Artificial intelligence for detection of intracranial haemorrhage on head computed tomography scans: diagnostic accuracy in Hong Kong.

INTRODUCTION: The use of artificial intelligence (AI) to identify acute intracranial haemorrhage (ICH) on computed tomography (CT) scans may facilitate initial imaging interpretation in the accident and emergency department. However, AI model construction requires a large amount of annotated data for training, and validation with real-world data has been limited. We developed an algorithm using an open-access dataset of CT slices, then assessed its utility in clinical practice by validating its performance on CT scans from our institution. METHODS: Using a publicly available international dataset of >750 000 expert-labelled CT slices, we developed an AI model which determines ICH probability for each CT scan and nominates five potential ICH-positive CT slices for review. We validated the model using retrospective data from 1372 non-contrast head CT scans (84 [6.1%] with ICH) collected at our institution. RESULTS: The model achieved an area under the curve of 0.842 (95% confidence interval=0.791-0.894; P<0.001) for scan-based detection of ICH. A pre-specified probability threshold of ≥50% for the presence of ICH yielded 78.6% accuracy, 73% sensitivity, 79% specificity, 18.6% positive predictive value, and 97.8% negative predictive value. There were 62 true-positive scans and 22 false-negative scans, which could be reduced to six false-negative scans by manual review of model-nominated CT slices. CONCLUSION: Our model exhibited good accuracy in the CT scan-based detection of ICH, considering the low prevalence of ICH in Hong Kong. Model refinement to allow direct localisation of ICH will facilitate the use of AI solutions in clinical practice.

HbA1c values and hospital admissions in children and adolescents receiving continuous subcutaneous insulin infusion therapy.

AIMS: To assess HbA1c values and hospitalization rates before, during and after continuous subcutaneous insulin infusion (CSII) therapy. METHODS: Demographic and hospitalization data were extracted from 161 individuals with Type 1 diabetes who received continuous subcutaneous insulin infusion (CSII) therapy between 2002 and 2013 at the Leeds Children and Young People's Diabetes Service for those aged < 20 years. The median (range) age at CSII start was 11.9 (1.1-17.6) years. The median (range) follow-up time was 2.3 (0-8.1) years. Random intercept models were used to compare HbA1c values before and during CSII initiation (and after CSII for those who discontinued it). Hospitalization rates were calculated for diabetic ketoacidosis and severe hypoglycaemia. RESULTS: The mean HbA1c concentration decreased by 7 mmol/mol [95% CI 6-8; 0.6% (95% CI 0.5-0.7%)]. For the discontinued group (n=30), mean HbA1c decreased by 5 mmol/mol [95% CI 2-8; 0.4% (95% CI 0.2-0.7%)]. HbA1c returned to pre-CSII start levels at the end of this therapy. Diabetic ketoacidosis admissions increased threefold during CSII compared with before CSII start [2.2 per 100 person-years (95% CI 1.3 to 3.6) vs 7.4 per 100 person-years (95% CI 5.1 to 10.8)] and was highest during the first year of CSII. No difference in severe hypoglycaemia incidence rate was found during CSII compared with the pre-CSII period. CONCLUSIONS: Despite significant reductions in HbA1c levels for individuals treated with CSII, improvements are needed to reduce diabetic ketoacidosis hospitalizations for those new to the therapy.

Mortality and acute complications in children and young adults diagnosed with Type 1 diabetes in Yorkshire, UK: a cohort study.

