catheter-derived haemodynamic parameters of the disease for all matching time points and for changes in scores and clinical measurements over time. RESULTS: The MLwHF and SF-36 scores correlated well with the 6-min walk test distance and New York Heart Association functional class, but did not correlate with haemodynamic measurements. MLwHF and SF-36 scores also correlated with the rate of change of the 6-min walk test distance and New York Heart Association functional class over time. CONCLUSION: The MLwHF questionnaire and SF-36 are useful tools for the assessment of QoL in pulmonary hypertension and may be useful in the ongoing evaluation of QoL in the treatment and study of pulmonary hypertension.

Will "no blood" kill Jehovah Witnesses?

A 46-year-old Indonesian woman presented with signs and symptoms suggestive of an ovarian tumour and was advised to have surgery with exploratory laparotomy and removal of the mass. She agreed but refused blood transfusion any time in the course of her treatment or procedure, as she was a Jehovah Witness. As there was a high risk of intraoperative haemorrhage, steps were taken to reduce any consequent complications due to the surgery. The ethical conflict is between respecting patient autonomy and compromising standards of care, arising from the refusal of a standard therapy. The latest developments in the blood transfusion doctrine policy for the Jehovah Witnesses are also discussed in this case study.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

The contribution of vision to asymmetries in manual aiming.

An experiment was conducted to examine the hypothesis that the right hand system is superior in the processing of visual information. A manual aiming task utilizing four visual conditions was employed. In the full-vision (FV) condition subjects were afforded vision of both the hand and the target throughout the course of the movement. In the ambient-illumination-off (AO) condition, the room lights were extinguished at movement initiation, thus preventing vision of the moving limb. The target remained illuminated. In the target-off (TO) condition, the target was extinguished upon initiation of the movement. Ambient illumination and thus vision of the hand remained present. Finally there was a no-vision (NV) condition in which ambient illumination was removed and the target was extinguished upon initiation of the response movement. Although the manipulation of vision had potent effects upon terminal accuracy, and influenced reaction and movement time measures, the hands did not differ in the extent to which these characteristics were expressed. A left hand advantage for reaction time was observed. This may reflect a relative increase in right hemisphere involvement prior to aiming movements which are spatially complex.

A century later: Woodworth's (1899) two-component model of goal-directed aiming.

In 1899, R. S. Woodworth published a seminal monograph, "The Accuracy of Voluntary Movement." As well as making a number of important empirical contributions, Woodworth presented a model of speed-accuracy relations in the control of upper limb movements. The model has come to be known as the two-component model because the control of speeded limb movements was hypothesized to entail both a central and a feedback-based component. Woodworth's (1899) ideas about the control of rapid aiming movements are evaluated in the context of current empirical and theoretical contributions.

Changes in posture alter the attentional demands of voluntary movement.

Two simple experiments reveal that the ease with which an action is performed by the neuromuscular-skeletal system determines the attentional resources devoted to the movement. Participants were required to perform a primary task, consisting of rhythmic flexion and extension movements of the index finger, while being paced by an auditory metronome, in one of two modes of coordination: flex on the beat or extend on the beat. Using a classical dual-task methodology, we demonstrated that the time taken to react to an unpredictable visual probe stimulus (the secondary task) by means of a pedal response was greater when the extension phase of the finger movement sequence was made on the beat of the metronome than when the flexion phase was coordinated with the beat. In a second experiment, the posture of the wrist was manipulated in order to alter the operating lengths of muscles that flex and extend the index finger. The attentional demands of maintaining the extend-on-the-beat pattern of coordination were altered in a systematic fashion by changes in wrist posture, even though the effector used to respond to the visual probe stimulus was unaffected.

Human anti-HLA-DQw2 monoclonal antibody secreted by an Epstein-Barr-virus--transformed lymphoblastoid cell line: assessment of the monoclonality, allospecificity, and target.

IgM molecules were purified by the use of anti-IgM antibody-coupled Sepharose from the culture supernatant of an Epstein-Barr-virus-transformed lymphoblastoid cell line, MP1, that secretes alloantibodies possessing HLA-DQw2 specificity as defined by the cytotoxicity assay. The obtained IgM preparation was labeled with radioactive iodine-125I and fractionated by gel filtration. It contained pentameric IgM and smaller oligomeric IgMs. When tested by the direct cellular binding assay against a panel of HLA-typed cell lines, they all showed the DR3 and DR7 association pattern characteristic of DQw2. A weak but significant binding was detected for DR1, DR6, and DR9. On isoelectrofocusing, MP1 pentameric IgM gave a restricted banding pattern comparable to monoclonal IgM obtained from a patient with Waldenström's syndrome. Moreover, the pattern was identical to that of IgM purified from the culture supernatant of a defined hybrid clone, 162, that was generated by fusing MP1 cells with heteromyeloma D33 cells. The target class II molecules showed the dimeric structure that conforms to DQw2 molecules.