Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.

Prevalence and Determinants of Low Birth Weight among the Newborns in Dadra and Nagar Haveli: A Community-based Study.

Background: The world is not on track to meet the World Health Assembly (WHA) global target on Low Birth Weight (LBW). To estimate the prevalence and to identify the associated determinants of LBW among the newborns. Material and Methods: We conducted a cross-sectional study among the 364 mothers registered under the all government health facilities of Dadra & Nagar Haveli (DNH) during November 2021 to January 2022. Results: The prevalence of LBW was found to be 39%. On uni-variable logistic regression, live in relationship, caste, weight of mother, Body Mass Index (BMI), weight gain <5 kg in 2nd and 3rd trimester, high-risk pregnancy, complication present in previous pregnancy and preterm delivery, while on multi-variable logistic regression, weight gain <5 kg in 2nd and 3rd trimester (AOR 2, 95% CI 1.007-4.2) and having high-risk pregnancy (AOR 2, 95% CI 1.1-3.0) were found to be the significant predictors of LBW among the newborns. Conclusions: We conclude from the study that the prevalence of low birth weight among the newborn was high. There is a need to address maternal and child health issues like low birth weight, malnutrition and high-risk pregnancy under the RMNCAH+N program through various effective interventions. Future research should evaluate the feasibility of collaborative activities between RMNCAH+N program and the UNICEF in India.

Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Prion protein conversion at two distinct cellular sites precedes fibrillisation.

The self-templating nature of prions plays a central role in prion pathogenesis and is associated with infectivity and transmissibility. Since propagation of proteopathic seeds has now been acknowledged a principal pathogenic process in many types of dementia, more insight into the molecular mechanism of prion replication is vital to delineate specific and common disease pathways. By employing highly discriminatory anti-PrP antibodies and conversion-tolerant PrP chimera, we here report that de novo PrP conversion and formation of fibril-like PrP aggregates are distinct in mechanistic and kinetic terms. De novo PrP conversion occurs within minutes after infection at two subcellular locations, while fibril-like PrP aggregates are formed exclusively at the plasma membrane, hours after infection. Phenotypically distinct pools of abnormal PrP at perinuclear sites and the plasma membrane show differences in N-terminal processing, aggregation state and fibril formation and are linked by exocytic transport via synaptic and large-dense core vesicles.

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.

Core Shell Lipid-Polymer Hybrid Nanoparticles for Oral Bioavailability Enhancement of Ibrutinib via Lymphatic Uptake.

The purpose of this research was to develop ibrutinib (IBR)-loaded lipid-polymer hybrid nanoparticles (IBR-LPHNPs) to improve oral absorption by intestinal lymphatic uptake. IBR-LPHNPs were fabricated by nanoprecipitation method using poly(lactic-co-glycolic acid), lipoid S 100, and DSPE-MPEG 2000. The IBR-LPHNPs showed particle size of 85.27±3.82 nm, entrapment efficiency of 97.70±3.85%, and zeta potential of -24.9±3.08 mV respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry study revealed compatibility between IBR and excipients. X-ray diffraction study showed the conversion of IBR into amorphous form. High-resolution transmission electron microscopic image displayed spherical-shaped, discrete layered polymeric core and lipid shell structure. The drug release from IBR-LPHNPs exhibited prolong release profile up to 48 h and was best fitted to Korsmeyer-Peppas model. Higher fluorescence intensity at the end of 2 h in the intestinal tissue confirmed the uptake of LPHNPs by Peyer's patches. The oral bioavailability of IBR was improved 22.52-fold with LPHNPs as compared to free IBR. The intestinal lymphatic uptake study in rats pretreated with cycloheximide confirmed the intestinal lymphatic uptake of IBR-LPHNPs. All the results conclusively showed that LPHNPs could be a promising approach to improve oral bioavailability of IBR.

The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum.