AIMS: To examine all-cause and cause-specific mortality in a population-based cohort of people with early and late onset of Type 1 diabetes. METHODS: The Yorkshire Register of Diabetes in Children and Young People includes individuals with early (0-14 years) and late (15-29 years) Type 1 diabetes onset, diagnosed between 1978 and 2013. This register was linked to death certification data from the Office for National Statistics to calculate standardized mortality ratios, cumulative mortality curves using Kaplan-Meier survival estimates, and Cox regression modelling. Ethnicity was derived using Onomap. Deprivation status was classified using the Townsend index. The underlying cause of death in each case was clinically verified. RESULTS: There were 229 deaths in 5498 individuals with 100 959 person-years of follow-up. The overall standardized mortality ratio was 4.3 (95% CI 3.8 to 4.9). There were no significant differences in standardized mortality ratios according to age of onset, sex or deprivation status. The standardized mortality ratios were significantly higher for people of white ethnic origin [8.1 (95% CI 6.9 to 9.4)] than for those of South-Asian ethnic origin [3.4 (95% CI 1.7 to 6.4)]. The mortality risk was lower in those diagnosed in later years (2002 to 2013 for the early-onset and 2006 to 2013 for the late-onset group) compared with earlier years (1991 to 1997 for the early-onset and 1991 to 1997 for the late-onset group) for both onset groups [hazard ratio 0.13 (95% CI 0.05 to 0.33) vs 0.24 (95% CI 0.07 to 0.81)]. Mortality risk improved over time for chronic complications in the early-onset group only, but there was no improvement in either onset group with regard to acute complications. CONCLUSIONS: An excess of deaths in the population with Type 1 diabetes remains. Although the all-cause mortality risk has fallen over time, no improvement has been found in the mortality risk associated with acute complications.

An uncommon cause of recurrent falls in an elderly man.

Falls are common among the elderly population. Examinations for the cause of falls are usually mundane, but may be challenging, leading to surprising diagnoses. We report on a previously healthy elderly man who presented with repeated falls and rapidly progressive limitations in mobility, in addition to a stutter. Neuroimaging was particularly helpful for making the diagnosis in this patient.

Evaluation of testing capabilities for the determination of melamine in milk through an interlaboratory proficiency test programme during the melamine crisis.

An interlaboratory proficiency testing programme for melamine in milk was organized for field laboratories in Hong Kong, China, during the melamine crisis in late September 2008. One blank test sample and three homogenous samples prepared by gravimetric spiking of melamine at the concentration range of zero to 4.5 mg kg(-1) were given to participants in this programme. A total of 13 participants returned the results to the organizer and they used either liquid chromatography-tandem mass spectrometry (LC-MS/MS) or gas chromatography-mass spectrometry (GC-MS) for their determinations. The performance of the participants was assessed by determining z-scores, calculated from the bias from the assigned reference values and Horwitz standard deviation. The median values of pooled data were found to be in good agreement with the reference values and the majority of the participants demonstrated their capabilities in the quantitative measurement of melamine in milk samples. However, four participants gave false-positive results for the blank test sample, probably due to cross-contamination from other samples, and they were requested to investigate the actual causes. In summary, eight participants (or 62%) demonstrated their competence for all the four test samples.

Performance assessment for determining malachite green and leucomalachite green in swamp eel (Monopterus albus) muscle using assigned reference values in a proficiency test.

This paper presents the results of a proficiency test (APLAC T058) for malachite green (MG) and leucomalachite green (LMG) in swamp eel (Monopterus albus). The programme was organized by the Hong Kong Government Laboratory and Hong Kong Accreditation Service (HKAS), under the auspices of the Asia-Pacific Laboratory Accreditation Co-operation (APLAC) in 2007. Results submitted by participants were compared with the assigned reference values, which were determined by an accurate liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) technique, and their performance was evaluated on the basis of z-score index. The distribution of data was very wide and discrepancy from the assigned reference values was found to be method dependent. Only 48% and 62% of participants achieved satisfactory z-scores (i.e. |z|

Repeated intestinal perforation caused by an incomplete form of Behçet's syndrome.

Behçet's disease, as initially described, is a triad of recurrent oral and genital ulcers and relapsing uveitis. The incomplete form, in which there is no ocular involvement, has been described in Japan and Korea, but this is not commonly recognized in the southern Chinese. We reported herein a rare case of repeated intestinal perforations caused by an incomplete form of Behçet's syndrome in a southern Chinese man.

Induction of apoptosis by green tea catechins in human prostate cancer DU145 cells.

