Asymptomatic Carriers Research Articles

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion.

To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.

Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

Adaptive evolution of traits for parasitism and pathogen transmission potential in bat flies

Abstract Deciphering the mechanisms underlying the transmission and spillover of zoonoses from reservoir hosts is essential in preventing future global pandemics. Bat flies, obligate blood-feeding ectoparasites of bats, are known carriers of diverse viruses. Here, we conducted a de novo assembly of a chromosome-level genome for the bat fly species Phthiridium sp. Comparative genomic analysis unveiled genes associated with specialized traits, such as the loss of eyes and wings, as well as elongated legs, which have adapted to parasitism on the dense fur of bats. Utilizing small RNA (sRNA) sequencing, we identified a spectrum of known and previously unclassified viruses in bat flies. Notably, experimental evidence indicated that bat flies can also feed on mammalian hosts other than bats, suggesting the potential for the spillover of bat-borne viruses. Furthermore, we demonstrated the role of the bat fly's RNA interference pathway in influencing the diversity and evolution of viruses. In summary, this study not only presents a new genome catalog to unveil the evolutionary mechanisms underpinning bat fly parasitism, but also provides a novel research system that can be used to investigate the mechanisms of cross-species transmission of bat-borne viruses and the co-evolution of bats and viruses.

Leukemia-related signaling pathways among HTLV-1 derived adult T-cell leukemia/lymphoma and asymptomatic carriers in comparison to normal group.

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATLL), a fetal malignant infection. Recently, The HTLV-1 new Asymptomatic careers (ACs) have frequently been reported among blood donors. Reaching the profound concept of HTLV-1-associated molecular pathogenesis could result in finding novel therapeutic strategies. The current study aimed to determine leukemia-related signaling regulation in ATLL. 30 participants were evaluated in three groups, including 10 ATLL patients, 10 ACs, and 10 normal controls. Blood samples were isolated without any chemotherapy history from ATLL patients. Also, blood samples were recovered from ACs and normal individuals. Lymphocyte isolation was done on collected blood samples. After this, RNA was extracted from the prepared samples and utilized for the cDNA synthesis. Tax and HBZ as viral genes and cellular genes, including MKP-1, EVI-1, JNK-1, FOXO-1, AKT-1, DEPTOR, MTOR, and JUN, were investigated using real-time PCR. The mean age of ATLL patients was 53.2 ± 7.32 years, and 9 (90%) were male. The EVI-1 and FOXO-1 expression levels were significantly associated with ATLL patients compared to internal control. However, the significant differences in expression of other genes in the remaining groups were not seen. Discovering viral and cellular signaling pathways that regulate HTLV-1 transformation is essential. A novel therapeutic strategy for ATLL regulating cellular signaling pathways in vivo could be considered. Therefore, clinical trials using activators and inhibitors of related cellular signaling pathways for cell therapy of ATLL are recommended. It is recommended more investigation on FOXO-1 and EVI-1 for targeting these genes to reveal the molecular pathogenesis of ATLL.

The Oral Cavity—Another Reservoir of Antimicrobial-Resistant Staphylococcus aureus?

Staphylococcus aureus is one of the most common potentially pathogenic bacteria that may asymptomatically colonize many sites of healthy carriers. Non-nasal carriage, especially in the oral cavity, and its role in transmitting antimicrobial-resistant S. aureus strains in the healthcare community, is poorly understood. This study aimed to assess the prevalence and antimicrobial susceptibility of S. aureus in both oral and nasal cavities among preclinical dentistry students. A total of 264 oral and nasal swabs were taken from 132 participants, and all specimens were cultured using standard diagnostic procedures and antimicrobial susceptibility testing (EUCAST). The prevalence of S. aureus exclusively in the nasal (11.4%) or oral (9.1%) cavity was comparable, while concurrent oral and nasal carriage was present in 27.3% of participants. Although antibiotic resistance rates observed in both oral and nasal isolates were similar (ranging from 2.7% to 95.5%), 16.7% of carriers exhibited distinct antibiotic resistance profiles between oral and nasal isolates. Three (2.7%) methicillin-resistant S. aureus (MRSA) were isolated from the mouth and nose but multidrug resistance (27.3%) was more frequent in the oral than in the nasal isolates: 34% and 21.1%, respectively. This study demonstrated that preclinical dentistry students have a similar rate of oral S. aureus carriage as the nasal carriage rate, and that the oral cavity can be colonized by antimicrobial-resistant strains that do not originate from the nose. Consequently, the oral cavity seems to be an unjustly overlooked body site in screening for S. aureus carriage.

