Protein phenotype diagnosis of autosomal dominant calmodulin mutations causing irregular heart rhythms.

The life-threatening group of irregular cardiac rhythmic disorders also known as Cardiac Arrhythmias (CA) are caused by mutations in highly conserved Calmodulin (CALM/CaM) genes. Herein, we present a multidimensional approach to diagnose changes in phenotypic, stability, and Ca2+ ion binding properties of CA-causing mutations. Mutation pathogenicity was determined by diverse computational machine learning approaches. We further modeled the mutations in 3D protein structure and analyzed residue level phenotype plasticity. We have also examined the influence of torsion angles, number of H-bonds, and free energy dynamics on the stability, near-native simulation dynamic potential of residue fluctuations in protein structures, Ca2+ ion binding potentials, of CaM mutants. Our study recomends to use M-CAP method for measuring the pathogenicity of CA causing CaM variants. Interestingly, most CA-causing variants we analyzed, exists in either third (V/H-96, S/I-98, V-103) or fourth (G/V-130, V/E/H-132, H-134, P-136, G-141, and L-142) EF-hands located in carboxyl domains of the CaM molecule. We observed that the minor structural fluctuations caused by these variants are likely tolerable owing to the highly flexible nature of calmodulin's globular domains. However, our molecular docking results supports that these variants disturb the affinity of CaM toward Ca2+ ions and corroborate previous findings from functional studies. Taken together, these computational findings can explain the molecular reasons for subtle changes in structure, flexibility, and stability aspects of mutant CaM molecule. Our comprehensive molecular scanning approach demonstrates the utility of computational methods in quick preliminary screening of CA- CaM mutations before undertaking time consuming and complicated functional laboratory assays.

A Case of Fibrinous Pericardial Effusion: Masquerading Presentation of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with varied presentations varying from nonspecific features like fever, malaise, and arthralgia to serious manifestations like serositis (pleural, pericardial effusions), neurological manifestations, and renal involvement (lupus nephritis). SLE is a great mimicker, especially for infections like tuberculosis (TB) which is rampant in low- and middle-income countries (LMIC). We report a case of massive pericardial effusion, which was initially diagnosed as TB on clinico-radiological basis, but the diagnosis was later revised owing to new findings.

Short Stature for Age in Children of 5 to 16 Years: The First Research from the Northern Himalayan Region of India.

Introduction: Anthropometric parameters play vital role in monitoring growth in pediatrics. Many etiological factors lead to short stature. So, before assessing the etiological factors short stature needs to be addressed. This study aimed to screen short stature for age in school-going children aged 5 to 16 years in Uttarakhand. Material and Methods: In this cross-sectional observational study, the height (through stadiometer) and weight (through weight machine) of 4189 students of government and private school in Rishikesh (Uttarakhand) aged 5-16 years were measured after the verbal assent of the students and individual's height is in the 3rd percentile for the mean height of a given age, sex, and population group and was considered short stature. The data collection was performed from October 2019 to July 2021. The data were categorized according to different age groups to 5-8 years, 9-12 years, and 13-16 years. The data were recorded in Microsoft (MS) Excel spreadsheet program. Statistical Package for the Social Sciences (SPSS) v23 (IBM Corp.) was used for data analysis. Descriptive statistics were elaborated in the form of means or standard deviations and medians or Interquartile range IQRs for continuous variables and frequencies and percentages for categorical variables. The Chi-square test was used for group comparisons for categorical data. Results: 7.1% of children were short stature (height 143.16 ± 15.09 cm) in the Himalayan belt, and males were more prone to short stature at age of 9-12 years. Conclusion: In the growing phase of children, the etiology of short stature has to be rectified, so the children can achieve such proper growth. Parents and physicians have to assess and monitor the growth of children timely. This study can be a stepping stone for further epidemiological studies.

Utility of MLPA in mutation analysis and carrier detection for Duchenne muscular dystrophy.

CONTEXT: Multiplex ligation probe amplification (MLPA) is a new technique to identify deletions and duplications and can evaluate all 79 exons in dystrophin gene in patients with Duchenne muscular dystrophy (DMD). Being semi-quantitative, MLPA is also effective in detecting duplications and carrier testing of females; both of which cannot be done using multiplex PCR. It has found applications in diagnostics of many genetic disorders. AIM: To study the utility of MLPA in diagnosis and carrier detection for DMD. MATERIALS AND METHODS: Mutation analysis and carrier detection was done by multiplex PCR and MLPA and the results were compared. RESULTS AND CONCLUSIONS: We present data showing utility of MLPA in identifying mutations in cases with DMD/BMD. In the present study using MLPA, we identified mutations in additional 5.6% cases of DMD in whom multiplex PCR was not able to detect intragenic deletions. In addition, MLPA also correctly confirmed carrier status of two obligate carriers and revealed carrier status in 6 of 8 mothers of sporadic cases.

Microspherophakia: A clinical approach and mini review with a case report.