Green tea catechins (GTCs) including (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and (-)-epicatechin (EC) were shown to suppress cell growth and induce apoptosis in various cell systems in addition to their chemo-preventive effect. In this study, except EC which was inactive, green tea extract (TE) and other 3 GTCs were found to suppress the growth and induce apoptosis in human prostate cancer DU145 cells largely through an increase in reactive oxygen species formation and mitochondrial depolarization. The conclusion was supported by the fact that the profiles for different GTCs in growth suppression, apoptosis induction, ROS formation and mitochondrial depolarization are in a similar order, i.e. ECG > EGCG > EGC > EC. Although the molecular mechanisms are still not clear, apoptosis induced by GTCs is not related to the members of BCL-2 family as EGCG did not alter the expression of BCL-2, BCL-X(L) and BAD in DU145 cells.

Discrete signaling regions in the lymphotoxin-beta receptor for tumor necrosis factor receptor-associated factor binding, subcellular localization, and activation of cell death and NF-kappaB pathways.

Lymphotoxin-beta receptor (LTbetaR), a member of the tumor necrosis factor receptor superfamily, is essential for the development and organization of secondary lymphoid tissue. Wild type and mutant LTbetaR containing successive truncations of the cytoplasmic domain were investigated by retrovirus-mediated gene transfer into HT29.14s and in 293T cells by transfection. Wild type receptors accumulated in perinuclear compartments and enhanced responsiveness to ligand-induced cell death and ligand-independent activation of NFkappaB p50 dimers. Coimmunoprecipitation and confocal microscopy mapped the TRAF3 binding site to amino acids PEEGDPG at position 389. However, LTbetaR truncated at position Pro(379) acted as a dominant positive mutant that down-modulated surface expression and recruited TRAF3 to endogenous LTbetaR. This mutant exhibited ligand-independent cell death and activated NF-kappaB p50 dimers. By contrast, truncation at Gly(359) created a dominant-negative mutant that inhibited ligand-induced cell death and activation of NF-kappaB p50/p65 heterodimers. This mutant also blocked accumulation of wild type receptor into perinuclear compartments, suggesting subcellular localization may be crucial for signal transduction. A cryptic TRAF-independent NF-kappaB activating region was identified. These mutants define discrete subregions of a novel proline-rich domain that is required for subcellular localization and signal transduction by the LTbetaR.

Luminescent mononuclear and binuclear cyclometalated palladium(II) complexes of 6-phenyl-2,2 bipyridines: spectroscopic and structural comparisons with platinum(II) analogues.

The mononuclear cyclometalated Pd(II) complexes [Pd(L1)X] (HL1 = 6-phenyl-2,2'-bipyridine; X = Cl, la; Br, 1b; I, 1c), [Pd(L1)PPh3]+ (1d), [Pd(L2-5)Cl] [2a-5a, HL2-5 = 4-(aryl)-6-phenyl-2,2'-bipyridine; aryl = phenyl (2), 4-chlorophenyl (3), 4-tolyl (4), 4-methoxyphenyl (5)] and the binuclear derivatives [Pd2(L1-5)2(mu-dppm)]2+ (1e-5e, dppm = bis(diphenylphosphino)methane) and [Pd2(L1)2(mu-dppCs)]2+, (1f, dppC5 = 1,5-bis(diphenylphosphino)pentane) were prepared. The crystal structures of 1d(ClO4), 1e(ClO4)2 x DMF, and 2e(ClO4)2 have been determined by X-ray crystallography. The magnitude of the Pd-Pd distances in le and 2e (3.230(1) and 3.320(2) A, respectively) suggest minimal metal-metal interaction, although pi-stacking of the aromatic ligands (interplanar separations 3.34 and 3.35 A, respectively) is evident. All complexes display low-energy UV absorptions at lambda approximately 390 nm, which are tentatively assigned to 1MLCT transitions; red shifts resulting from Pd-Pd interactions in the binuclear species are not apparent. The complexes in this work are non-emissive at 298 K, but the cationic derivatives exhibit intense luminescence at 77 K. The structured emissions of 1d and 1f in MeOH/EtOH glass (lambdamax 467-586 nm) and all cationic species in the solid state (lambdamax 493-578 nm) are assigned to intraligand excited states. Complexes le-5e display dual emissions in MeOH/EtOH glass at 77 K, and the broad structureless bands at lambdamax 626-658 nm are attributed to pi-pi excimeric IL transitions. A comparison between the photophysical properties of Pd(II) and Pt(II) congeners is presented.