Investigating the Correlation between Semi quantitative HBeAg and HBV DNA Levels: Validating HBeAg Quantification as a Marker in Asymptomatic HBeAg-Positive Carriers

Investigating the Correlation between Semi quantitative HBeAg and HBV DNA Levels: Validating HBeAg Quantification as a Marker in Asymptomatic HBeAg-Positive Carriers

Comparative genomics of quinolone-resistant Escherichia coli from broilers and humans in Norway

BackgroundThe usage of fluoroquinolones in Norwegian livestock production is very low, including in broiler production. Historically, quinolone-resistant Escherichia coli (QREC) isolated from Norwegian production animals rarely occur. However, with the introduction of a selective screening method for QREC in the Norwegian monitoring programme for antimicrobial resistance in the veterinary sector in 2014; 89.5% of broiler caecal samples and 70.7% of broiler meat samples were positive. This triggered the concern if there could be possible links between broiler and human reservoirs of QREC. We are addressing this by characterizing genomes of QREC from humans (healthy carriers and patients) and broiler isolates (meat and caecum).ResultsThe most frequent mechanism for quinolone resistance in both broiler and human E. coli isolates were mutations in the chromosomally located gyrA and parC genes, although plasmid mediated quinolone resistance (PMQR) was also identified. There was some relatedness of the isolates within human and broiler groups, but little between these two groups. Further, some overlap was seen for isolates with the same sequence type isolated from broiler and humans, but overall, the SNP distance was high.ConclusionBased on data from this study, QREC from broiler makes a limited contribution to the incidence of QREC in humans in Norway.

The pathologic and clinical outcomes of risk-reducing salpingo-oophorectomy in asymptomatic carriers of homologous recombination repair gene mutation.

To investigate the prevalence of pathological findings and clinical outcomes of risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic carriers with germline homologous recombination repair (HRR) gene pathogenic/likely pathogenic variants (PV/LPV). This retrospective study enrolled asymptomatic carriers with germline HR gene PV/LPV who underwent RRSO between 2006 and 2022 at the National Cancer Center in Korea. Clinical characteristics, including history of breast cancer, family history of ovarian/breast cancer, parity, and oral contraceptive use, were analyzed. Of the 255 women who underwent RRSO, 129 (50.6%) had PV/LPV in BRCA1, 121 (47.5%) in BRCA2, and 2 (0.7%) had both BRCA1 and BRCA2 PV/LPV. In addition, 1 carried PV/LPV in RAD51D, and 2 in BRIP1. Among the BRCA1/2 PV/LPV carriers, occult neoplasms were identified in 3.5% of patients: serous tubal intraepithelial carcinoma (1.1%, n=3), fallopian tubal cancers (0.8%, n=2), ovarian cancer (1.2%, n=3), and breast cancer (0.4%, n=1). Of the 9 patients with occult neoplasms, 5 (2.0%) were identified from the 178 breast cancer patients, and 4 (1.6%) were detected in 65 healthy mutation carriers. During the median follow-up period of 36.7 months (interquartile range, 25.9-71.4), 1 (0.4%) BRCA1 PV carrier with no precursor lesions at RRSO developed primary peritoneal carcinomatosis after 30.1 months. Women with HRR gene mutations PV/LPV who undergo RRSO are at a risk of detecting occult neoplasms, with a of 3.5%. Even in the absence of precursor lesions during RRSO, there was a cumulative risk of peritoneal carcinomatosis development, emphasizing the need for continued surveillance.