Microspherophakia refers to a spherophakic lens with a decreased equatorial diameter. Microspherophakia can be found in systemic or ocular conditions, such as Marfan's syndrome, Weill-Marchesani syndrome, iridocorneal endothelial syndrome, and Axenfeld-Rieger syndrome. A 3-year-old girl was brought with complaints of eyes appearing larger, watering and inability to see bright light for 1 year. On examination, she had megalocornea; the cornea was clear with a shallow anterior chamber, and microspherophakic lens. Her intraocular pressure (IOP) was recorded as 43 and 32 mmHg in the right and left eyes, respectively. This article guides in classifying, categorizing, and managing a case with microspherophakia.

The assemblage of skin findings in the type 1 DM with incorrect injection technique: A case report.

Correct insulin administration technique, insulin type, and dose play a pivotal role in attaining glycemic control. An error in any of the steps may lead to poor glycaemic control, which affects the patient in the short and long term. We are presenting here unusual skin findings in children with the wrong injection technique. A 10-year-old male child already diagnosed with type 1 Diabetes Mellitus (DM), presented with poor glycemic control. On examination, we found skin rashes encircling most of his abdominal area circularly. Rashes were round to oval, well-circumscribed, hyperpigmented to hypopigmented to depigmented macules to papules surrounded by a hyperpigmented halo, 0.5 to 1 cm in diameter, painless varying in color from white to pinkish-red to light brown to brownish-black. On observing the administration technique of insulin, we found it was administered incorrectly as intradermal instead of subcutaneous. Proper Diabetes education and insulin administration techniques remain the cornerstone in the management of type 1 DM. We should ensure appropriate insulin administration on every visit.

Subconjunctival cysticercosis - Is surgery always indicated? Role of medical management-literature review and report of two cases.

Ocular cysticercosis is caused by the larval form of pork tapeworm for which humans and pigs are the intermediate hosts. Intense inflammation secondary to immunological reaction is the hallmark feature of the infection, which can affect almost any tissue of the host. Orbital imaging yields specific features suggestive of the diagnosis. Although medical management is the recommended treatment for extra-ocular and retro-orbital cysticercosis, surgical removal has also been suggested by several authors. Here, we report two cases of subconjunctival cysticercosis, successfully managed with medical treatment alone using oral steroid and albendazole. Surgical excision for subconjunctival cysticercosis is associated with complications which can be observed even with the most experienced hands. Through these two cases, we wish to sensitize the practicing physicians regarding the most common ocular infestation seen in the developing countries along with brief literature review on the management protocols to be followed before any surgical reference.

Rare but not Abdicated: Status of Haemophilia in foothills of Himalaya, Uttarakhand: A cross-sectional study.

BACKGROUND: Haemophilia is one of the bleeding disorders, which is inherited, in an xlinked recessive pattern. The diagnosis is by estimation of factor levels of 8 and 9. Timebound treatment for people living with Haemophilia (PWH) is factor replacement during bleeding manifestation. The prevalence of Haemophilia was mostly underestimated, and it is more so in hilly terrains like the state of Uttarakhand. MATERIALS AND METHOD: This is a crosssectional study by compiling the data of PWH visiting the tertiary care centre for Haemophilia in Uttarakhand. We collected data from the patients with bleeding disorder reporting to the Haemophilia centre from July 2017 to December 2018. In this manuscript, we try to describe the pattern of Haemophilia and the degree of severity and incidence of inhibitors among the sample population of PWH who represent the population of Uttarakhand. The magnitude of problems faced by PWH from this hilly terrain to assess basic treatment in case of emergency is also being depicted. RESULT: We reported Haemophilia A contributing about 80% of the PWH in our centre. Average distance a PWH has to travel to obtain treatment was about 131.5 km (SD ± 83.7 km). Incidence of inhibitors was about 5%. CONCLUSION: We infer from our study that Hemophilia A is more common than Hemophilia B. Through this manuscript we hope to spread awareness of the Haemophilia care that is ongoing, the role of prophylaxis therapy and the future role of primary care physicians that may change the care of PWH in future.

Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia.

BACKGROUND: One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono-allelic mutations in the KCNQ1 gene. Bi-allelic mutations in the KCNQ1 gene are causal to Jervell and Lange-Nielsen syndrome (JLNS), characterized by severe and early-onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi-allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1). METHODS: We used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene in eight families from Saudi Arabia with autosomal recessive LQT1. RESULTS: We have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387-5T>A and p.Val172Met/p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced in all the probands comparable to the cardiac phenotype in JLNS patients. Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia. CONCLUSION: To the best of our knowledge, this is the first description of a large series of patients with familial autosomal recessive LQT, type 1. These mutations could be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia and in people of Arabic ancestry.

Broadband attenuation and nonlinear propagation in biological fluids: an experimental facility and measurements.