Cytomegalovirus colitis in individuals without apparent cause of immunodeficiency.

Cytomegalovirus infection is usually reported in immunocompromised patients. In this study, apparently immunocompetent patients with cytomegaloviral colitis were reviewed. Records with a diagnosis of cytomegaloviral colitis from January 1989 to June 1996 were retrieved for analysis. Ten patients were included (median age 70 yr). The major presenting symptoms were diarrhea and hematochezia. Ulceration was the main macroscopic finding. Rectal bleeding was mostly self-limiting. Three patients developed local complications (rectovaginal fistula in two; rectal stricture in one). In the two patients with rectovaginal fistula, lymphocytes subsets and proliferative response were entirely normal. In the other patient, low B lymphocyte count and low response to mitogen were demonstrated. However, the immunoglobulins were not suppressed and rectal biopsies revealed noncaseating granulomas, suggesting activated cell-mediated immunity. In conclusion, a high index of suspicion is crucial for early diagnosis of cytomegaloviral colitis in patients with bloody diarrhea, even though obvious evidence of immunodeficiency is lacking.

LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator.

Herpes simplex virus (HSV) 1 and 2 infect activated T lymphocytes by attachment of the HSV envelope glycoprotein D (gD) to the cellular herpesvirus entry mediator (HVEM), an orphan member of the tumor necrosis factor receptor superfamily. Here, we demonstrate that HVEM binds two cellular ligands, secreted lymphotoxin alpha (LTalpha) and LIGHT, a new member of the TNF superfamily. LIGHT is a 29 kDa type II transmembrane protein produced by activated T cells that also engages the receptor for the LTalphabeta heterotrimer but does not form complexes with either LTalpha or LTbeta. HSV1 gD inhibits the interaction of HVEM with LIGHT, and LIGHT and gD interfere with HVEM-dependent cell entry by HSV1. This characterizes herpesvirus gD as a membrane-bound viokine and establishes LIGHT-HVEM as integral components of the lymphotoxin cytokine-receptor system.

The lymphotoxin-alpha (LTalpha) subunit is essential for the assembly, but not for the receptor specificity, of the membrane-anchored LTalpha1beta2 heterotrimeric ligand.

The lymphotoxins (LT) alpha and beta, members of the tumor necrosis factor (TNF) cytokine superfamily, are implicated as important regulators and developmental factors for the immune system. LTalpha is secreted as a homotrimer and signals through two TNF receptors of 55-60 kDa (TNFR60) or 75-80 kDa (TNFR80). LTalpha also assembles with LTbeta into a membrane-anchored, heterotrimeric LTalpha1beta2 complex that engages a distinct cognate receptor, the LTbeta receptor (LTbetaR). To investigate the role of the LTalpha subunit in the function of the membrane LTalpha1beta2 complex, gene transfer via baculovirus was used to assemble LTalpha and -beta complexes in insect cells. LTalpha containing mutations at D50N or Y108F are secreted as homotrimers that fail to bind either TNF receptor and are functionally inactive in triggering cell death of the HT29 adenocarcinoma cell line. In contrast, these mutant LTalpha proteins retain the ability to co-assemble with LTbeta into membrane-anchored LTalpha1beta2 complexes that engage the LTbetaR and trigger the death of HT29 cells. Membrane-anchored LTbeta expressed on the cell surface in absence of the LTalpha subunit binds the LTbetaR but is functionally inactive in the cell death assay. These results indicate that the TNF receptor-binding regions of the LTalpha subunit are not necessary for engagement of the LTbetaR, but the LTalpha subunit is required for the assembly of LTbeta into a functional heteromeric ligand.

Occult gastric cancer presenting as cor pulmonale resulting from tumor cell microembolism.

Cor pulmonale resulting from tumor emboli is a rare presentation of gastric cancer, and only six similar cases have been reported in the English literature. We report the case of a 37-yr-old woman presenting with dyspnea who died of cor pulmonale. Autopsy revealed signet cell carcinoma of te stomach with intra-abdominal metastasis and right ventricular hypertrophy. There were no macroscopic pulmonary emboli or parenchymal lesions, but more than 60% of the small pulmonary arteries and arterioles were occluded. In most vessels, fibrocellular intimal proliferation was the major finding with only a few entrapped tumor cells.

Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-beta receptor.

Ligation of the lymphotoxin-beta receptor (LTbetaR) recruits tumor necrosis factor receptor-associated factor-3 (TRAF3) and initiates cell death in HT29 adenocarcinoma cells. The minimal receptor binding domain (TRAF-C) defined by two hybrid analyses is not sufficient for direct recruitment to the ligated receptor. A series of TRAF3 deletion mutants reveal that a subregion of the coiled coil motif is required for efficient recruitment to the LTbetaR. Furthermore, the ability of TRAF3 to self-associate maps to an adjacent subregion. A TRAF3 deletion mutant that lacks the N-terminal zinc RING and zinc finger motifs, but retains the coiled coil and TRAF-C motifs, competitively displaces endogenous TRAF3 from the LTbetaR. A second TRAF3 mutant that lacks the receptor binding domain, yet contains the TRAF3 self-association domain, prevents TRAF3 homodimers from being recruited to the LTbetaR. Both of these mutants have a dominant negative effect on cell death and demonstrate that the recruitment of TRAF3 oligomers is necessary to initiate signal transduction that activates the cell death pathway.

Transcriptional regulation of the human chromogranin A gene by its 5' distal regulatory element: novel effects of orientation, structure, flanking sequences, and position on expression.

In previous studies of human chromogranin A (hCgA) gene expression, we had identified a 27 bp distal regulatory element (DRE) located between -576 and -550 bp that interacts with a CRE-containing promoter to enhance gene transcription specifically in neuroendocrine (NE) cells. To characterize the DRE we have now mutated its various parts and assessed the effects on protein binding by electrophoretic mobility shift assays (EMSAs) and hCgA transcription within BEN cells. We found that the sequence TGACTAA, an AP-1 binding site that we refer to as DRE-AP-1, was necessary but not sufficient to produce the DRE's enhancer effect. Moreover, while AP-1 (Jun/Fos) bound this site, binding was not correlated with transcriptional effects. Protein binding by the DRE-AP-1 could be attenuated by mutations of its flanking sequences, and transcriptional enhancement by the DRE was dependent on its orientation and spatial relationship to the hCgA proximal promoter. Mutation of the DRE-AP-1 to a consensus AP-1 did not produce greater transcriptional activity, even though it increased binding of nuclear factors. Co-transfection with c-jun and/or c-fos expression plasmids showed that the DRE was unresponsive to the over-expressed AP-1 proteins. Co-transfection with wild-type DRE oligonucleotides competitively inhibited DRE-mediated transcription, while co-transfection with mutant DRE oligonucleotides had a lesser effect. Our studies indicate that transcriptional enhancement of hCgA by the DRE is dependent on a unique NE-specific DRE-binding factor, which we refer to as DBF, that specifically and directionally binds the DRE to assemble and synergize a functional transcription complex.

Parathyroid hormone-related protein, an autocrine regulatory factor in alveolar epithelial cells.

Alveolar epithelial cells in vivo, primary cultures of adult rat type II cells, and human A549 alveolar carcinoma cells express parathyroid hormone-related protein (PTHrP). Here we demonstrated that type II cells and A549 cells also express the PTHrP receptor and that they exhibit differentiation-related responses to the amino-terminal PTHrP fragment, PTHrP-(1-34). PTHrP receptor expression in A549 cells was shown by detection of a 0.3-kb reverse transcriptase polymerase chain reaction product formed by primers specific for PTHrP receptor. In situ hybridization studies localized the site of production of PTHrP and PTHrP receptor mRNA in rat lung cells with morphology and location typical of type II cells. Primary cultures of such type II cells also expressed PTHrP receptor mRNA. Incubation with PTHrP-(1-34) stimulated disaturated phosphatidylcholine (DSPC) synthesis in A549 cells and increased the release of newly synthesized DSPC by cultured type II cells and A549 cells. In addition, PTHrP-(1-34) increased the number of lamellar bodies per type II cell and increased their expression of alkaline phosphatase in a dose-dependent manner. Thus PTHrP-(1-34) promoted a differentiated type II cell phenotype. Since cultured type II cells, alveolar epithelial cells in vivo, and A549 cells express PTHrP and the PTHrP receptor, PTHrP-(1-34) may be an autocrine regulatory factor in type II cells and lung cancer cells.

