Systemic artery to pulmonary artery aneurysm malformations associated with variants at MCF2L.

Arteriovenous malformations (AVM) are characterized by abnormal vessels connecting arteries and veins resulting in a disruption of normal blood flow. Hereditary hemorrhagic telangiectasia (HHT) is the most common cause of pulmonary AVM characterized by a right to left shunt. Here we describe a distinct malformation where the flow of blood was from a systemic artery to the pulmonary artery (PA) resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT. This distinct malformation was identified in seven probands, one from a multiplex family containing 10 affected individuals from five generations. To identify the molecular basis of this distinct malformation, we performed exome sequencing (ES) on the seven probands and the affected paternal female cousin from the multiplex family. PhenoDB was used to prioritize candidate causative variants along with burden analysis. We describe the clinical and radiological details of the new systemic artery to PA malformation with or without pulmonary artery aneurysm (SA-PA(A)) and recommend distinct treatment techniques. Moreover, ES analysis revealed possible causative variants identified in three families with variants in a novel candidate disease gene, MCF2L. Further functional studies will be necessary to better understand the molecular mechanisms involved on SA-PA(A) malformation, however our findings suggest that MCF2L is a novel disease gene associated with SA-PA(A).

Diversity and geographic distribution of soil streptomycetes with antagonistic potential against actinomycetoma-causing Streptomyces sudanensis in Sudan and South Sudan.

BACKGROUND: Production of antibiotics to inhibit competitors affects soil microbial community composition and contributes to disease suppression. In this work, we characterized whether Streptomyces bacteria, prolific antibiotics producers, inhibit a soil borne human pathogenic microorganism, Streptomyces sudanensis. S. sudanensis represents the major causal agent of actinomycetoma - a largely under-studied and dreadful subcutaneous disease of humans in the tropics and subtropics. The objective of this study was to evaluate the in vitro S. sudanensis inhibitory potential of soil streptomycetes isolated from different sites in Sudan, including areas with frequent (mycetoma belt) and rare actinomycetoma cases of illness. RESULTS: Using selective media, 173 Streptomyces isolates were recovered from 17 sites representing three ecoregions and different vegetation and ecological subdivisions in Sudan. In total, 115 strains of the 173 (66.5%) displayed antagonism against S. sudanensis with different levels of inhibition. Strains isolated from the South Saharan steppe and woodlands ecoregion (Northern Sudan) exhibited higher inhibitory potential than those strains isolated from the East Sudanian savanna ecoregion located in the south and southeastern Sudan, or the strains isolated from the Sahelian Acacia savanna ecoregion located in central and western Sudan. According to 16S rRNA gene sequence analysis, isolates were predominantly related to Streptomyces werraensis, S. enissocaesilis, S. griseostramineus and S. prasinosporus. Three clusters of isolates were related to strains that have previously been isolated from human and animal actinomycetoma cases: SD524 (Streptomyces sp. subclade 6), SD528 (Streptomyces griseostramineus) and SD552 (Streptomyces werraensis). CONCLUSION: The in vitro inhibitory potential against S. sudanensis was proven for more than half of the soil streptomycetes isolates in this study and this potential may contribute to suppressing the abundance and virulence of S. sudanensis. The streptomycetes isolated from the mycetoma free South Saharan steppe ecoregion show the highest average inhibitory potential. Further analyses suggest that mainly soil properties and rainfall modulate the structure and function of Streptomyces species, including their antagonistic activity against S. sudanensis.

Basidiobolus haptosporus-like fungus as a causal agent of gastrointestinal basidiobolomycosis.

Basidiobolus species were isolated from colonic biopsy samples of patients with gastrointestinal basidiobolomycosis (GIB) in southern Saudi Arabia. Isolated fungi were initially identified using classical mycological tools and confirmed by sequence analysis of the large subunit ribosomal RNA gene. Phenotypic tests revealed zygomycete-like fungi which conform to those of Basidiobolus species. Five sequenced strains formed a monophyletic clade in the 28S ribosomal RNA gene phylogenetic tree. They shared 99.97% similarity with B. haptosporus and 99.97% with B. haptosporus var. minor, and relatively lower similarity with B. ranarum (99.925%). The study suggests a new and a serious causal agent of GIB related to Basidiobolus haptosporus. These isolates are not related to B. ranarum, which is commonly linked to this disease.

Multidrug-Resistant Acinetobacter baumannii: An Emerging Health Threat in Aseer Region, Kingdom of Saudi Arabia.

