Disseminated tuberculosis, CMV viraemia & haemophagocytic-lymphohistiocystosis syndrome in an adult patient with anti- IFNγ autoantibodies - case report and brief review.

We report a case of an adult female with disseminated tuberculosis, cytomegalovirus viraemia and haemophagocytic-lymphohistiocystosis syndrome associated with neutralizing anti- interferon gamma (IFNγ) autoantibodies demonstrated by absent IFNγ stimulated STAT1 phosphorylation in the presence of patient sera. A brief review of immunodeficiency caused by anti-IFNγ autoantibodies is also described.

Sarcopenia in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI): A Systematic Review of the Literature.

BACKGROUND: In older patients, sarcopenia is a prevalent disease associated with negative outcomes. Sarcopenia has been investigated in patients undergoing transcatheter aortic valve implantation (TAVI), but the criteria for diagnosis of the disease are heterogeneous. This systematic review of the current literature aims to evaluate the prevalence of sarcopenia in patients undergoing TAVI and to analyse the impact of sarcopenia on clinical outcomes. METHODS: A comprehensive search of the literature has been performed in electronic databases from the date of initiation until March 2020. Using a pre-defined search strategy, we identified studies assessing skeletal muscle mass, muscle quality and muscle function as measures for sarcopenia in patients undergoing TAVI. We evaluated how sarcopenia affects the outcomes mortality at ≥1 year, prolonged length of hospital stay, and functional decline. RESULTS: We identified 18 observational studies, enrolling a total number of 9'513 patients. For assessment of skeletal muscle mass, all included studies used data from computed tomography. Cut-off points for definition of low muscle mass were heterogeneous, and prevalence of sarcopenia varied between 21.0% and 70.2%. In uni- or multivariate regression analysis of different studies, low muscle mass was found to be a significant predictor of mortality, prolonged length of hospital stay, and functional decline. No interventional study was identified measuring the effect of nutritional or physiotherapy interventions on sarcopenia in TAVI patients. CONCLUSIONS: Sarcopenia is highly prevalent among patients undergoing TAVI, and negatively affects important outcomes. Early diagnosis of this condition might allow a timely start of nutritional and physiotherapy interventions to prevent negative outcomes in TAVI patients.

Barriers and enablers in the implementation of a standardised process for nutrition care: findings from a multinational survey of dietetic professionals in 10 countries.

BACKGROUND: To explore the barriers and enablers experienced by nutrition and dietetic professionals in the implementation of the standardised Nutrition Care Process (NCP) across 10 different countries. NCP related beliefs, motivations and values were investigated and compared. METHODS: A validated online survey was disseminated to nutrition and dietetics professionals in 10 countries in the local language during 2017. Cross-sectional associations and differences between countries were explored for level of implementation, barriers/enablers and attitudes/motivation among the respondents. RESULTS: Higher NCP implementation was associated with greater occurrence of enabling aspects, as well as fewer occurrences of barriers. The most common enabler was 'recommendation by the national dietetic association' (69%) and the most common barrier was 'lack of time' (39%). A longer experience of NCP use was associated with a more positive attitude towards all NCP aspects. Differences between countries were identified, regarding both the occurrence of barriers/enablers and attitudes/motivations. CONCLUSIONS: Implementation efforts need to be tailored to country-specific contexts when implementing a new standard of care framework among nutrition and dietetic professionals. Additional research is needed to further assess the management and workplace strategies to support the development of nutrition and dietetics professionals in multidisciplinary healthcare organisations.

The size, shape, density and ring of the dwarf planet Haumea from a stellar occultation.

Haumea-one of the four known trans-Neptunian dwarf planets-is a very elongated and rapidly rotating body. In contrast to other dwarf planets, its size, shape, albedo and density are not well constrained. The Centaur Chariklo was the first body other than a giant planet known to have a ring system, and the Centaur Chiron was later found to possess something similar to Chariklo's rings. Here we report observations from multiple Earth-based observatories of Haumea passing in front of a distant star (a multi-chord stellar occultation). Secondary events observed around the main body of Haumea are consistent with the presence of a ring with an opacity of 0.5, width of 70 kilometres and radius of about 2,287 kilometres. The ring is coplanar with both Haumea's equator and the orbit of its satellite Hi'iaka. The radius of the ring places it close to the 3:1 mean-motion resonance with Haumea's spin period-that is, Haumea rotates three times on its axis in the time that a ring particle completes one revolution. The occultation by the main body provides an instantaneous elliptical projected shape with axes of about 1,704 kilometres and 1,138 kilometres. Combined with rotational light curves, the occultation constrains the three-dimensional orientation of Haumea and its triaxial shape, which is inconsistent with a homogeneous body in hydrostatic equilibrium. Haumea's largest axis is at least 2,322 kilometres, larger than previously thought, implying an upper limit for its density of 1,885 kilograms per cubic metre and a geometric albedo of 0.51, both smaller than previous estimates. In addition, this estimate of the density of Haumea is closer to that of Pluto than are previous estimates, in line with expectations. No global nitrogen- or methane-dominated atmosphere was detected.