Identification of a SPH element in the distal region of a human U6 small nuclear RNA gene promoter and characterization of the SPH binding factor in HeLa cell extracts.

Vertebrate small nuclear RNA (snRNA) gene promoters contain a distal, enhancer-like region that is composed of an octamer motif adjacent to at least one other element. Here we show that a human U6 snRNA distal region contains a SPH motif previously found in several chicken snRNA gene enhancers and the 5'-flanking region of vertebrate selenocysteine tRNA genes. SPH binding factor (SBF) was detected in either chicken or HeLa cell extracts that could bind SPH elements in a species-independent manner. Both human and chicken SBF required divalent cation to bind effectively to DNA. DNase I footprinting experiments indicated that human SBF specifically protected the human U6 SPH element. Furthermore, a SBF polypeptide of approximately 85 kDa was detected in both HeLa and chicken extracts following ultraviolet light-mediated cross-linking to human U6 or chicken U4 SPH elements. A part of the human U6 SPH element was quite sensitive to mutation, as demonstrated by both specific protein binding and transcription assays. From these data it is apparent that the distal regions of some RNA polymerase III- and RNA polymerase II-transcribed small RNA promoters are virtually identical in composition, and their mechanisms of transcriptional activation are possibly quite similar.

Identification and characterization of a neuroendocrine-specific 5'-regulatory region of the human chromogranin A gene.

Chromogranin A (CgA) expression is specific to cells of endocrine and neuroendocrine (NE) tissues. Our transfection studies with CgA have identified two DNA regions 5' of the transcription start site that regulate CgA gene transcription: a distal regulatory region (DRR) located between -726 and -455, and a proximal regulatory region (PRR) between -60 and -26. In studies of the DRR using four human NE and six human non-NE cell lines, we demonstrated enhanced transcription of DRR-containing CgA-GH plasmids by the NE cells as a group compared to the non-NE cells. DNase I footprinting identified a protected area in the DRR from -570 to -555 base pairs (bp) composed of the sequence TAATGATGACTAAACA. Centered in this sequence is the simian virus 40 version of the activator protein-1-binding site, TGACTAA. Electrophoretic mobility shift assays (EMSAs) with an oligonucleotide containing the 27 bp of the DRR between -576 and -550, which we refer to as the distal regulatory element (DRE), produced a specific complex with the NE BEN and non-NE COS-1 cell nuclear extracts. The addition of c-Jun and c-Fos antibodies produced strong supershifts of the complex generated by COS-1 extract, but very weak supershifts of the complex formed by BEN extract. These EMSA studies suggest that NE cells such as BEN contain unique nuclear factors distinguishable from activator protein-1 that interact with the DRE. The enhancer effect of the 271-bp DRR could be replaced by the 27-bp DRE in both CgA and calcitonin promoter constructs in BEN cells. Replacement of the DRR with the DRE resulted in a further increase in expression from these plasmids, suggesting the presence of suppressor sequences in the DRR. In transfection studies of the PRR, deletion of its cAMP response element (CRE) dramatically lowered transcription. In addition to demonstrating that its CRE can bind CRE-binding protein, EMSAs with the PRR demonstrated that an intervening sequence between the CRE and the TATA box formed a complex with BEN cell nuclear extract. Our studies demonstrate that both the PRR and DRR are important for high level transcription of the CgA gene in NE cells. The presence of both distal and proximal 5'-regulatory regions in the human CgA gene indicates a complex mechanism of transcriptional regulation. Although the PRR is important for the formation of a functional transcription complex at the TATA region, the DRR is important for the enhancement of CgA gene expression in NE cells.

Late metabolic acidosis in low-birth-weight babies: report of four cases.

Four low-birth-weight babies, though fed an adequate amount of formula, failed to regain their birth weight within ten days. Blood gas studies revealed metabolic acidosis in all. Their body weight gain improved dramatically after adding sodium bicarbonate to the milk. Late metabolic acidosis was presented, even using special premature formula, in three of them.