Establishing a surveillance programme for Salmonella Dublin in Austrian dairy herds by comparing herd-level vs. individual animal detection methods

Due to its increasing occurrence in cattle farms in various countries, leading to significant economic losses in affected livestock, Salmonella enterica subspecies enterica serovar Dublin (S. Dublin) has become a highly investigated pathogen in cattle production. In Austria, there have been occasional human cases of S. Dublin as well as an increase in laboratory-confirmed cases in cattle, indicating the need for a screening programme to determine the current status in Austria. The aims of this study were, firstly, to determine the seroprevalence of S. Dublin in dairy herds through bulk milk screenings in two federal states (Salzburg, Tyrol) of Austria. Secondly, the study aimed to identify the infection status of the herds through individual animal and herd level detection, comparing microbiological, molecular and serological detection methods. The results of the study will allow the development of a sampling strategy for a surveillance programme in Austria.A total of 6973 dairy farms were tested through serological bulk milk screening. The seroprevalence for the federal state of Tyrol was 14.8 % and for Salzburg it was 18.2 %, resulting in an average seroprevalence of 16.5 %. At an individual animal level, 205 (11.3 %) animals tested positive for shedding of S. Dublin in the faeces through microbiological detection, and 268 (17.0 %) animals had positive values (ct value ≤ 38) by qPCR. The association between microbiological and molecular detection was statistically significant (p < 0.001), with a calculated kappa value of 0.65 ± 0.27 (p ≤ 0.001), assuming a substantial level of agreement. In 17 herds, where an individual animal tested positive for shedding of S. Dublin, environmental sampling and testing were carried out. At a herd level 16 (94.1 %) out of the 17 participating herds, tested positive for S. Dublin either microbiologically or by molecular assay in boot swab samples. Bulk milk samples from 14 out of the 17 participating herds were analysed for antibodies to S. Dublin and 12 samples (85.7 %) were positive. In total 111 (18.9 %) out of 587 blood samples tested positive for S. Dublin antibodies, demonstrating a statistically significant correlation (p < 0.001) both with microbiological (κ = 0.32 ± 0.49; p ≤ 0.001) and molecular (κ=0.23 ± 0.06; p ≤ 0.001) findings.It was possible to identify S. Dublin by culture from boot swabs in 14 (82.4 %) out of 17 herds and by molecular assay using qPCR in 15 (88.2 %) out of 17 herds, indicating a suitable sample type for screening on a herd level-basis for acute infections, but not for identifying chronic infections or asymptomatic carriers. Other environmental samples, such as sponge-sticks, are only suitable to a limited extent for the detection of S. Dublin. The results of this study demonstrate a moderate S. Dublin prevalence in dairy herds in the selected Austrian regions, signalling further screening and management programmes for the future.

Pupillary Light Reflex Reveals Melanopsin System Alteration in the Background of Myopia-26, the Female Limited Form of Early-Onset High Myopia.

The purpose of this study was to evaluate pupillary light reflex (PLR) to chromatic flashes in patients with early-onset high-myopia (eoHM) without (myopic controls = M-CTRL) and with (female-limited myopia-26 = MYP-26) genetic mutations in the ARR3 gene encoding the cone arrestin. Participants were 26 female subjects divided into 3 groups: emmetropic controls (E-CTRL, N = 12, mean age = 28.6 ± 7.8years) and 2 myopic (M-CTRL, N = 7, mean age = 25.7 ± 11.5years and MYP-26, N = 7, mean age = 28.3 ± 15.4years) groups. In addition, one hemizygous carrier and one control male subject were examined. Direct PLRs were recorded after 10-minute dark adaptation. Stimuli were 1-second red (peak wavelength = 621nm) and blue (peak wavelength = 470nm) flashes at photopic luminance of 250 cd/m². A 2-minute interval between the flashes was introduced. Baseline pupil diameter (BPD), peak pupil constriction (PPC), and postillumination pupillary response (PIPR) were extracted from the PLR. Group comparisons were performed with ANOVAs. Dark-adapted BPD was comparable among the groups, whereas PPC to the red light was slightly reduced in patients with myopia (P = 0.02). PIPR at 6 seconds elicited by the blue flash was significantly weaker (P < 0.01) in female patients with MYP-26, whereas it was normal in the M-CTRL group and the asymptomatic male carrier. L/M-cone abnormalities due to ARR3 gene mutation is currently claimed to underlie the pathological eye growth in MYP-26. Our results suggest that malfunction of the melanopsin system of intrinsically photosensitive retinal ganglion cells (ipRGCs) is specific to patients with symptomatic MYP-26, and may therefore play an additional role in the pathological eye growth of MYP-26.

Prevalence, Antimicrobial Resistance, and Diversity of Campylobacter Isolated from U.S. Goat Feces: 2019 NAHMS Survey.

