Quantitative digital pathology enables automated and quantitative assessment of inflammatory activity in patients with autoimmune hepatitis.

Background: Chronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component. Methods: Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC). Results: ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation. Conclusion: Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity.

Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Quantitative MR in Paediatric Patients with Wilson Disease: A Case Series Review.

Wilson disease (WD) is a liver disorder characterized by improper copper metabolism. Although non-invasive tools are currently used to support diagnosis and management, this is still an area of unmet need, as patients present with a wide range of symptoms. Our aim was to investigate the potential utility of multiparametric magnetic resonance imaging (mpMRI) and quantitative magnetic resonance cholangiopancreatography (MRCP+) to support patient management. MRI examinations of 7 children and young adults aged 8-16 years (six at diagnosis) were performed alongside a standard of care clinical and histological examination. Images were quantitatively analyzed to derive metrics of liver (corrected T1 (cT1; fibro-inflammation), MR liver fat (proton density fat fraction; PDFF)), and biliary health (MRCP+). MRI-PDFF provided a more dynamic characterization of fat compared with that provided by ultrasound. Those with elevated histological scores of fibrosis, inflammation, and steatosis had elevated mpMRI values. MRCP+ managed to identify dilatations in the biliary tree which were not observed during the standard of care examination. mpMRI and MRCP+ metrics show early promise as markers to assess both liver and biliary health in Wilson disease. Investigations to understand and explore the utility of these markers are warranted and should be performed.

Isolated systolic hypertension is associated with increased left ventricular mass index and aortic stiffness in adolescents: a cardiac magnetic resonance study.

OBJECTIVES: Despite the high prevalence of isolated systolic hypertension (ISH) among hypertensive adolescents, its clinical significance is not determined. In addition, it is hypothesized that ISH with normal central blood pressure (BP) in young patients is a benign phenomenon and was hence labeled spurious hypertension (sHTN). METHODS: Using cardiac magnetic resonance we evaluated a group of 73 patients with suspected primary hypertension, aged 13-17 years (median: 16.9, interquartile range 15.8-17.4; 13 girls), in whom, based on 24-h ambulatory BP monitoring either ISH (n = 30) or white-coat hypertension (WCH) (n = 43) was diagnosed. Based on noninvasive central BP measurement 13 participants in the ISH group were classified as having sHTN and 17 were diagnosed with true hypertension. RESULTS: Compared with WCH adolescents, ISH patients presented with higher indexed left ventricular mass index (LVMI) (P  < 0.001), maximal left ventricular (LV) wall thickness (P  < 0.001), LV concentricity (P  = 0.001) and more often had LV hypertrophy (47 vs. 14%, P  = 0.002). They had higher average pulse wave velocity (PWV) in the proximal aorta (P = 0.016) and the whole thoracic aorta (P = 0.008). In addition, we observed higher indexed LV stroke volume (P  = 0.025) in patients with ISH. The sHTN subgroup had significantly higher LVMI and aortic PWV, and more often had LV hypertrophy compared with the WCH group. The sHTN and true hypertension subgroups did not differ in terms of aortic PWV, LVMI or LV geometry. CONCLUSION: Compared with adolescents with WCH patients with ISH, including the sHTN subtype, have more pronounced markers of cardiac end-organ damage, higher aortic stiffness and stroke volume.

Segmenting pediatric optic pathway gliomas from MRI using deep learning.

