Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients

BackgroundWalker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them.MethodsWe retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated.ResultsAll patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally.ConclusionWWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.     

The antiprotozoal activity of methylated flavonoids from Ageratum conyzoides L.

Aim of the study

The dichloromethane extract prepared from aerial parts of Ageratum conyzoides L. (Asteraceae), a plant commonly used in folk medicine for a number of illnesses including sleeping sickness, was recently found to exhibit a prominent activity (IC₅₀ = 0.78 μg/mL) against bloodstream forms of Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). This extract also exhibited noticeable activities against Leishmania donovani (Kala-Azar, IC₅₀ = 3.4 μg/mL) as well as Plasmodium falciparum (Malaria tropica, IC₅₀ = 8.0 μg/mL). In the current study, we sought for potentially active constituents of Ageratum conyzoides.

Materials and methods

Extracts prepared with solvents of different polarity were tested for activity against the above mentioned parasites as well as against Trypanosoma cruzi (Chagas’ disease) and for cytotoxicity using established protocols. The dicholoromethane extract showed the highest level of activity and was chosen for phytochemical studies aimed at the isolation of potential active constituents.

Results and conclusion

Five highly methoxylated flavonoids along with the chromene derivative encecalol methyl ether were isolated. All isolated compounds were previously reported from Ageratum conyzoides. While the chromene turned out to be inactive against the tested parasites, the flavonoids showed activity against the protozoan pathogens, some in the lower micromolar range. However, none of these isolated compounds was as active as the crude extract. This is the first report on antiprotozoal activity of this plant species and some of its constituents. The chemical principle accounting for the high activity of the crude extract, however, remains to be identified.     

Exposure to Vehicular Pollution and Assessment of Respiratory Function in Urban Inhabitants

Particulate matter less than PM₁₀ and aromatic chemicals formed during incomplete combustion of organic matter are major environmental pollutants because of their toxic potential. The present study reports on the respiratory morbidity pattern of people exposed to auto exhaust as a result of the traffic load consisting of three varieties of vehicles (heavy, medium, and light) at three different points: North (B), South (E), and Central (C) regions of Kolkata, India. Particle size distribution was analyzed by an Anderson cascade impactor and volatile organic compounds (VOCs) were analyzed by sorbent tube and capillary gas chromatography with flame ionization detector. Levels of VOCs, particularly benzene and toluene (at B, 15.2 and 20.1 μg/m³; at E, 67.4 and 74.6 μg/m³, and at C, 40.7 and 61.3 μg/m³, respectively), were found to be appreciably high in three sites in Kolkata compared with the values reported by the U.S. EPA. PM₁₀ concentrations also have been found to be higher than the Central Pollution Control Board of India’s permissible standard (≤10 μm: B, 535.9; E, 909.2; C, 1114.5 μg/m³; <10–3.3 μm: B, 269.8 μg/m³; E, 460.1; C, 679.2 μg/m³; and <3.3–0.4 μm: B, 266.1; E, 449.1; C, 435.3 μg/m³). Pulmonary function tests (PFT) of 505 inhabitants were performed in the three different areas using Spirovit SP-10 and Wrights peak flowmeter. The traffic load in the vicinity supported the occurrence of higher respiratory functional deterioration. PFT status showed restrictive (3.76%), obstructive (3.17%), and combined restrictive and obstructive types (1.98%) of impairment. Higher restrictive impairments in males might be due to their combined occupational and environmental exposures. The rate of increase of the number of vehicles on the roads of the city adds to the risk of greater problems due to exposure to hazardous substances that are less than PM₁₀, in particular, polycyclic aromatic hydrocarbons and VOCs. An erratum to this article can be found at     

Novel Marine Compounds: Anticancer or Genotoxic?

In the past several decades, marine organisms have generouslygifted to the pharmaceutical industries numerous naturallybioactive compounds with antiviral, antibacterial,antimalarial, anti-inflammatory, antioxidant, and anticancerpotentials. But till date only few anticancer drugs (cytarabine,vidarabine) have been commercially developed from marinecompounds while several others are currently in differentclinical trials. Majority of these compounds were tested in thetumor xenograft models, however, lack of anticancer potentialdata in the chemical- and/or oncogene-induced pre-initiationanimal carcinogenesis models might have cost some of the marineanticancer compounds an early exit from the clinical trials. Thisreview critically discusses importance of preclinicalevaluation, failure of human clinical trials with certainpotential anticancer agents, the screening tests used, and choiceof biomarkers.     

Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome

The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression.     

Development of a novel pulsatile bioreactor for tissue culture

The construction of tissue-engineered parts such as heart valves and arteries requires more than just the seeding of cells onto a biocompatible/biodegradable polymeric scaffold. It is essential that the functionality and mechanical integrity of the cell-seeded scaffold be investigated in vitro prior to in vivo implantation. The correct hemodynamic conditioning would lead to the development of tissues with enhanced mechanical strength and cell viability. Therefore, a bioreactor that can simulate physiological conditions would play an important role in the preparation of tissue-engineered constructs. In this article, we present and discuss the design concepts and criteria, as well as the development, of a multifunctional bioreactor for tissue culture in vitro. The system developed is compact and easily housed in an incubator to maintain sterility of the construct. Moreover, the proposed bioreactor, in addition to mimicking in vivo conditions, is highly flexible, allowing different types of constructs to be exposed to various physiological flow conditions. Initial verification of the hemodynamic parameters using Laser doppler anemometry indicated that the bioreactor performed well and produced the correct physiological conditions.     

A long-term study of bone mineral density in patients with phenylketonuria under diet therapy

Introduction

Dietary control of classic phenylketonuria (PKU) needs restriction of natural proteins; adequate protein intake is achieved by adding low phenylalanine (phe) formulae. The adequacy of this diet for normal bone mineralization had not been sufficiently evaluated. Our aim was to evaluate and follow up bone mineral density (BMD) in children and adolescents with PKU within a 2-year time interval to assess the adequacy of a phenylalanine restricted diet for bone mineralization and to search for a possible relationship between BMD, dietary control and blood phenylalanine (phe) concentrations.

Material and methods

Thirty-two patients with classic PKU (3-19 years) were evaluated for their bone mineral status using dual energy X-ray absorptiometry (DEXA) both at the beginning (baseline) and the end (follow-up) of the study.

Results

Low BMD was detected in 31.25% at the start and in 6.25% of patients after 2 years follows-up. No relationship was found between BMD and the duration of diet compliance and phe level as well.

Conclusions

In this study the low BMD detected in our patients was both at baseline and follow-up independent of diet restriction. A yearly DEXA would be highly beneficial for early detection and treatment, thus preventing osteoporosis and decreasing the risk of fractures. We also suggest the importance of searching for new emerging therapies such as enzyme substitution or gene therapy as low protein diet compliance was not enough to maintain normal bone mineral density.     

Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing

ObjectiveWe explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory.MethodsThe combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression.ResultsFourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes.ConclusionsWomen with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.     

Prelabour myocardial deformation and cardiac output in fetuses that develop intrapartum compromise at term: a prospective observational study

Objective: Redistribution of cardiac output is responsible for the “brain sparing” effect seen during periods of acute or chronic fetal stress. We investigated the relationship between prelabour cardiac function in fetuses that subsequently developed intrapartum fetal compromise (IFC).

Methods: A blinded, prospective, observational, cohort study, at Mater Mother’s Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent ultrasound every 2 weeks from 36 weeks until delivery. Fetal cardiac output was assessed by conventional Doppler ultrasound and myocardial deformation was measured using velocity vector imaging.

Results: Two hundred and seventy three women were included in the final analysis, of which 19% had an emergency operative delivery for intrapartum fetal compromise (IFC). Global left ventricular strain (?12.1%, interquartile ranges (IQR)???10.3 to ?14% versus 13%, IQR ?11.3 to ?14.2%, p?=?.01) and strain rate (?1.00, IQR 0.85–1.16?s^?1 versus ?1.11, IQR ?1.00 to ?1.21?s^?1, p??1 versus 1.13?±?0.22?s^?1, p?p?p?Conclusion: Lower global left ventricular strain and strain rate and cardiac output are associated with IFC and poorer condition of the newborn. Assessment of fetal cardiac function may be useful for risk stratification for intrapartum fetal compromise in apparently “low risk” term pregnancies.