Goats are often asymptomatic carriers of Campylobacter, including the foodborne pathogen Campylobacter jejuni. Infections can have significant and economically detrimental health outcomes in both humans and animals. The primary objective of this study was to estimate the prevalence of Campylobacter in U.S. goat herds. Campylobacter species were isolated from 106 of 3,959 individual animals and from 42 of 277 goat operations that participated in fecal sample collection as part of the National Animal Health Monitoring System Goat 2019 study. Weighted animal-level prevalence was 2.3% (SE = 0.5%) and operation prevalence was 13.0% (SE = 3.2%). Animal-level prevalence ranged widely from 0 to 70.0%, however, 52.4% of positive operations (22/42) had only a single isolate. C. jejuni was the most frequently isolated species (68.9%; 73/106), followed by C. coli (29.3%, 31/106). A total of 46.2% (36/78) of viable isolates were pan-susceptible to 8 antimicrobials. Resistance to tetracycline (TET) was observed in 44.9% (35/78) of isolates, while 12.8% (10/78) were resistant to ciprofloxacin (CIP) and nalidixic acid (NAL). Among all isolates, a single resistance profile CIP-NAL-TET was observed in 3.8% (3/78) of isolates. A total of 35 unique sequence types (STs) were identified, 11 of which are potentially new. Multiple C. jejuni STs were observed in 48.1% (13/27) of positive operations. Goats with access to surface water, operations reporting antibiotics in the feed or water (excluding ionophores and coccidiostats), and operations reporting abortions and without postabortion management tasks had significantly greater odds of being Campylobacter positive. This snapshot of the U.S. goat population enriches the limited pool of knowledge on Campylobacter species presence in U.S. goats.

Prevalence, antimicrobial susceptibility patterns and associated factors of Streptococcus pyogenes among apparently healthy school children in Mekelle city primary schools, Northern Ethiopia

BackgroundStreptococcus pyogenes is one of the major public health concerns causing human infections ranging from skin and throat infections to acute rheumatic fever and post streptococcal glomerulonephritis. Moreover, nowadays drug-resistant strains of S. pyogenes are emerging and can be transmitted through apparently healthy carriers to susceptible individuals. ObjectiveTo assess the prevalence, antimicrobial susceptibility pattern and associated factors S. pyogenes among apparently healthy school children in Mekelle city primary schools, Northern Ethiopia. MethodsA cross-sectional study was conducted among 504 apparently healthy school children from February to May 2018. We used structured questionnaire to collect socio-demographic data. Throat specimens were collected using sterile cotton Swab and transported for culture, antimicrobial susceptibility and identification of S. pyogenes according to standard operating procedures. Data were analyzed using Stata 13 for descriptive statistics, bivariate and multivariate logistic regression. P-value < 0.05 was declared statistically significance. ResultsThe mean age of the study participants was 11.5 years of which 55 % of them were females. The overall prevalence of S. pyogenes was 8.3%. Being female, having low monthly income, weak personal hygiene, poor hand washing habit and crowded living style were significantly associated with the occurrence of S. pyogenes. The isolates of S. pyogenes showed resistance to Penicillin (69.1%), Amoxicillin-Clavulanic acid (62%), Ampicillin (54.6%), Ceftriaxone (47.6%), Tetracycline (14.4%), Cefoxitin (7.2%). About 57.15% isolates were multidrug-resistant. ConclusionsThis study revealed that some isolates of S. pyogenes among the apparently healthy school children were resistant to commonly prescribed antibiotic agents and associated with hygienic conditions and living style. Therefore, it is recommended to practice antimicrobial susceptibility test to maintain rational antibiotic use and improve hygienic and hand washing practices to decrease the likelihood of carriage rate.

“Whatever is bad goes back to the woman”: The gendered blame game of sickle cell disease in Malawi and Uganda

Mothers are commonly blamed for the ill-health of their children, and this is well documented in research. However, few studies have considered gendered patterns of blame for hereditary conditions caused by mutations from both parents through dual, shared genetic inheritance. This paper explores the ‘gendering’ of blame in the context of an inherited blood disorder known as sickle cell disease. The findings are drawn from 18 focus group discussions with 117 caregivers of children with sickle cell disease in Malawi and Uganda. Although one mutation from each parent is required for the disease to develop, low awareness about their status as healthy carriers of a sickle cell trait complicated the caregivers' recognition and acceptance of their genetic link to the child's condition. This study demonstrates how fathers and other members of the paternal side of the child's family would deflect blame from their own lineage by directing sole ‘genetic responsibility’ for the child's disease towards mothers. We discuss the implications of gendered blame on household dynamics and healthcare-seeking for children with sickle cell disease in this setting.

