The potential role of artificial intelligence-assisted chest X-ray imaging in detecting early-stage lung cancer in the community-a proposed algorithm for lung cancer screening in Malaysia.

INTRODUCTION: The poor prognosis of lung cancer has been largely attributed to the fact that most patients present with advanced stage disease. Although low dose computed tomography (LDCT) is presently considered the optimal imaging modality for lung cancer screening, its use has been hampered by cost and accessibility. One possible approach to facilitate lung cancer screening is to implement a risk-stratification step with chest radiography, given its ease of access and affordability. Furthermore, implementation of artificial-intelligence (AI) in chest radiography is expected to improve the detection of indeterminate pulmonary nodules, which may represent early lung cancer. MATERIALS AND METHODS: This consensus statement was formulated by a panel of five experts of primary care and specialist doctors. A lung cancer screening algorithm was proposed for implementation locally. RESULTS: In an earlier pilot project collaboration, AI-assisted chest radiography had been incorporated into lung cancer screening in the community. Preliminary experience in the pilot project suggests that the system is easy to use, affordable and scalable. Drawing from experience with the pilot project, a standardised lung cancer screening algorithm using AI in Malaysia was proposed. Requirements for such a screening programme, expected outcomes and limitations of AI-assisted chest radiography were also discussed. CONCLUSION: The combined strategy of AI-assisted chest radiography and complementary LDCT imaging has great potential in detecting early-stage lung cancer in a timely manner, and irrespective of risk status. The proposed screening algorithm provides a guide for clinicians in Malaysia to participate in screening efforts.

New computational approach to shunt design in congenital heart palliation.

Shunts are commonly used to redirect blood to pulmonary arteries in procedures that palliate congenital cardiovascular defects. Previous clinical studies and hemodynamic simulations reveal a critical role of shunt diameter in balancing flow to pulmonary versus systemic vessels, but the biomechanical process of creating the requisite anastomosis between the shunt and host vessel has received little attention. Here, we report a new Lagrange multiplier-based finite element approach that represents the shunt and host vessels as individual structures and predicts the anastomosis geometry and attachment force that result when the shunt is sutured at an incision in the host, followed by pressurization. Simulations suggest that anastomosis orifice opening increases markedly with increasing length of the host incision and moderately with increasing blood pressure. The host artery is further predicted to conform to common stiff synthetic shunts, whereas more compliant umbilical vessel shunts should conform to the host, with orifice area transitioning between these two extremes via a Hill-type function of shunt stiffness. Moreover, a direct relationship is expected between attachment forces and shunt stiffness. This new computational approach promises to aid in surgical planning for diverse vascular shunts by predicting in vivo pressurized geometries.

The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system.

Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. As in the USA and Canada, in Europe, the demand for pain-relieving medicines used in chronic pain has also significantly increased, but most European countries are not experiencing an opioid crisis. In this review, the role of various endogenous transmitters (noradrenaline, dopamine, serotonin, met- and leu-enkephalins, ß-endorphin, dynorphins, cannabinoids, ATP) and various receptors (α2, µ, etc.) in the innate pain-relieving system will be discussed. Furthermore, the modulation of pain processing pathways by transmitters, focusing on neuropathic pain and the role of the sympathetic nervous system in the side effects of excessive opioid treatment, will be explained.

West Nile virus infections in Hungary, August-September 2008.

Between 2003 and 2007, a yearly average of six cases of West Nile virus neuroinvasive infection were diagnosed in Hungary. In 2008, 14 cases have been confirmed by the end of October. In contrast with previous years the infection has now appeared also in the north-western part of the country which is endemic for tick-borne encephalitis.

Immunochemical study of equine chorionic gonadotropin (eCG/PMSG): antigenic determinants on alpha- and beta-subunits.

In the present study we have established an immunochemical mapping of equine Chorionic Gonadotropin (eCG/PMSG) using three monoclonal antibodies (mAbs), namely the antibodies ECG01, E10 and D7, raised against the native hormone. These antibodies do not bind to reduced, alkylated hormone, suggesting that they recognize discontinuous rather than continuous epitopes. We have also assessed the reactivity of mAbs towards human CG, and ovine, porcine, equine and bovine LH and FSH. The antigenic determinant recognized by ECG01 is localized on the alpha-subunit of equine gonadotropins and of human CG and LH. The epitopes recognized by E10 and D7 mAbs appear to be very similar and are present on the beta-subunit of eCG and of LHs from all species tested, except hLH, as well as on porcine and equine FSHs. Attempts to specify the amino-acid residues involved in these epitopes suggest that ECG01 mAb might preferentially bind to residues around position 70 whereas the region around disulfide bridges Cys-88-Cys-90 might be involved in the epitopes recognized by D7 and E10 mAbs. Topographical relationships of epitopes show that ECG01 mAb never binds to eCG simultaneously with either D7 or E10 mAbs. Furthermore, simultaneous binding of D7 and E10 mAbs on eCG could not be achieved. Thus, these three epitopes appear to be closely located on the surface of eCG. Finally, ECG01 mAb inhibits eCG binding to LH and FSH receptors, suggesting that its antigenic site is closely related to hormone-receptor interaction site(s).