Effect of intravitreal ranibizumab in avascular pigment epithelial detachment.

PURPOSE: To evaluate long-term morphologic and functional changes after intravitreal ranibizumab in avascular pigment epithelial detachment (PED) secondary to age-related macular degeneration (AMD). PATIENTS AND METHODS: Interventional, prospective case series; the first group of six patients received three and the second group of six patients received six intravitreal injections of ranibizumab (0.5 mg) at monthly intervals. Outcome measures included the change of PED and retinal volume as determined by spectral domain optical coherence tomography (Cirrus), best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study), and macular sensitivity using microperimetry (MP-1; Nidek Co. Ltd). RESULTS: The mean baseline PED volume of 1.33 mm3 decreased significantly by 42% at month 6 (-0.55 mm3, P<0.05). Compared to baseline no significant change was observed at months 9 and 12. BCVA, retinal volume, and macular sensitivity remained stable during the entire follow-up. In one case a tear of the retinal pigment epithelium was observed after five injections with a consequent decrease of BCVA of four lines. CONCLUSION: Treatment with intravitreal injections of ranibizumab may temporarily decrease the volume of avascular PED secondary to AMD, however this effect was not maintained over the 1-year study period. The treatment was ineffective for improving retinal function as measured with BCVA and microperimetry.

Visual performance 3 years after successful macular hole surgery.

BACKGROUND/AIMS: To evaluate the visual performance of patients with successful macular hole surgery with a minimum follow-up of 3 years. Results were compared with the performance of the healthy fellow eyes. METHODS: 15 patients were studied. The healthy fellow eyes of the patients (13 eyes) served as a control group. Age, gender and best-corrected logMAR visual acuity were recorded. Reading acuity (in log reading acuity determination (RAD), reading equivalent of logMAR) and speed were tested monocularly. Scotoma size was measured with SLO perimetry, and hole closure was confirmed with an OCT scan. RESULTS: The mean distance visual acuity of the operated eyes (logMAR 0.32 (SD 0.21)) was significantly lower than that of the healthy fellow eyes (logMAR 0.05 (0.17)), but significantly higher than preoperatively (logMAR 0.71 (0.32)). The mean reading acuity was logRAD 0.47 (0.25) for the operated eyes ( = 77.9% of logMAR), and statistically significantly higher (logRAD 0.16 (0.16)) for the fellow eyes ( = 89.4% of logMAR). The mean maximum reading speeds were comparable for the operated eyes (168.3 (23.1) words per minute (wpm)) and the fellow eyes (178.7 (26.1) wpm) (p = 0.3). Within logRAD 1.3 and 0.5, the mean reading speeds of the two groups were comparable, but critical print size (CPS) for the operated group (logRAD 0.7 (0.2)) was significantly worse than those for the fellow eyes (logRAD 0.4 (0.2)). The SLO analysis showed absence of absolute scotoma in 12 eyes. CONCLUSION: Distance and reading acuity showed remaining deficits compared with the healthy fellow eyes; however, mean maximum reading speeds of the operated eyes achieved results comparable with healthy eyes. The results show a long-term benefit in the visual function of eyes with closed macular holes.

Combination of verteporfin photodynamic therapy and ranibizumab: effects on retinal anatomy, choroidal perfusion and visual function in the protect study.