Asymptomatic colonization of stray dogs and domestic cats with Trichophyton mentagrophytes II* in Northern Iran

BackgroundDespite changes in the epidemiology of dermatophyte infections, the incidence of fungal infections associated with Trichophyton species still remains high among dogs and cats. The objective of the present study was to isolate and characterize dermatophytes from dogs and cats in Iran. Method:From December 2022 to May 2023, skin and hair samples were collected from symptomatic and asymptomatic cats and dogs in Mazandaran, a northern province of Iran. The samples were then inoculated into Mycosel™ Agar. Dermatophyte isolates were identified by sequencing the internal transcribed spacer region. Antifungal susceptibility tests were conducted using the Clinical and Laboratory Standards Institute (CLSI-M38-A3). ResultOf the 250 samples collected (from 200 dogs and 50 cats), 20 (from 19 dogs and one cat) (8.0 %) were positive for dermatophyte growth. Based on sequence and phylogenetic analysis, all isolates belonged to T. mentagrophytes II*. Of these positive samples, 14 (70.0 %), 3 (15.0 %), 2 (10.0 %), and 1 (2.0 %) were isolated from asymptomatic stray dogs, symptomatic stray dogs, symptomatic domestic dogs, and symptomatic cats, respectively. Luliconazole and terbinafine displayed potent activity against all T. mentagrophytes isolates, with Minimum inhibitory concentration (MIC) values of 0.016 µg/ml. Miconazole and griseofulvin demonstrated higher MIC (1 and 8 µg/ml). ConclusionThe present study indicated that T. mentagrophytes II* asymptomatic carriage is frequent in stray dogs in Iran. The potential risk to public health needs to be evaluated However, T. mentagrophytes genotype VIII, considered as an endemic and emerging human pathogenic clone in several countries, was not detected during the present survey.

The characteristic and biomarker value of transcranial sonography in cerebellar ataxia.

Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment. TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing. The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated. Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.

HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

Relationship Between Serum HBV-RNA Levels, Sero-biochemical Indices, and Clinicopathological Parameters in Patients with Hepatitis B Virus

Background: Studies have indicated that HBV RNA exhibits a distinct profile, and the plasma amino acid profile significantly correlates with the different stages of HBV infection. Objectives: This study investigates the relationship between HBV RNA and the plasma amino acid profile and the levels of HBeAg, HBsAg, HBV DNA levels, and other clinical indexes in diagnosing chronic HBV infection diseases. Methods: In this observational study, a total of 155 patients were included. They were categorized as Hepatitis B virus carriers, chronic Hepatitis B (CHB), Hepatitis B-related cirrhosis, and hepatocellular carcinoma patients. Following routine laboratory techniques, the DNA, RNA, serological indexes (HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb), biochemical indexes (ALT, AST), and the concentration of amino acids were determined from the serum. Results: Any relationship between different parameters considered was determined with the chi-square test, correlation, and multivariate logistic regression analysis. We observed that the HBV DNA and RNA levels were significantly higher in patients with chronic Hepatitis B compared to other groups (P &lt; 0.01). The HBV RNA levels significantly correlated with methionine levels (P &lt; 0.05) and not with other amino acids considered in this study. Further, the HBV DNA levels emerged as an independent risk factor for HBV RNA levels, and the area under the ROC curve was 0.840 (P &lt; 0.01) when the levels of HBV RNA, HBV DNA, and methionine were combined to diagnose chronic Hepatitis B. Conclusions: Our study shows that the levels of HBV RNA are correlated with methionine metabolism levels, and this relationship can be used to diagnose and predict the efficacy of treatment for different stages of HepatitisHepatitis B virus infectious diseases.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Oculomotor Dysfunction in Idiopathic and LRRK2-Parkinson's Disease and At-Risk Individuals.

Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers.

Flow cytometric profiles with CD7 and CADM1 in CD4+ T cells are promising indicators for prognosis of aggressive ATL

AbstractAdult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)–infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1–uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1–infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7–) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1–infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.