Background: Diagnostic testing for primary ciliary dyskinesia (PCD) started in 2013 in Palestine. We aimed to describe the diagnostic, genetic and clinical spectrum of the Palestinian PCD population. Methods: Individuals with symptoms suggestive of PCD were opportunistically considered for diagnostic testing: nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM) and/or PCD genetic panel or whole-exome testing. Clinical characteristics of those with a positive diagnosis were collected close to testing including forced expiratory volume in 1 s (FEV1) Global Lung Index z-scores and body mass index z-scores. Results: 68 individuals had a definite positive PCD diagnosis, 31 confirmed by genetic and TEM results, 23 by TEM results alone, and 14 by genetic variants alone. 45 individuals from 40 families had 17 clinically actionable variants and four had variants of unknown significance in 14 PCD genes. CCDC39, DNAH11 and DNAAF11 were the most commonly mutated genes. 100% of variants were homozygous. Patients had a median age of 10.0 years at diagnosis, were highly consanguineous (93%) and 100% were of Arabic descent. Clinical features included persistent wet cough (99%), neonatal respiratory distress (84%) and situs inversus (43%). Lung function at diagnosis was already impaired (FEV1 z-score median -1.90 (-5.0-1.32)) and growth was mostly within the normal range (z-score mean -0.36 (-3.03-2.57). 19% individuals had finger clubbing. Conclusions: Despite limited local resources in Palestine, detailed geno- and phenotyping forms the basis of one of the largest national PCD populations globally. There was notable familial homozygosity within the context of significant population heterogeneity.

Process Evaluation of COVID-19 Vaccination Sessions in Dadra and Nagar Haveli District During SARS-CoV-2 Pandemic.

Context: Efficient roll out of COVID-19 vaccines requires high-quality preparedness at all levels and robust planning and training regarding COVID-19 vaccination, use of CoWIN software, post-vaccination care and communication for all health functionaries. Aims: The current study attempts to fill the research gap in monitoring of COVID-19 vaccination session sites in tribal areas of UT of Dadra and Nagar Haveli (DNH) during COVID-19 pandemic. Methods and Material: It was a cross sectional observational study conducted from April to May 2021 at 36 purposively selected COVID-9 vaccination session sites. Sites were monitored independently for assessing various parameters like infrastructure, HR status, vaccine, logistics availability, and AEFI management using the WHO Session Site Monitoring Form for COVID-19 Vaccination. Results: Out of 36 session sites observed, three separate designated rooms were available at 21 (58.3%) sites. Almost two-third of the session sites (61.1%) had displayed information, education, communication (IEC) materials. Mean number of team members was 5.1 (SD 1.7). Adequate stock of vaccine vials and AD syringes, AEFI kits or anaphylaxis kits were available and biomedical waste segregation was as per guidelines at all the session sites. Conclusions: Logistics availability, safe injection practices, and COVID-appropriate behavior were adequate; however, infrastructure and post-vaccination care needs strengthening for successful rollout of COVID-19 vaccination.

Mother and child protection card as a resource tool for health care providers on VHND sessions: Providers' views in rural area of Valsad district in south Gujarat, India.

Background: The Mother and Child Protection card (MCP card) is used for tracking of each child right from conception till 3 years of age by community health workers. It is a rich source of information for HCPs about mother and child health. A well-versed health care provider (HCP) can deliver the services efficiently to the beneficiaries. Objectives: To assess knowledge of HCPs about information provided in the MCP card. Methodology: It was a descriptive cross-sectional study carried out in the rural area of Valsad. Nineteen HCPS were interviewed on VHND sessions for their knowledge about health information provided in MCP card. Results: Mean age of HCPs was 38.11 years with mean 9.3 years of work experience. Of these 94.7% were providing the MCP card while registering the beneficiary. Around 78.9% knew growth chart, 68.4% knew vaccination information and nearly half were aware about the various government schemes. About 36.84% could mention five cleans of safe delivery at home. Conclusion: HCPs were aware about vaccination, antenatal care, growth chart but their knowledge about five cleans of home delivery and postnatal care needs to be improved.

Continuing medical education about postexposure prophylaxis of rabies in tribal area medical college hospital of Gujarat, India: One step towards rabies elimination.