OBJECTIVE: To evaluate verteporfin and same-day ranibizumab on retina, choroid, vasculature, choroidal neovascularisation (CNV) and visual function. METHODS: Eleven patients with occult or predominantly classic subfoveal CNV secondary to age-related macular degeneration received verteporfin and four monthly intravitreal ranibizumab injections. Eyes were examined using fluorescein angiography (FA) and indocyanine green angiography (ICGA), optical coherence tomography (OCT), visual acuity (VA) and microperimetry. RESULTS: Over 9 months, seven patients gained three to 24 letters and one had unchanged VA. Three patients lost eight to 24 letters due to recurrence and received another verteporfin treatment at month 6. Median retinal sensitivity of the central 4 degrees of the macula increased from 0.9 (SD 2.3) dB (baseline) to 5.2 (1.8) dB (only baseline verteporfin) and 4.1 (4.5) dB (second verteporfin treatment) at study end. OCT showed sub- and intraretinal leakage increased with verteporfin, but resolved after 2 weeks. After combination treatment, CNV was completely occluded on FA within 1 week. ICGA showed non-perfusion of small/medium choroidal vessels. Recovery of choroidal perfusion began after 1 month, but remained impaired throughout follow-up. CONCLUSION: Verteporfin/ranibizumab was associated with CNV occlusion, reduced oedema, improved visual function and retinal sensitivity. The clinical significance of these findings requires further investigation.

Fluorescence linked immunosorbant assays using microtiter plates.

Fluorescence methods are widely used in the detection of antibodies and other binding events. However, as a general screening and detection tool in microtiter plates, enzyme linked immunosorbant (ELISA) methods predominate. In this paper we explore all parameters for effective use of fluorescence as a plate based detection method, including which microtiter plates can be used, the most effective means of immobilization, and the use of different fluorescent dyes or fluorescent proteins. These studies indicate that fluorescent immunosorbant assays (FLISA) can be used as effectively as enzymatic method in microtiter plate based screening methods, including the screening of phage antibody selections.

Using T7 phage display to select GFP-based binders.

Filamentous phage do not display cytoplasmic proteins very effectively. As T7 is a cytoplasmic phage, released by cell lysis, it has been prospected as being more efficient for the display of such proteins. Here we investigate this proposition, using a family of GFP-based cytoplasmic proteins that are poorly expressed by traditional phage display. Using two single-molecule detection techniques, fluorescence correlation spectroscopy and anti-bunching, we show that the number of displayed fluorescent proteins ranges from one to three. The GFP derivatives displayed on T7 contain binding loops able to recognize specific targets. By mixing these in a large background of non-binders, these derivatives were used to optimize selection conditions. Using the optimal selection conditions determined in these experiments, we then demonstrated the selection of specific binders from a library of GFP clones containing heavy chain CDR3 antibody binding loops derived from normal donors inserted at a single site. The selected GFP-based binders were successfully used to detect binding without the use of secondary reagents in flow cytometry, fluorescence-linked immunosorbant assays and immunoblotting. These results demonstrate that specific GFP-based affinity reagents, selected from T7-based libraries, can be used in applications in which only the intrinsic fluorescence is used for detection.

No influence of SLC22A4 C6607T and RUNX1 G24658C genotypic variants on the circulating carnitine ester profile in patients with rheumatoid arthritis.

OBJECTIVE: In a Japanese study, the C6607T SNP mapping to intron 1 of the SLC22A4 gene encoding the OCTN1 protein was found to be associated with rheumatoid arthritis. Similarly, a G24658C transversion in intron 6 of the gene encoding the RUNX1 transcription factor that regulates OCTN1 and also likely OCTN2 expression was also found to confer susceptibility to the disease. METHODS: We investigated the prevalence of these two SNPs by RFLP analysis in a cohort of 209 Hungarian rheumatoid arthritis patients, and 217 healthy controls. Since both the OCTN1 and OCTN2 play a central role in the transmembrane transport of carnitine, we also determined the quantitative serum carnitine ester profile by ESI tandem mass spectrometry. RESULTS: No statistically significant differences were found comparing the genotype prevalence rates between the patients and the controls for either the SLC22A4 genotypes or for the RUNX1 SNPs. There was no significant difference in the serum carnitine ester profile when the rheumatoid arthritis patients were compared with the controls; furthermore, no significant difference in the carnitine esters could be detected when genotype specific subgroups of the patients and the controls were studied. CONCLUSION: Data of the current study do not confirm the universal and population independent susceptibility role of the SLC22A4 C6607T and RUNX1 G24658C variants for rheumatoid arthritis; furthermore, the data presented here show, that there are no significant carnitine-metabolism associated functional consequences of the different genotypes evidenced by the lack of detectable differences in the carnitine ester profiles.

Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy.