Demonstration of lactogenic receptors in rat endocrine pancreases by quantitative autoradiography.

A direct effect of growth hormone and/or prolactin on the growth of the pancreatic beta-cell has been proposed. This study assessed the presence of human growth hormone (hGH)-binding sites in male adult rat endocrine pancreas via quantitative autoradiography. The binding of 125I-labeled hGH was evaluated by receptor autoradiography on frozen-pancreas cryostat cut sections. The sections were incubated with 125I-hGH (10(-10) M) for 75 min at room temperature, and nonspecific binding was determined in the presence of excess native hGH (5 X 10(-7) M). The specificity of the binding was assessed in competition experiments with bovine GH and ovine prolactin. The autoradiograms were quantified with a computer-assisted image-processing system. The sections were then stained to visualize the endocrine islets. Nondiabetic control and streptozocin (STZ)-injected rats were used. Our results show that 1) there is specific binding of iodinated hGH in small areas of the pancreas, which appear as the Langerhans islets when the autoradiogram and the stained sections are superimposed; 2) the specificity of hGH binding in rat islets is lactogenic; 3) the density of the hGH-binding sites in the endocrine pancreas is estimated at 4.8 fmol/mg protein, with IC50 ranging from 0.98 to 2.50 nM; and 4) binding sites may be present on the beta-cell, because specific binding disappears in STZ-injected rats. In conclusion, by use of a quantitative autoradiographic technique, we provide evidence for the presence of lactogenic receptors on rat beta-cells.

Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity.

In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways.

Identification of suppressin-producing cells in the rat pituitary.

Suppressin (SPN) is a novel polypeptide that is synthesized and secreted by normal rat pituitary cells and a rat pituitary tumor cell line, GH3. Specifically, SPN is a negative regulator of growth that inhibits lymphoid and neuroendocrine cell proliferation. The objective of the present study was to identify the cells in the normal rat pituitary that produce SPN. A double immunofluorescence technique, using antibodies to SPN in conjunction with antibodies to the six major adenohypophyseal hormones, was used to colocalize SPN and a specific hormone in a single dispersed pituitary cell. The results of these experiments showed that, on the average, 42% of the cells in the pituitary produce SPN. Suppressin production in the pituitary was restricted to the adenohypophysis. The SPN-producing population in the pituitary was composed of somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and mammosomatotrophs, while gonadotrophs did not produce SPN. Additionally, a PRL reverse hemolytic plaque assay was used to examine SPN production in lactotrophs. The results of these experiments showed that SPN production and the amount of PRL secreted covaried. Specifically, SPN production was observed primarily in non-PRL-secreting lactotrophs or in lactotrophs secreting a high amount of PRL. The results of these experiments suggest a potential regulatory relationship between the synthesis and secretion of SPN and PRL. In summary, this report provides the first identification of SPN-producing cells in the pituitary and shows that SPN production occurs primarily in somatotrophs and lactotrophs.

Suppressin: an endogenous negative regulator of immune cell activation.

We have recently identified a new suppressor molecule we named suppressin (SPN) that has all the characteristics of a global negative regulator of the immune system. SPN is a unique 63-kD monomeric polypeptide with a pI of 8.1 that is produced and secreted under basal conditions by murine splenocytes, human peripheral mononuclear cells, and hormone-secreting pituitary cells. The biological actions of SPN in vitro include the inhibition of mitogen-induced proliferation and immunoglobulin synthesis of lymphocytes and the suppression of interleukin-2-dependent CTLL-2 cell proliferation. In addition, SPN enhances natural killer cell activity by eliciting interferon-alpha and -beta synthesis and secretion. SPN effects are reversible, nontoxic, and require the continuous presence of exogenous SPN. T lymphocytes stimulated with concanavalin A or phytohemagglutinin are more sensitive to SPN (90% inhibition) than are lipopolysaccharide-stimulated B cells (60% inhibition). SPN arrests lymphocytes in the G0/G1 phase of the cell cycle after reduction of their RNA, protein and DNA synthesis, suggesting that SPN inhibits the processes required for G0 transition to G1. SPN is found intracellularly in all unstimulated lymphocyte subsets, monocytes, and in phytohemagglutinin-activated T lymphocytes immunopositive for the low affinity interleukin-2 receptor. These results suggest that SPN may be a major negative regulator of cell proliferation in the immune system. All SPN-producing cell types are also sensitive to SPN. Collectively, the results of these experiments provide the foundations for a model in which SPN regulates lymphocyte proliferation in an autocrine and/or paracrine manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus.