Background: Continuing Medical Education (CME) is an essential feature of the clinical practice and helps to improve the health care provider's ability to provide quality patient care. The World Health Organization has given a global strategic plan to end human deaths from dog-mediated rabies by 2030 known as "Zero by thirty." Methodology: A CME session was organized for staff nurses working in a tertiary medical care hospital of Valsad district about anti rabies vaccination. Ninety-one participants were administered the questionnaire about antirabies vaccine (ARV) and related practical aspects before and after the CME session. Results: Mean pre- and post-CME Score of the participants was 5.38 and 8.68 out of 10, respectively which was statistically significant. The majority of the participants could score from 5 to 6 (33, 36.2%) before CME which rose to 9 to 10 after CME (58, 63.7%). A total of 52 participants (57%) showed improvement in total score by more than 5 points after attending CME, whereas 13 (14%) showed no improvement. The maximum improvement (52.1%) was found in the fact that currently available vaccine vials are the same for intradermal (ID) and intramuscular (IM) regimes, followed by the need for immunoglobulins in category III animal bites (44.3%). Conclusion: CME showed significant improvement in knowledge regarding rabies and antirabies vaccination. The knowledge regarding the similar schedule for both adults and children needs improvement. Subsequent CME programs should focus on these aspects for the effective management of animal bite patients.

The Impact of the Covid-19 Pandemic on Applicants to Advanced Education in Pediatric Dentistry Programs and Recommendations for Virtual Interviews.

Purpose:To assess the impact of the Covid-19 pandemic on applicants for advanced education programs in pediatric dentistry in the United States and provide recom- mendations for virtual interviews (VI).
Methods:A cross-sectional survey was emailed to pediatric dentistry applicants in the 2020-2021 cycle.
Results:One hundred seventy-five applicants responded. Virtual interviews were the universal format during this timeframe. Forty-four percent admitted to applying to programs they were not initially strongly considering and 42 percent accepted inter- views they would have declined if they had to travel. Applicants found social events with residents only (80 percent), a program overview presentation (86 percent), a virtual tour (77 percent) and a question-and-answer session with residents (85 percent) to be helpful. One-on-one or paired faculty interviews were the most preferred inter- view method. More than half (55 percent) thought programs were not able to learn about them as effectively through virtual compared to an in-person format.
Conclusions: VI caused different applicant behavior due to the low time and financial investment. Applicants valued their time with residents to learn about programs, but were split in their preferences for virtual, in-person or hybrid interviews. Programs can use findings from this study to plan future recruitment cycles.

Graphene quantum dots: A review on the effect of synthesis parameters and theranostic applications.

The rising demand for early-stage diagnosis of diseases such as cancer, diabetes, neurodegenerative can be met with the development of materials offering high sensitivity and specificity. Graphene quantum dots (GQDs) have been investigated extensively for theranostic applications owing to their superior photostability and high aqueous dispersibility. These are attractive for a range of biomedical applications as their physicochemical and optoelectronic properties can be tuned precisely. However, many aspects of these properties remain to be explored. In the present review, we have discussed the effect of synthetic parameters upon their physicochemical characteristics relevant to bioimaging. We have highlighted the effect of particle properties upon sensing of biological molecules through 'turn-on' and 'turn-off' fluorescence and generation of electrochemical signals. After describing the effect of surface chemistry and solution pH on optical properties, an inclusive view on application of GQDs in drug delivery and radiation therapy has been given. Finally, a brief overview on their application in gene therapy has also been included.

Development of Self-Microemulsifying Drug Delivery System to Improve Nisoldipine Bioavailability: Cell Line and In Vivo Evaluations : Development of Self-Microemulsifying Drug Delivery System.

The authors attempted to fabricate a novel lipid-based formulation of a lipophilic drug, nisoldipine (NISO). As NISO belongs to BCS class 2 drug, it suffers from low bioavailability (5%). Hence, the research was intended to ameliorate oral bioavailability of NISO via intestinal lymphatic transport. The NISO loaded self microemulsifying drug delivery system (SMEDDS) (NISO SMEDDS) was prepared using Peceol, Cremophor EL, and Transcutol HP. The Cremophor EL and Transcutol HP at 1:1 ratio showed maximum microemulsifying area, and average globule size was 16.78 ± 0.97 nm with PDI 0.121 ± 0.024. Cellular uptake studies (confocal microscopy and flow cytometry) using Caco-2 cells depicted higher fluorescence with coumarin-6 loaded SMEDDS as that of coumarin-6 solution which indicated deeper penetration. Mean fluorescence intensity (MFI) of coumarin-6 loaded SMEDDS was significantly improved (9.92-fold) in contrast to coumarin-6 solution. The NISO SMEDDS showed enhanced permeability (5.02 times) across Caco-2 cells compared to NISO suspension. The bioavailability improvement with NISO SMEEDS was 2.14 times relative to suspension, and lymphatic uptake was involved in oral absorption of NISO SMEDDS.