The design and construction of a versatile experimental facility for making measurements of the frequency-dependence of attenuation coefficient (over the range 1 MHz to 25 MHz) and nonlinear propagation in samples of biological fluids is described. The main feature of the facility is the ability to perform all of the measurements on the same sample of fluid within a short period of time and under temperature control. In particular, the facility allows the axial development of nonlinear waveform distortion to be measured with a wideband bilaminar polyvinylidene difluoride membrane hydrophone to study nonlinear propagation in biological fluids. The system uses a variable length bellows to contain the fluid, with transparent Mylar end-windows to couple the acoustic field into the fluid. Example results for the frequency-dependence of attenuation of Dow Corning 200/350 silicone fluid, used as a standard fluid, are presented and shown to be in good agreement with alternative measurements. Measurements of finite amplitude propagation in amniotic fluid, urine and 4.5% human albumin solutions at physiological temperature (37 degrees C) are presented and compared with theoretical predictions using existing models. The measurements were made using a 2.25-MHz single-element transducer coupled to a polymethyl methacrylate lens with a focal amplitude gain of 12 in water. The transducer was driven with an eight-cycle tone burst at source pressures up to 0.137 MPa. In general, given an accurate knowledge of the medium parameters and source conditions, the agreement with theoretical prediction is good for the first five harmonics.

Broadband measurements of the frequency dependence of attenuation coefficient and velocity in amniotic fluid, urine and human serum albumin solutions.

The frequency dependence of attenuation coefficient in amniotic fluid, urine and 4.5% and 20% human serum albumin solutions over the frequency range 5 MHz to 25 MHz was measured at both room temperature and physiological temperature using a variable path length technique. A 15 MHz (13 mm diameter) transducer was used to produce a broadband single-cycle pulse and a 4 mm diameter bilaminar polyvinylidene difluoride membrane hydrophone was used to detect the attenuated pulse. Standard time-of-flight measurement techniques were used to measure the acoustic velocity in the same fluid samples. At physiological temperature, the attenuation coefficients in amniotic fluid, urine and 4.5% and 20% human albumin solution were found to be 0.0053 f(1.65), 0.0047 f(1.67), 0.019 f(1.57) and 0.167 f(1.27) dB cm(-1), respectively, where f is in MHz. The velocities in amniotic fluid, urine and 4.5% human albumin solution at physiological temperature were found to be 1541.1 m s(-1) +/- 1.3 m s(-1), 1551.3 m s(-1) +/- 1.3 ms(-1) and 1547.3 m s(-1) +/- 1.0 m s(-1), respectively. The results provide unique data over the diagnostic and therapeutic ultrasonic frequency range that can be used as input data for theoretical models that attempt to simulate nonlinear pressure fields and temperature rises from medical ultrasonic transducers.

Spectrum of Lysosomal storage disorders at a medical genetics center in northern India.

BACKGROUND: There is limited literature available on the phenotypic and mutation spectrum of Indian patients with Lysosomal storage disorders (LSD). OBJECTIVE: To elucidate the clinical, biochemical and mutation spectrum and to study the management options in Indian patients with lysosomal storage disorders. DESIGN: Descriptive study. SUBJECTS AND METHODS: All patients with lysosomal storage disorders diagnosed in the Medical Genetics department of a tertiary care institute in North India over a three year period from January 2008 to December 2010. RESULTS: Out of the total of 93 patients clinically suspected to have LSDs, 68 (mean age at presentation 4.5 years) were confirmed to have LSDs based on the laboratory/neuroimaging findings and documentation of deficient enzymatic activity in the peripheral blood (leucocytes or plasma) and/or skin fibroblasts. The commonest clinical features at presentation were growth retardation (failure to thrive 47.2% and short stature 17.6%), hepatosplenomegaly (41.2%) and neuroregression (33.8%). A history of consanguinity was present in 32.4% of the families. Prenatal diagnosis was done in a total of 6 affected families; two pregnancies were found to be affected (one each with Gaucher disease and Tay Sachs disease) and in both cases the parents opted for termination of pregnancy. Of the remaining four pregnancies which were found to be unaffected and therefore continued, three were confirmed to be normal on post-natal follow up. Enzyme replacement therapy (ERT) is being given for a total of 8 LSD patients and all of them are showing a gradual amelioration of their symptoms and an improvement in the quality of life. CONCLUSIONS: Lysosomal storage disorders constitute an important group of genetic metabolic disorders for many of which therapeutic options are now available.

MR derived volumetric flow rate waveforms at locations within the common carotid, internal carotid, and basilar arteries.

The volumetric flow rate (VFR) waveform over the cardiac cycle in the cerebral vasculature is a significant factor in many studies, which involve cerebrovascular function. Perhaps contrary to expectation, the literature in this area is sparse and the characteristics of blood flow waveforms are ill defined. A better understanding of the variation of blood flow rate and pulsatility may aid our knowledge of risk factors involved in diseases and conditions, such as stroke, arteriovenous malformation, or aneurysm rupture. This study sought to characterise the blood flow waveform over the cardiac cycle at levels within the carotid artery and basilar artery (BA) in a normal cohort. The study cohort consisted of 22 subjects (recruitment age: 20 to 40 years) with no history of vascular disease (median age=26 years, interquartile range=25 to 32 years). Two-dimensional quantitative phase-contrast magnetic resonance imaging was performed on each subject at nine anatomic locations within the carotid artery and BA. Significant differences in pulsatility were present within the carotid tree. Archetypal VFR waveforms were established for this group at the nine locations. A normal individual's VFR waveform at a location within the carotid tree can be estimated by taking the group's archetypal waveform for that location, and scaling by the individual's average flow rate.