Optic pathway gliomas are low-grade neoplastic lesions that account for approximately 3-5% of brain tumors in children. Assessing tumor burden from magnetic resonance imaging (MRI) plays a central role in its efficient management, yet it is a challenging and human-dependent task due to the difficult and error-prone process of manual segmentation of such lesions, as they can easily manifest different location and appearance characteristics. In this paper, we tackle this issue and propose a fully-automatic and reproducible deep learning algorithm built upon the recent advances in the field which is capable of detecting and segmenting optical pathway gliomas from MRI. The proposed training strategies help us elaborate well-generalizing deep models even in the case of limited ground-truth MRIs presenting example optic pathway gliomas. The rigorous experimental study, performed over two clinical datasets of 22 and 51 multi-modal MRIs acquired for 22 and 51 patients with optical pathway gliomas, and a public dataset of 494 pre-surgery low-/high-grade glioma patients (corresponding to 494 multi-modal MRIs), and involving quantitative, qualitative and statistical analysis revealed that the suggested technique can not only effectively delineate optic pathway gliomas, but can also be applied for detecting other brain tumors. The experiments indicate high agreement between automatically calculated and ground-truth volumetric measurements of the tumors and very fast operation of the proposed approach, both of which can increase the clinical utility of the suggested software tool. Finally, our deep architectures have been made open-sourced to ensure full reproducibility of the method over other MRI data.

Quantitative multiparametric MRI as a non-invasive stratification tool in children and adolescents with autoimmune liver disease.

Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC) are two very closely related autoimmune liver diseases with overlapping clinical features and similar management strategies. The purpose of this study was to assess the utility of quantitative imaging markers to distinguish ASC from AIH in paediatrics. 66 participants (N = 52 AIH, N = 14 ASC) aged 14.4 ± 3.3 years scheduled to undergo routine biopsy and baseline serum liver biochemistry testing were invited to undergo MRI (non-contrast abdominal MRI and 3D fast spin-echo MRCP). Multiparametric MRI was used to measure fibro-inflammation with corrected T1 (cT1), while the biliary tree was modelled   using quantitative MRCP (MRCP +). Mann-Whitney U tests were performed to compare liver function tests with imaging markers between patient groups (ASC vs AIH). Receiver operating characteristic curves and stepwise logistic regressions were used to identify the best combination of markers to discriminate between ASC and AIH. Correlations between liver function tests and imaging markers were performed using Spearman's rank correlation. cT1 was significantly correlated with liver function tests (range 0.33 ≤ R ≤ 56, p < 0.05), as well as with fibrosis, lobular and portal inflammation (range 0.31 ≤ R ≤ 42, p < 0.05). 19 MRCP + metrics correlated significantly with liver function tests (range 0.29 ≤ R ≤ 0.43, p < 0.05). GGT and MRCP + metrics were significantly higher in ASC compared to those with AIH. The best multivariable model for distinguishing ASC from AIH included total number of ducts and the sum of relative severity of both strictures and dilatations AUC: 0.91 (95% CI 0.78-1). Quantitative MRCP metrics are a good discriminator of ASC from AIH.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

Deficiency in Acyl-CoA:Wax Alcohol Acyltransferase 2 causes evaporative dry eye disease by abolishing biosynthesis of wax esters.

Lipids secreted by the meibomian glands (MGs) of the eyelids are essential to the protection of the eye's surface. An altered meibum composition represents the primary cause of evaporative dry eye disease (DED). Despite the critical importance of the meibum, its biosynthetic pathways and the roles of individual lipid components remain understudied. Here, we report that the genetic deletion of Acyl-CoA:wax alcohol acyltransferase 2 (AWAT2) causes the obstruction of MGs and symptoms of evaporative DED in mice. The lipid composition of the meibum isolated from Awat2-/- mice revealed the absence of wax esters, which was accompanied by a compensatory overproduction of cholesteryl esters. The resulting increased viscosity of meibum led to the dilation of the meibomian ducts, and the progressive degeneration of the MGs. Overall, we provide evidence for the main physiological role of AWAT2 and establish Awat2-/- mice as a model for DED syndrome that can be used in studies on tear film-oriented therapies.

Abnormal Cannabidiol Modulates Vitamin A Metabolism by Acting as a Competitive Inhibitor of CRBP1.

Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Here we identify abnormal cannabidiol (abn-CBD) as a nonretinoid inhibitor of cellular retinol-binding protein 1 (CRBP1). X-ray crystal structures of CRBP1 in complex with abn-CBD and its derivatives revealed a distinctive mode of protein-ligand interaction and provided a molecular basis for the high affinity and selectivity of this compound. We demonstrated that abn-CBD modulates the flux of retinoids via the retinoid cycle in vivo. Furthermore, the biological activity of abn-CBD was evidenced by its ability to protect against light-induced retinal damage in Balb/cJ mice. Altogether, our findings indicate that targeting selected CRBPs with a small-molecule inhibitor can potentially lead to the development of new therapeutic agents to counteract diseases with etiologies involving imbalance in retinoid metabolism or signaling.

Impact of LCA-Associated E14L LRAT Mutation on Protein Stability and Retinoid Homeostasis.

Vitamin A (all-trans-retinol) is metabolized to the visual chromophore (11-cis-retinal) in the eyes and to all-trans-retinoic acid, a hormone like compound, in most tissues. A key enzyme in retinoid metabolism is lecithin:retinol acyltransferase (LRAT), which catalyzes the esterification of vitamin A. The importance of LRAT is indicated by pathogenic missense and nonsense mutations, which cause devastating blinding diseases. Retinoid-based chromophore replacement therapy has been proposed as treatment for these types of blindness based on studies in LRAT null mice. Here, we analyzed the structural and biochemical basis for retinal pathology caused by mutations in the human LRAT gene. Most LRAT missense mutations associated with retinal degeneration are localized within the catalytic domain, whereas E14L substitution is localized in an N-terminal α-helix, which has been implicated in interaction with the phospholipid bilayer. To elucidate the biochemical consequences of this mutation, we determined LRAT(E14L)'s enzymatic properties, protein stability, and impact on ocular retinoid metabolism. Bicistronic expression of LRAT(E14L) and enhanced green fluorescence protein revealed instability and accelerated proteosomal degradation of this mutant isoform. Surprisingly, instability of LRAT(E14L) did not abrogate the production of the visual chromophore in a cell-based assay. Instead, expression of LRAT(E14L) led to a rapid increase in cellular levels of retinoic acid upon retinoid supplementation. Thus, our study unveils the potential role of retinoic acid in the pathology of a degenerative retinal disease with important implications for the use of retinoid-based therapeutics in affected patients.

Allosteric modulation of the substrate specificity of acyl-CoA wax alcohol acyltransferase 2.

The esterification of alcohols with fatty acids is a universal mechanism to form inert storage forms of sterols, di- and triacylglycerols, and retinoids. In ocular tissues, formation of retinyl esters is an essential step in the enzymatic regeneration of the visual chromophore (11-cis-retinal). Acyl-CoA wax alcohol acyltransferase 2 (AWAT2), also known as multifunctional O-acyltransferase (MFAT), is an integral membrane enzyme with a broad substrate specificity that has been shown to preferentially esterify 11-cis-retinol and thus contribute to formation of a readily available pool of cis retinoids in the eye. However, the mechanism by which this promiscuous enzyme can gain substrate specificity is unknown. Here, we provide evidence for an allosteric modulation of the enzymatic activity by 11-cis retinoids. This regulation is independent from cellular retinaldehyde-binding protein (CRALBP), the major cis-retinoid binding protein. This positive-feedback regulation leads to decreased esterification rates for 9-cis, 13-cis, or all-trans retinols and thus enables preferential synthesis of 11-cis-retinyl esters. Finally, electron microscopy analyses of the purified enzyme indicate that this allosteric effect does not result from formation of functional oligomers. Altogether, these data provide the experimental basis for understanding regulation of AWAT2 substrate specificity.

Molecular Basis for Vitamin A Uptake and Storage in Vertebrates.

