Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India.

Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.

Extraction of apex beat waveform from acoustic pulse wave by sound sensing system using stochastic resonance.

With a sound sensing system using stochastic resonance (4SR), it became possible to obtain an acoustic pulse wave (APW)-a waveform created via a mixture of apex beat and heart sound. We examined 50 subjects who were healthy, with no underlying cardiovascular diseases. We could determine boundary frequency (BF) using APW and phonocardiogram signals. APW data was divided into two bands, one from 0.5 Hz to BF, and a second one from BF to 50 Hz. This permitted the extraction of cardiac apex beat (CAB) and cardiac acoustic sound (CAS), respectively. BF could be expressed by a quadratic function of heart rate, and made it possible to collect CAB and CAS in real time. According to heart rate variability analysis, the fluctuation was 1/f, which indicated an efficient cardiac movement when heart rate was 70 to 80/min. In the frequency band between 0.5 Hz and BF, CAB readings collected from the precordial region resembled apex cardiogram data. The waveforms were classified into five types. Therefore, the new 4SR sensing system can be used as a physical diagnostic tool to obtain biological pulse wave data non-invasively and repeatedly over a long period, and it shows promise for broader applications, including AI analysis.

Recurrent probabilistic neural network-based short-term prediction for acute hypotension and ventricular fibrillation.

In this paper, we propose a novel method for predicting acute clinical deterioration triggered by hypotension, ventricular fibrillation, and an undiagnosed multiple disease condition using biological signals, such as heart rate, RR interval, and blood pressure. Efforts trying to predict such acute clinical deterioration events have received much attention from researchers lately, but most of them are targeted to a single symptom. The distinctive feature of the proposed method is that the occurrence of the event is manifested as a probability by applying a recurrent probabilistic neural network, which is embedded with a hidden Markov model and a Gaussian mixture model. Additionally, its machine learning scheme allows it to learn from the sample data and apply it to a wide range of symptoms. The performance of the proposed method was tested using a dataset provided by Physionet and the University of Tokyo Hospital. The results show that the proposed method has a prediction accuracy of 92.5% for patients with acute hypotension and can predict the occurrence of ventricular fibrillation 5 min before it occurs with an accuracy of 82.5%. In addition, a multiple disease condition can be predicted 7 min before they occur, with an accuracy of over 90%.

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

Background: Severe Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce. Objective: To describe clinical and laboratory features of SCID diagnosed at immunology centers across India. Methods: A detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID. Results: We obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%). Conclusion: We document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

Unconstrained Vital Sign Monitoring System Using an Aortic Pulse Wave Sensor.

This paper proposes a novel unconstrained monitoring system that measures heart and respiratory rates and evaluates autonomic nervous activity based on heart rate variability. The proposed system measures the aortic pulse waves (APWs) of a patient via an APW sensor that comprises a single microphone integrated into a mattress. Vital signs (i.e., heart rate, respiratory rate) and autonomic nervous activity were analyzed using the measured APWs. In an experiment with supine and seated participants, vital signs calculated by the proposed system were compared with vital signs measured with commercial devices, and we obtained the correlations of r > 0.8 for the heart rates, r > 0.7 for the respiratory rates, and r > 0.8 for the heart rate variability indices. These results indicate that the proposed system can produce accurate vital sign measurements. In addition, we performed the experiment of image stimulus presentation and explored the relationships between the self-reported psychological states evoked by the stimulus and the measured vital signs. The results indicated that vital signs reflect psychological states. In conclusion, the proposed system demonstrated its ability to monitor health conditions by actions as simple as sitting or lying on the APW sensor.

A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency.

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.

Unconstrained Monitoring of Biological Signals Using an Aortic Pulse Wave Sensor.

This paper proposes a system to extract biological signals from aortic pulse waves which are measured by a microphone type pulse wave sensor. Theproposed system enables extraction of three biological signals corresponding to respiratory rate, pulse pressure wave, and RR interval simply by sitting on the seat on which the sensor is laid. Experiment results demonstrated that the mean absolute errors between the signals measured by the proposed system and the conventional sensors are as low as 0.38 times per minute for the respiratory rate, 11.2 mmHg for the pulse pressure wave, and 16.6 ms for the RR interval. The proposed system thus may be applied to monitor the physiological state of a human subject to prevent accident caused by health condition.

Droplet Digital PCR-Based Chimerism Analysis for Primary Immunodeficiency Diseases.