Interleukin-I receptors were mapped and characterized in mouse brain by quantitative autoradiography using human recombinant [125I]interleukin-I alpha and [125I]interleukin-1 beta as ligands. Both ligands provide identical receptor mapping. In terms of specificity, interleukin-1 alpha and interleukin-1 beta were equally potent in binding competitions assays with either [125I]interleukin-1 alpha or [125I]interleukin-1 beta (EC50 11 pM). These receptors were shown to be highly concentrated in the dentate gyrus, in the choroid plexus at various levels of the brain, in the pituitary and in the meninges. They were also present at low concentrations in the cortex but undetectable in other brain structures. In the dentate gyrus, interleukin-1 receptors were localized on the granular and molecular layers (granule cells) when visualized on slides dipped in nuclear emulsion. Cellular localization of interleukin-1 receptors was assessed using selective lesion by colchicine. The complete loss of [125I]interleukin-1 binding in hippocampal areas where neurons were destroyed by colchicine demonstrates that interleukin-1 receptors are located on granule cells. Following lesion, sparse undestroyed cells, with glial cell morphology, also showed significant labelling. In conclusion, interleukin-1 receptors are located on the granule cells in the mouse dentate gyrus. These neurons may therefore be targets for neuromodulation by interleukin-1 and they may play a key role in the central effect of interleukin-1 as well as in the control of the immune response by the brain.

Interleukin-1 binding sites on astrocytes.

Interleukin-1 has been shown to have regulatory effects on glial cell functions. In this study, we examined the capacity of astroglial cells to specifically bind recombinant iodinated human interleukin-1 alpha. This was performed in mouse brain by both in situ and in vitro autoradiography, on areas of gliosis and on astrocytes and microglia primary and secondary cultures respectively. Specific binding was shown in the brain sections over areas of glial proliferation, and in addition, quantitative autoradiography was performed. Analysis of competition experiments by autoradiography led to EC50 values of 5 x 10(-11) M for human interleukin-1 alpha and approximately 10(-9) M for the interleukin-1 receptor antagonist. In cultures, iodinated human interleukin-1 alpha bound specifically to astrocytes but was unable to bind to microglial cells. Competition binding experiments in astrocyte cultures led to EC50 values of 8 x 10(-11) M and 1 x 10(-10) M for human interleukin-1 alpha and mouse interleukin-1 beta respectively, and an EC50 higher than 10(-9) M for the antagonist. The presence of interleukin-1 receptors on astroglial cells provides biochemical support for the various effects of interleukin-1 in the central nervous system, particularly those concerning the formation of scar tissue, possibly by astroglia proliferation after brain injury.

GnRH receptors in rat brain, pituitary and testis; modulation following surgical and gonadotropin-releasing hormone agonist-induced castration.

The regulation of rat gonadotropin-releasing hormone (GnRH) receptors in male rat pituitary, hippocampus and testis was studied, in vivo, under steady-state conditions during treatment with D-Trp6 GnRH (triptorelin, slow-release form, at 300 micrograms/kg/month). GnRH receptors were characterized on tissue sections by quantitative autoradiography using 125I-GnRHa as a tracer. Castrating doses of triptorelin strongly down-regulated pituitary GnRH receptors (50% of reduction after 8 h, 80% on days 1-30); in contrast, only a transient decrease (20% at 8 h) was observed in the hippocampus with a rapid return to control levels. Triptorelin induced a marked (2-fold) increase in GnRH receptors in testicular interstitial tissue during 5 days with a return to control value by day 20. Administration of a GnRH antagonist (BIM 21009, 1 mg/kg/24 h) induced a rapid reduction of pituitary and testicular receptors to undetectable levels at 24 h, while hippocampal receptors were strongly reduced only. This indicates that GnRH receptors with similar pharmacology are differently controlled in various tissues and that brain receptors are likely to be also regulated by GnRH agonists and antagonists.

Increased adrenal androgen functioning in children with oppositional defiant disorder: a comparison with psychiatric and normal controls.

OBJECTIVE: To examine the relationship between adrenal androgens and aggression in children with oppositional and antisocial behavior and to compare their levels with those of psychiatric and normal controls. METHOD: Dehydroepiandrosterone sulfate (DHEAS) was measured in 24 children with oppositional defiant disorder (ODD), 42 psychiatric controls (including 20 children with attention-deficit/hyperactivity disorder [ADHD]), and 30 normal controls. The children's parents filled out the Child Behavior Checklist (CBCL). RESULTS: Children with ODD had higher DHEAS levels than either the psychiatric control or normal control groups; DHEAS levels of the latter groups did not differ. Moreover, it was possible to classify children as having either ODD or ADHD on the basis of their DHEAS levels, whereas this was not the case on the basis of the CBCL data. CONCLUSIONS: The results indicate that adrenal androgen functioning is specifically elevated in children with ODD. It is speculated that the mechanism could be a shift in balance of ACTH-beta-endorphin functioning in the hypothalamic-pituitary-adrenal axis due to early stress or genetic factors.