The ability to store and distribute vitamin A inside the body is the main evolutionary adaptation that allows vertebrates to maintain retinoid functions during nutritional deficiencies and to acquire new metabolic pathways enabling light-independent production of 11-cis retinoids. These processes greatly depend on enzymes that esterify vitamin A as well as associated retinoid binding proteins. Although the significance of retinyl esters for vitamin A homeostasis is well established, until recently, the molecular basis for the retinol esterification enzymatic activity was unknown. In this review, we will look at retinoid absorption through the prism of current biochemical and structural studies on vitamin A esterifying enzymes. We describe molecular adaptations that enable retinoid storage and delineate mechanisms in which mutations found in selective proteins might influence vitamin A homeostasis in affected patients.

Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures.

Important in regulating the uptake, storage, and metabolism of retinoids, cellular retinol-binding protein 1 (CRBP1) is essential for trafficking vitamin A through the cytoplasm. However, the molecular details of ligand uptake and targeted release by CRBP1 remain unclear. Here we report the first structure of CRBP1 in a ligand-free form as well as ultra-high resolution structures of this protein bound to either all-trans-retinol or retinylamine, the latter a therapeutic retinoid that prevents light-induced retinal degeneration. Superpositioning of human apo- and holo-CRBP1 revealed major differences within segments surrounding the entrance to the retinoid-binding site. These included α-helix II and hairpin turns between ß-strands ßC-ßD and ßE-ßF as well as several side chains, such as Phe-57, Tyr-60, and Ile-77, that change their orientations to accommodate the ligand. Additionally, we mapped hydrogen bond networks inside the retinoid-binding cavity and demonstrated their significance for the ligand affinity. Analyses of the crystallographic B-factors indicated several regions with higher backbone mobility in the apoprotein that became more rigid upon retinoid binding. This conformational flexibility of human apo-CRBP1 facilitates interaction with the ligands, whereas the more rigid holoprotein structure protects the labile retinoid moiety during vitamin A transport. These findings suggest a mechanism of induced fit upon ligand binding by mammalian cellular retinol-binding proteins.

Evaluation of brain lesions in patients after coronary artery bypass grafting using MRI with the emphasis on susceptibility-weighted imaging.

INTRODUCTION: Patients undergoing coronary artery bypass grafting (CABG) are at risk of strokes and neurocognitive disorders. THE AIM OF THE STUDY: The aim of the study was to assess the clinical utility of susceptibility-weighted imaging (SWI) MRI in detection of new brain lesions in patients after CABG. We assessed the incidence and types of brain lesions and correlated the data with neurological examinations in groups of patients who underwent on-pump and off-pump CABG. MATERIAL AND METHODS: Patients underwent a neurological examination and MRI before, 6-20 days after and 6 months after the CABG. Fifty-one patients (43 men, mean age 63.12 years) were analyzed. RESULTS: Fifteen (29.4%) patients underwent on-pump CABG, 36 (70.6%) off-pump CABG. On postoperative scans new lesions were detected in 12 (23.5%) patients. Ischemic lesions (visible on diffusion-weighted imaging [DWI]) were detected in 4 patients, in 6 lesions were visible on SWI, in 1 case lesions were visible on SWI and DWI. Hemorrhagic stroke was observed in 1 patient. In the group of patients who underwent on-pump CABG, new brain lesions were observed in 60.0% of patients vs. 8.3% of those who underwent off-pump CABG (p < 0.0001); these changes more frequently were multiple (p < 0.0013) and located infratentorially (p < 0.0218). Lesions visible on SWI were observed only in patients undergoing on-pump CABG (p = 0.00005). In all patients (except for 1 with stroke), lesions visible in MRI were clinically silent. CONCLUSIONS: The use of SWI enables one to detect lesions occurring in the brain after CABG, invisible in other sequences. On-pump CABG is associated with a greater risk of clinically silent brain damage compared to off-pump CABG.

CD34+ progenitor cells in pulmonary sarcoidosis.