OBJECTIVE: In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT). METHODS: We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases. RESULTS: The accuracy of the male/female chimerism analysis using ddPCR was confirmed by comparing the results with those of conventional methods (fluorescence in situ hybridization and short tandem repeat-PCR) and evaluating dilution assays. In particular, we found that this method was useful for analyzing small samples. Thus, this method could be used with patient samples, especially to sorted leukocyte subpopulations, during the early post-transplant period. Four mutation-specific ddPCR accurately detected post-transplant chimerism. CONCLUSION: ddPCR-based male/female chimerism analysis and mutation-specific ddPCR were useful for all HSCT, and these simple methods contribute to following the post-transplant chimerism, especially in disease-specific small leukocyte fractions.

CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy.

BACKGROUND: Four genes responsible for pseudohypoaldosteronism type II (PHA-II) have been identified, thereby facilitating molecular diagnostic testing. CASE-DIAGNOSIS/TREATMENT: A 1-year-old boy with prolonged hyperkalemia, metabolic acidosis, hyperchloremia, growth delay, and mild hypertension was diagnosed with PHA-II based on the detection of exon 9 skipping in CUL3 mRNA. The impaired splicing was the result of a de novo, previously unreported single nucleotide substitution in the splice acceptor site of CUL3 intron 8. Among the four genes reported to be involved in PHA-II, CUL3 was the primary suspect in our patient because in patients with the CUL3 mutation, the onset of disease is often early in infancy and the phenotypes of PHA-II are more severe. Our patient was treated with trichlormethiazide, which inhibits the function of the sodium-chloride co-transporter (NCC), and the outcome was favorable, with correction of body fluids and blood electrolyte homeostasis. CONCLUSION: Since chronic acidosis and hypertension associated with PHA-II can result in delayed growth and development in pediatric patients, genetic analysis to detect the CUL3 mutation and to enable intervention early in the disease course would be beneficial for infants with suspected PHA-II.

Severe human herpesvirus 6-associated encephalopathy in three children: analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene.

Three children developed severe encephalopathy associated with human herpesvirus 6 infection. Magnetic resonance imaging of the brain showed either basal ganglia involvement or diffusion abnormalities in the cerebral white matter. Coagulopathy with hypercytokinemia was observed in 2 patients. One demonstrated thermolabile variation in carnitine palmitoyltransferase 2. These results suggest a heterogeneous pathogenic mechanism in encephalopathy associated with human herpesvirus 6 infection.

Noninvasive biological sensor system for detection of drunk driving.

Systems capable of monitoring the biological condition of a driver and issuing warnings during instances of drowsiness have recently been studied. Moreover, many researchers have reported that biological signals, such as brain waves, pulsation waves, and heart rate, are different between people who have and have not consumed alcohol. Currently, we are developing a noninvasive system to detect individuals driving under the influence of alcohol by measuring biological signals. We used the frequency time series analysis to attempt to distinguish between normal and intoxicated states of a person as the basis of the sensing system.

Multiple regression analysis of pharmacogenetic variability of carvedilol disposition in 54 healthy Japanese volunteers.

The aim of this study was to evaluate the pharmacogenetic variability in the disposition of carvedilol in the Japanese population. Five or 10 mg of carvedilol was orally administered to 54 healthy Japanese subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A5, UGT2B7, and MDR1 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. We then examined the effect of the genetic polymorphisms on the variability in the pharmacokinetics of carvedilol using a multiple regression analysis. The oral clearance (CL/F) and also apparent volume of distribution (V/F) of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than those with the CYP2D6*1/*1, *1/*2, or *2/*2 genotype, confirming our previous finding that the bioavailability (F) and systemic clearance (CL) of R- and S-carvedilol in the liver is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, and MDR1 C3435T did not significantly affect the pharmacokinetics of carvedilol in Japanese subjects.

Effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers.

This study was performed to investigate the effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Five or 10 mg of carvedilol was orally administered to 23 subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. The mean values of oral clearance for R- and S-carvedilol were estimated to be 1.01 and 2.15 l/h/kg, respectively. The oral clearance was highly correlated with the apparent volume of distribution among the subjects, suggesting that the interindividual difference in bioavailability was largely responsible for the pharmacokinetic variability of carvedilol. The oral clearance and also volume of distribution of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than with the CYP2D6*1/*1 or *1/*2 genotype. These results suggested that the systemic and/or pre-systemic metabolism of R- and S-carvedilol in the liver is significantly decreased in Japanese with the CYP2D6*10 allele.