A controlled multivariate chart review of multiple complex developmental disorder.

OBJECTIVE: The primary aim of the study was to ascertain the usefulness and the validity of the set of criteria proposed to define a subgroup within the DSM-III-R category of pervasive developmental disorder-not otherwise specified under the name of multiple complex developmental disorder (MCDD). METHOD: A multivariate analysis (cluster and principal-components analysis) was performed on the characteristics, reliably extracted from the charts of 105 children with MCDD, 32 with autistic disorder, 51 with externalizing disorders, and 56 with internalizing disorders, all with an IQ greater than 70, fully assessed in our department between 1984 and 1991. RESULTS: The main finding was a strong correspondence between the classification of the cases by DSM-III-R categories and the subdivision by means of a multivariate cluster analysis. The cluster analysis did not discriminate between children with emotional and disruptive disorders. Furthermore, children with MCDD and autistic disorder were significantly different both on symptom factors ("psychotic thinking/anxiety," "aggression," "deficient interaction/communication," "stereotyped and rigid behavior," and "suspiciousness/odd interaction") and on factors that reflected developmental and environmental background variables. CONCLUSION: The results of this study add to the nosology of autistic spectrum disorders and lend additional support to the need for a separate subcategory of MCDD within DSM-V. Further corroboration of these results in independent (multicenter) samples will be required.

Specific binding sites for growth hormone in cultured mouse thymic epithelial cells.

Growth Hormones bound specifically to murine Thymic epithelial cells, which represent the major component of thymic micro-environment and can be modulated by pituitary hormones. The Kds found with human growth hormone and bovine growth hormone were 0.14 and 0.27 nM with a Bmax 0.56 and 0.35 fmol/10(6) cells respectively. Competition experiment analysis showed ED50 of 0.24 nM for hGH, 0.46 nM for rGH, 0.71 nM for bGH, 11.8 nM for hPRL and 11.2 nM for oPRL. No specific binding of [125I]-oPRL was observed under the same conditions. Both hPRL and bGH showed a negative regulatory effect on the number of the hGH binding sites when incubated with the culture for three days. The presence of GH receptors on Thymic epithelial cells provides biochemical evidence for the effect of GH on thymic function.

Competitive immunoassay for recombinant hirudin using capillary electrophoresis with laser-induced fluorescence detection.

A competitive immunoassay based on capillary electrophoresis (CE) with laser-induced fluorescence (LIF) has been developed for the determination of recombinant hirudin (r-hirudin) in biological mixtures. Hirudin, a thrombin inhibitor, is a polypeptide of 65 amino acids. To check purity levels and perform pharmacokinetic studies of (r-hirudin), specific and reproducible analysis methods are demanded. The work involved the development of separation conditions allowing for routine analysis of plasma samples. In this study, r-hirudin was labeled with fluorescein isothiocyanate (FITC), and FITC-labeled r-hirudin was purified using high-performance liquid chromatography. The purified product was then mixed with the sample followed with the addition of anti-hirudin antibody. Free, antibody-bound, and tagged r-hirudin could be separated within 5 min by CE analysis using uncoated fused-silica capillary with high reproducibility. The developed method can be used to determine r-hirudin with good precision and a detection limit lower than 20 nM. This result demonstrates the feasibility of the CE-LIF immunoassay method for the determination of r-hirudin in plasma samples.

Cyclodextrin-mediated micellar electrokinetic chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for the enantiomer separation of racemorphan in human urine.

Micellar electrokinetic chromatography (MEKC) was successfully and conveniently applied to the chiral separation with the addition of cyclodextrins (CDs) as chiral selector to the running buffer. Chiral separation depended on the type of CD; in particular, beta-CD was effective for the chiral separation of racemorphan. We investigated the optimal conditions of type and concentration of CD as chiral selector for the routine enantiomeric separation of racemorphan with good reproducibility. The effects of other parameters such as buffer pH and detection wavelength were also investigated to obtain the optimum conditions for the enantiomeric separation of racemorphan. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for confirmation of racemorphan. The optimal conditions for enantiomeric separation of the racemorphan were as follows: 50 mM borate buffer at pH 9.4 with 50 mM SDS, 10 mM beta-CD and 20% 1-propanol, 57 cm x 50 microns fused-silica capillary column, and UV detection at 192 nm. Based on the developed method, racemorphan in human urine was also separated and determined using solid-phase extraction and MEKC.