UNLABELLED: Sarcoidosis is a disease of unclear etiology, immunopathogenesis complex and diverse clinical course. AIM: The aim of study was to evaluate the usefulness of CD34+ cells, CD4 and CD8 lymphocytes in peripheral blood for the diagnosis and better understanding of the sarcoidosis pathogenesis. MATERIALS AND METHODS: The study included 40 patients (16 women and 24 men) aged 29-71 years (mean 45 years) with newly diagnosed pulmonary sarcoidosis. The control group consisted of 30 healthy subjects (18 women and 12 men) aged 24-65 years (mean 47 years). Tests were performed in peripheral blood, and lymphocytes CD4 and CD8 and progenitor CD34+ cells surface antigens were determined by flow cytometry. RESULTS: It has been shown that number of CD34+ progenitor cells in peripheral blood was significantly higher in patients with newly diagnosed pulmonary sarcoidosis and showed a positive correlation with CD4/ CD8 rate. CONCLUSIONS: CD34+ progenitor cells may be important in the pathogenesis of sarcoidosis. It is necessary to conduct further studies that identify heterogenous population of CD34+ cells with particular focus on fibrocytes.

IGRA as a predictive factor of silent pulmonary changes in individuals following exposure to tuberculosis.

OBJECTIVES: We conducted a study on usefulness of the tuberculin skin test (TST) and the Quantiferon-TB Gold IT (QFT) tests as predictors of radiological changes after contact with tuberculosis. MATERIALS AND METHODS: The study group consisted of TB-exposed HCWs working in the Military Institute of Medicine (Warsaw, Poland). The usefulness of TST, QFT, and a combination of both tests was assessed for prediction of silent radiological findings. RESULTS: 83 previously TB-exposed participants were recruited. None of the participants had a history of active tuberculosis. Positive TST results were reported in 72 (86.8 %) participants, and positive QFTs were observed in 27 (32.5 %) cases. Chest radiographs revealed 23 findings specific for non-active tuberculosis in 18 (21.7 %) participants. The results of the QFTs were associated with the highest negative predictive value, positive predictive value, and positive likelihood ratio of silent chest X-ray findings suggestive of latent tuberculosis infection. Positive QFT was the only statistically significant variable that increases the odds ratio (OR-8.3) of the presence of typical of tuberculosis radiological changes in the lung. CONCLUSION: A positive QFT result in an individual with no TB history who was exposed to tuberculosis in the past is associated with a significantly higher risk of clinically silent parenchymal lesions in lungs suggestive of previous tuberculosis.

[The role of fibrocytes in pulmonary fibrosis]. / Rola fibrocytów w procesach wlóknienia pluc.

Fibrocytes are bone-marrow derived mesenchymal progenitor cells. They express typical markers of leukocytes, hematopoietic stem cells and fibroblasts. They play a pivotal role in the tissue remodeling and fibrosis in both physiologic and pathologic settings. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. Circulating fibrocytes may play a role in pulmonary fibrosis and clinical outcomes. Recent data obtained from the clinical setting suggest that high numbers of circulating fibrocytes correlate with pulmonary function test parameters and disease activity in patients with different interstitial lung diseases. A greater understanding of the immunologic mediator that influence fibrocyte biology suggest new opportunities for therapeutic manipulation of these cells in fibrogenesis.

MR venography in children and adolescents with multiple sclerosis does not show increased prevalence of extracranial veins anomalies.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects mainly young adults, but can occur also in children and adolescents. The pathogenesis of MS is still not fully understood and chronic cerebrospinal venous insufficiency (CCSVI) was suggested to be implicated in MS. Although there is no strong evidence to support this hypothesis, a considerable number of MS patients, including adolescents, have undergone endovascular treatment procedures. The aim of this study was the evaluate the prevalence of extracranial venous system anomalies in children and adolescents with multiple sclerosis in comparison to age-matched controls. MATERIAL AND METHODS: Twenty-one children with clinically definite diagnosis of MS (mean age 13.8 years), and 19 age-matched controls (mean age 12.5 years) were investigated using 1.5 T scanner with coronal 3D contrast-enhanced coronal venography. The diameters of internal jugular veins (IJV) at both sides of the neck were estimated separately, from the level C1 to Th1. RESULTS: Anomalies of the extracranial venous system were found in 10 MS patients (47.6%) and 13 controls (68.4%). Normal anatomy of extracranial veins was recognized in 11 MS patients (53%) and 6 controls (31%). Comparison of the measurement results for MS patients and the control group revealed that there are no significant statistical differences in cross-section areas for a given level. CONCLUSIONS: We found no evidence to suggest that MS children and adolescents have more extracranial veins anomalies than healthy patients. Considering the risk of such treatment, endovascular interventions should be discourage.