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases. METHODS: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. RESULTS: Disease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV1) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. CONCLUSIONS: This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutation) and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.

Enhanced oral bioavailability of nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: In vitro, cell line and in vivo evaluation.

The present research work was aimed to explore the ability of nanostructured lipid carriers (NLCs) to improve oral bioavailability of Nintedanib esylate (NE) via lymphatic uptake. The NE loaded NLCs (NE-NLCs) were fabricated using high speed homogenization followed by probe sonication method and physiochemically characterized. The NE-NLCs had particle size of 125.7 ± 5.5 nm, entrapment efficiency of 88.5 ± 2.5% and zeta potential of -17.3 ± 3.5 mV. DSC and XRD studies indicated that NE was converted to amorphous form. TEM images showed uniformly distributed spherical shaped particles. In vitro release study of NE-NLCs showed drug release of 6.87 ± 2.72% in pH 1.2 and 92.72 ± 3.40% in phosphate buffer pH 6.8 and obeyed higuchi model. Lipolysis study showed higher amount of drug in aqueous layer in NE-NLCs compared to NE-suspension. Tissue distribution study showed deeper penetration of FITC loaded NLCs compared to FITC solution. The cellular uptake across Caco-2 cells exhibited more uptake of FITC loaded NLCs. Cytotoxicity study using A549 cell line revealed higher potential of NE-NLCs in inhibiting tumor cell growth in comparison to that of suspension. The oral bioavailability of NE was ameliorated over 26.31 folds after inclusion into NLCs in contrast to NE-suspension. Intestinal lymphatic uptake of NE-NLCs in cycloheximide treated mice was lower as compared to control without cycloheximide treatment. Thus, the developed NE-NLCs can be an encouraging delivery strategy for increasing oral bioavailability of NE via lymphatic uptake.

Nanostructured Lipid Carriers- A Versatile Carrier for Oral Delivery of Lipophilic Drugs.

BACKGROUND: Around 40% of newly discovered chemical entities in pharmaceutical industries have poor water solubility and hence they suffer from low oral bioavailability owing to undesirable physicochemical and pharmacokinetic properties. So, it is the challenge for the formulation scientists to develop the oral formulation that can mitigate the pitfalls associated with such lipophilic drugs. METHODS: Lipid nanoparticles hold a promising tool to decrease the pitfalls of lipophilic drugs as lipid components can effectively increase the absorption of drugs, which leads to improvement in oral bioavailability. They are also considered as safe because they are made up of physiological lipids, which are biocompatible and biodegradable in nature. Amongst the lipid nanoparticles, Nanostructured Lipid Carriers (NLCs) are the second-generation lipid nanoparticles and were developed to conquer the limitations of solid lipid nanoparticles. They increase the solubility, permeability, reduce metabolism, P-glycoprotein efflux, and thereby increase the bioavailability of poorly soluble drugs. CONCLUSION: This review highlights the various aspects of NLCs, such as structural components, types, in vivo fate, pharmacokinetic, toxicity, recent applications, and patent reviews of NLCs in drug delivery.

PCD Detect: enhancing ciliary features through image averaging and classification.

Primary ciliary dyskinesia (PCD) is an inherited disorder of the motile cilia. Early accurate diagnosis is important to help prevent lung damage in childhood and to preserve lung function. Confirmation of a diagnosis traditionally relied on assessment of ciliary ultrastructure by transmission electron microscopy (TEM); however, >50 known PCD genes have made the identification of biallelic mutations a viable alternative to confirm diagnosis. TEM and genotyping lack sensitivity, and research to improve accuracy of both is required. TEM can be challenging when a subtle or partial ciliary defect is present or affected cilia structures are difficult to identify due to poor contrast. Here, we demonstrate software to enhance TEM ciliary images and reduce background by averaging ciliary features. This includes an option to classify features into groups based on their appearance, to generate multiple averages when a nonhomogeneous abnormality is present. We validated this software on images taken from subjects with well-characterized PCD caused by variants in the outer dynein arm (ODA) heavy chain gene DNAH5. Examining more difficult to diagnose cases, we detected 1) regionally restricted absence of the ODAs away from the ciliary base, in a subject carrying mutations in DNAH9; 2) loss of the typically poorly contrasted inner dynein arms; and 3) sporadic absence of part of the central pair complex in subjects carrying mutations in HYDIN, including one case with an unverified genetic diagnosis. We show that this easy-to-use software can assist in detailing relationships between genotype and ultrastructural phenotype, improving diagnosis of PCD.