Polymorphisms of the ABCB1 (MDR1) and ABCG2 (BCRP) genes were reported to alter the expression and function of these drug transporters. Both proteins are present at the main pharmacokinetic barriers including the blood-brain barrier. Data from 291 children with acute lymphoblastic leukaemia were analysed in this retrospective study. ABCB1 3435T>C, 2677G>T/A, 1236C>T and ABCG2 421C>A, 34G>A genotypes were determined. Encephalopathy episodes were more frequent among those with ABCB1 3435TT genotype than in the 3435CC/CT group (odds ratio (OR) 3.5; P=0.03). Patients with the ABCG2 421A allele tended to have more complications than wild type homozygotes (OR=2.0; P=0.25). The rate of the adverse effect was similar in those harbouring no or only one of the predisposing genotypes, that is, either ABCB1 3435TT or ABCG2 421AA/AC. However, significantly more children suffered encephalopathy in the group with both predisposing genotypes (OR=12.3; P=0.005). In conclusion, these variations exert synergistic effect in predisposing patients to toxic neurological complications of chemotherapy.

Central visual field impairment during and following cystoid macular oedema.

AIM: To determine differential light threshold values obtained with the Micro Perimeter 1 (MP1) in uveitis patients suffering from cystoid macular oedema (CMO) and to compare these measures to retinal thickness. METHODS: Static threshold perimetry was performed with the MP1 Microperimeter in 27 eyes of 21 patients with a history of chronically recurring CMO. Active CMO was confirmed in 19 eyes. Eight eyes with a history of recurrent CMO were found to have normal foveal contours in optical coherence tomography (OCT). Differential light threshold values (MP1) were compared with the corresponding retinal thickness measures (OCT). RESULTS: Mean differential threshold values within the central two degrees of the stimulation pattern were reduced compared with normal values and ranged from 5.8 to 9.5 dB in CMO eyes and from 9.3 to 12.9 dB in eyes with a normal foveal contour but a history of previous CMO. The corresponding mean retinal thickness ranged from 390 (SD 90) to 389 (88) microm (at 0 degrees and 1 degree, respectively) for active CMO and from 199 (36) to 211 (33) microm in eyes with normal fovea following CMO resolution. Statistical correlations between mean differential sensitivity threshold and retinal thickness were only weak and showed no association. CONCLUSIONS: Active CMO causes a marked reduction in central retinal sensitivity. In addition, following the resolution of the CMO, a substantial impairment of central retinal sensitivity remains. Morphology in terms of retinal thickness in OCT does not correlate with visual function in terms of retinal sensitivity in these patients.

Prevalence of functional haplotypes of the peptidylarginine deiminase citrullinating enzyme gene in patients with rheumatoid arthritis: no influence of the presence of anti-citrullinated peptide antibodies.

OBJECTIVE: Citrullinated peptides produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases are of particular interest in the pathogenesis of rheumatoid arthritis (RA). One type of citrullinated protein - the cyclic citrullinated peptide - is the target of the anti-cyclic citrullinated peptide antibody, the most sensitive and specific autoantibody in RA. The peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has genetic variants that confer susceptibility to RA in Asian, but not in European populations. METHODS: Genetic associations were examined in 214 Hungarian RA patients characterized for the presence of anti-CCP and rheumatoid factor. The patients were characterized for the existing haplotypes of the PADI4 gene (defined by the combinations of 4 exonic padi4_89: 163G/A, padi4_90: 245T/C, padi4_92: 335C/G, padi4_104: 349T/C and 2 intronic padi4_94: 17535226C/T and padi4_102: 17546809C/T variants) by the PCR-RFLP method. RESULTS: None of the PADI4 haplotypes was accumulated in RA patients. One new finding was that we also did not detect the accumulation of any haplotypes either in the anti-CCP or in the RF-positive subgroups of patients. CONCLUSION: The data presented here show that none of the naturally occurring haplotypes of the PADI4 gene conferred susceptibility to RA in an average group of Hungarian patients; this is in agreement with findings for other European populations. In addition, none of the functional PADI4 haplotypes were associated with the pathologic immune response, which was evidenced by the absence of accumulation of anti-CCP-positive subjects in the specific PADI4 haplotypes.

Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity.