Tuberculin skin test and interferon-γ release assay in the detection of latent tuberculosis infection among Polish health care workers.

INTRODUCTION:  For many years, Poland has had a mandatory vaccination program against tuberculosis, which recommended repeated vaccinations from birth to adulthood. Therefore, the clinical value of the tuberculin skin test (TST) in diagnosing latent tuberculosis infection (LTBI) in Poland remains unclear. OBJECTIVES:  We conducted a study on the usefulness of the TST and QuantiFERON®-TB test (QFT) for the evaluation of the prevalence and risk factors of L TBI among Polish health care workers. PATIENTS AND METHODS:  The study group consisted of the Polish health care workers. TST and QFT were performed in each participant. The usefulness of TST and QFT was tested in relation to occupational risk factors. RESULTS:  A total of 305 participants were included. A positive TST result was observed in 149 cases (48.9%) and a positive QFT result was observed only in 27 cases (8.9%). In the subgroup that declared contact with tuberculosis (n = 44), positive QFT and TST results were found in 20.5% and 63.3% cases, respectively. Past contact with tuberculosis was the only significant variable associated with a positive TST result. Independent variables associated with positive QFT results were older age, lower education level, longer period of work in health care, and previous contact with tuberculosis. CONCLUSIONS:  The QFT has a higher diagnostic value than the TST in the assessment of LTBI in Polish health care workers.

"Drop attacks" as first clinical symptoms in a child carrying MTTK m.8344A>G mutation.

UNLABELLED: We describe a child with dyslexia and difficulty in school who, at the age of 13 years, began to suffer from several head injuries resulting from falls of uncertain cause. Two years later, the patient developed symptoms of a severe mitochondrial disorder (involving bulbar-pyramidal paralysis, ophthalmoplegia, and hyperlactatemia) that coincided with VPA administration. Brain MR imaging revealed rapidly developing Leigh syndrome (LS), and muscle biopsy showed ragged blue fibres (RBF). A diminished expression of the E1α subunit of pyruvate dehydrogenase was found in muscle homogenate (signal 28.7% of normal). The accurate diagnosis of mitochondrially inherited LS (MILS) and the identification of an almost homoplasmic m.8344G>A mutation in the MTTK gene was delayed due to an initial incorrect diagnosis of epilepsy, misdiagnosis of neuroinfection, and failure to note LS on the first brain MRI. Periods of exacerbation or improvement were observed in association with the administration of certain drugs or procedures (VPA administration or intensive rehabilitation associated with worsening; ketogenic diet associated with remission). However, the random association of these factors with natural disease fluctuations cannot be excluded. CONCLUSIONS: 1) To improve the early detection of mitochondrial disorder, we recommend screening for mtDNA (and nDNA) mutations in all patients with LS present on brain MRI. 2) Brain MRI protocols should include diffusion-weighted and T2-weighted imaging, and LS-like changes should be analysed by a neuroradiologist experienced in the field. 3) Additional controlled studies are urgently needed to assess the causal relationship between management strategies and the natural history of the disease. Until the association between VPA and disease exacerbation can be ruled out, VPA should be avoided in patients with these symptoms unless the mitochondrial disorder has been excluded.