Preparation and Surface Modification of Polymeric Nanoparticles for Drug Delivery: State of the Art.

Nanotechnology is one of the emerging fields in drug delivery for targeting the drug to the site of action. The polymeric nanoparticles as drug delivery systems have gained importance for the last few decades. They offer advantages over liposomes, dendrimers, emulsions etc. Surface engineering of polymeric nanoparticles is widely utilized to effectively target the cells in various diseases such as cancer, HIV infection. Surface modified nanoparticles offer various advantages such as targeted drug delivery, reduction in side effects, dose reduction and improved therapeutic efficacy. Moreover, they can aid in improving physical and biochemical properties, pharmacokinetic and pharmacodynamic profiles of the drug. Surface modified polymeric nanoparticles can provide targeted delivery of drugs into specific cells, especially when targets are intracellularly localized. This approach of surface modification would be more advantageous for the delivery of various anticancer, anti-inflammatory, anti-HIV drugs for more effective therapy. This review focuses on the techniques used for the fabrication of polymeric nanoparticles, the material used for surface modification and their applications.

Hydrocephalus and diffuse choroid plexus hyperplasia in primary ciliary dyskinesia-related MCIDAS mutation.

OBJECTIVE: To report a neuroradiologic phenotype associated with reduced generation of multiple motile cilia (RGMC) and mutations in the multicilin gene. We hypothesize that the observed phenotype may reflect the emerging role that ependymal cilia play in regulating CSF production. METHOD: Clinical and radiologic records were retrospectively reviewed for 7 consecutive patients diagnosed by the Leicester UK national primary ciliary dyskinesia (PCD) diagnostic laboratory. RESULTS: On MRI scanning, all patients demonstrated hydrocephalus, choroid plexus hyperplasia (CPH), and arachnoid cysts. No patient had any sign of neurologic deficit. All patients had significant lung disease. CONCLUSIONS: We conclude that there is a high incidence of hydrocephalus, arachnoid cysts, and CPH in MCIDAS-associated RGMC. In all cases, the observed hydrocephalus seems arrested in childhood without progression or adverse neurologic sequelae. Our new observation of CPH, which is associated with CSF overproduction, is the first macroscopic evidence that ependymal cilia may be involved in the regulation of CSF production and flow. We suggest that brain imaging should be performed in all cases of RGMC and that a diagnosis of PCD or RGMC be strongly considered in patients with unexplained hydrocephalus and a lifelong "wet"-sounding cough.

Enhanced bioavailability and antihypertensive activity of nisoldipine loaded nanoemulsion: optimization, cytotoxicity and uptake across Caco-2 cell line, pharmacokinetic and pharmacodynamic studies.

Objective: The present study explored the antihypertensive activity of nisoldipine in oil in water nanoemulsion to improve its oral bioavailability via intestinal lymphatic uptake.Methods: Nanoemulsion was prepared by ultrasonication technique using Peceol, Cremophor EL and Transcutol HP as oil, surfactant and cosurfactant respectively. Optimization was done employing 32 full factorial design. The developed formulation was assessed for in vitro,cell line, ex vivo and in vivo studies.Results: The experimental results indicated homogeneity of the nanoemulsion with globule size of 62.35 ± 2.55 nm and PDI value of 0.108 ± 0.01 with negative zeta potential (-26.2 ± 3.6 mV). Transmission electron microscopy showed spherical oil globules morphology. The in vitro diffusion study showed significant increase in drug release from NE formulations (98.51 ± 2.64%) as compared to plain drug dispersion (29.73 ± 2.15%) in 0.1 N HCl + 0.5% SLS medium. Moreover, higher quantitative and qualitative uptake of nanoemulsion via Caco-2 cells showed superior intestinal absorption and improved therapeutic activity of nisoldipine when compared to drug dispersion. Pharmacokinetic and pharmacodynamic study confirmed significantly (p ˂ 0.05) greater bioavailability and antihypertensive activity of nisoldipine nanoemulsion when compared to its dispersion. These results are visualized in abstract figure.Conclusion: Thus, prepared nanoemulsion showed potential as oral delivery system for nisoldipine with superior oral bioavailability and therapeutic efficacy over drug dispersion.