OBJECTIVE: To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. METHODS: Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. RESULTS: All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P < 0.05). Allele frequencies of the 'shared epitope' (HLA-DR1 and -DR4) were significantly increased in SSc-RA (32% and 27%, respectively) and RA patients (46% and 31%, respectively) in comparison with SSc patients (10.5% and 16%, respectively) or healthy controls (16% and 14%, respectively) (P < 0.05). CONCLUSIONS: To date this is the largest SSc-RA overlap cohort. Genetics, clinical and immunolaboratory features suggest a mixed phenotype. Our data suggest that SSc-RA overlap syndrome may be a distinct genetic, immunological and clinical entity.

Hungarian experience with Langerhans cell histiocytosis in childhood.

The Langerhans cell histiocytosis (LCH) in children is relatively rare and the long-term analysis of therapy results has not been done yet in Hungary. The aim of this study was to investigate the incidence, clinical features, prognostic risk factors, and treatment results of children's LCH in Hungary in a 20-year period. Children less than 18 years of age with newly diagnosed LCH in Hungary were entered in this study. Clinical data of all children with LCH were reported to the National Childhood Cancer Registry in Hungary from 1981 to 2000. The clinical files were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. Median follow-up duration of surviving patients is 10.98 years. Between January 1981 and December 2000, 111 children under 18 years of age were newly diagnosed with LCH in Hungary. The annual incidence of LCH in children younger than 18 years of age was 2.24/million children. The male-female ratio was 1.36:1; the mean age was 4 years 11 months. Thirty-eight children had localized disease and in 73 cases systemic dissemination was found already at the time of diagnosis. Twenty-two patients were treated only by local surgery, 7 by surgery with local irradiation, and 5 children got only local irradiation. In 2 cases remission was achieved with local steroid administration. Seventy-five patients received chemotherapy. In the 20 years of the study 14 children died, 9 due to the progression of the disease. Sixteen patients had relapse with a mean of 2.16 +/- 1.29 years after the first diagnosis. Three patients with relapse got chemotherapy generally used in lymphoma and remission was achieved. The overall survival of all patients (n = 111) was 88.3 +/- 3.1% at 5 years and 87.3 +/- 3.2% at 10 and 20 years. Childhood LCH is a well-treatable disease and the survival rate is high. Even disseminated diseases have a quite good prognosis in childhood.

Survey of Raynaud's phenomenon and systemic sclerosis based on a representative study of 10,000 south-Transdanubian Hungarian inhabitants.

OBJECTIVES: To assess the prevalence of Raynaud's phenomenon (RP) and of RP associated systemic sclerosis (SSc) in a large regional representative study. METHODS: Ten thousand individuals aged between 14-65 years participated in face-to-face interviews. The stratified sample of the South-West Hungarian population was representative for age, sex and urban or rural residence. Individuals reporting complaints suggesting the presence of "clinically significant" RP were asked to undergo a clinical investigation. Patients showing complaints provoked by taking something out of the freezer (-20 degrees C) compartment of the refrigerator and/or whether they had experienced digital ulcers were sorted into this category. RESULTS: The overall prevalence of RP was at least 578.9/10,000, and the prevalence of "clinically significant" RP could be calculated as at least 87.7/10,000 inhabitants. In this latter group 17.2% of the cases had either established SSc or anticentromere antibody or scleroderma capillary pattern on nailfold capillaroscopy. SSc with "clinically significant" RP and/or ulcers was identified in a prevalence of 9.1/10.000 individuals, whilst there was a prevalence of 14.7/10,000 of RP with either anticentromere antibody or scleroderma capillary pattern. CONCLUSIONS: "Clinically significant" RP affects almost 1% of the population. We identified cases with early stages of scleroderma spectrum disorder showing either anticentromere autoantibody or scleroderma capillary pattern. The prevalence of SSc was found to be higher than expected. It is reasonable to screen "clinically significant" RP cases for scleroderma-related symptoms because this approach makes it possible to identify patients with both SSc and early scleroderma related symptoms.

Secretory breast cancer in a 7.5-year old boy.

Breast cancer is extremely rare in children, and consequently no consensus has been reached on the optimal treatment modalities. The medical history and treatment plan for a 7.5-year old male breast cancer patient is described. Radical mastectomy with sentinel node biopsy was performed in October 2002. As no malignant cells were detected in the sentinel node, and no BRCA1-2 mutations were detected, no further radio- or chemotherapy was performed. A "wait-and-see" policy was decided on. Further treatment will be given if this becomes necessary with the development of metastases.