OBJECTIVE: The study aims to determine the prevalence of multidrug-resistant A. baumannii in Aseer Region, Kingdom of Saudi Arabia. METHODS: This study evaluated the antibiotic susceptibility of ninety-four (n = 94) clinical isolates of A. baumannii. The isolates were collected from the south region of Saudi Arabia, and notably Aseer Region, during the period from 15 October 2014 to 15 January 2015. The isolates were tentatively identified as A. baumannii by routine bench tests and were confirmed by using VITEK® 2 Compact. The latest instrument was used to identify antibiotic susceptibility of these isolates. RESULTS: Antibiotic susceptibility in this study showed that 69% of these isolates were multidrug-resistant strains. Moreover, they were highly resistant to carbapenem drugs. Several strains of these isolates were found to be extremely resistant to test antibiotics and were only sensitive to one or two of them. CONCLUSION: High rate of multidrug-resistant A. baumannii bacteraemia has emerged in the south region of Saudi Arabia as an important health problem. Therefore, it is considered as a new threat in hospitals, which requires a tremendous effort to stop its escalation and spread.

Osteoblastic cells regulate the haematopoietic stem cell niche.

Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.

A multimodality approach to decreasing ICU infections by hydrogen peroxide, silver cations, and compartmentalization.

PURPOSE: Hospital-acquired infections in the Intensive Care Unit (ICU) account for an increase in morbidity and mortality leading to serious health complications. This study aims to determine the effect of a multimodality approach including disinfection and physical separation on the infections prevailing in ICU. METHODS: The study employed prospective cross-over analysis to assess the 738 individuals (560 males and 178 females) at the ICU, Aseer Central Hospital, Saudi Arabia. The intervention programs were carried out for 3 years (2013-2015). It included the application of hydrogen peroxide and silver cations, physical separation, and compartmentalization of ICU. Acinetobacter spp., E. coli, and staphylococci were isolated, identified, and used to evaluate the efficacy of the intervention program. RESULTS: The results provide endotracheal tube as the main specimen type (34.7%) followed by blood (29.1%), tracheal secretion (7.7%), wound (6%), urine (5.7%), throat swab (5.4%), sputum (3.7%), and other specimens (7.7%). It also showed the infection rate decreased from 14.3% to 4% in the last three months after continuous interventions (R2 = 0.44). There was a decrease in the occurrence of bacteria after an intervention (p = 0.036). CONCLUSION: The outcome of the study revealed that mist and separation measures offered a significant decrease in infections at the ICU as per the measurement of the most hazardous nosocomial pathogens.

Clinical Relevance and Antimicrobial Profiling of Methicillin-Resistant Staphylococcus aureus (MRSA) on Routine Antibiotics and Ethanol Extract of Mango Kernel (Mangifera indica L.).

Methicillin-resistant Staphylococcus aureus (MRSA) is known for serious health problems. Testing new inexpensive natural products such as mango kernel (Mangifera indica L., Anacardiaceae) may provide alternative and economically viable anti-MRSA drugs. In the current study, we screened clinical isolates from Aseer Central Hospital, Saudi Arabia, during 2012-2017 for MRSA and tested an ethanolic extract of mango kernel for anti-MRSA activity. Brief confirmation of MRSA was performed by the Vitek 2 system, while antibiotic sensitivity of strains was tested for their clinical relevance. The In vitro disc diffusion method was used to test the anti-MRSA activity of the ethanolic mango kernel extract. The antimicrobial activity of mango kernel was compared to that of standard drugs (oxacillin and vancomycin). Of the identified 132 S. aureus strains, 42 (31.8%) were found to be MRSA and their prevalence showed a clear increase during the last two years (2016-2017; p < 0.001). MRSA strains showed 100% sensitivity to vancomycin, teicoplanin, linezolid, tetracycline, daptomycin, tigecycline, and tobramycin and 100% resistance to ampicillin and 98% to penicillin. The ethanolic extracts of mango kernel were found active against both S. aureus and the MRSA strains. Inhibitory activities (mean ± SE) were achieved at concentrations of 50 mg/mL (20.77 ± 0.61), 5 mg/mL (16.18 ± 0.34), and 0.5 mg/mL (8.39 ± 0.33) exceeding that of vancomycin (p=0.0162). MRSA strains were sensitive to mango kernel extracts when compared to vancomycin. Therefore, ethanolic extracts of mango kernel can be escalated to animal model studies as a promising leading anti-MRSA drug candidate and can be an economic alternative to high-priced synthetic antibiotics.

Isolation and Identification of Streptomyces spp. from Desert and Savanna Soils in Sudan.

The purpose of this study was to investigate streptomycete populations in desert and savanna ecozones in Sudan and to identify species based on 16S rRNA gene sequences. A total of 49 different Streptomyces phenotypes (22 from sites representing the desert and semi-desert ecozone; 27 representing the savanna ecozone) have been included in the study. The isolates were characterized phenotypically and confirmed using 16S rRNA gene sequence analysis. The two ecozones showed both similarities and uniqueness in the types of isolates. The shared species were in cluster 1 (Streptomyces (S.) werraensis), cluster 2 (Streptomyces sp.), cluster 3 (S. griseomycini-like), and cluster 7 (S. rochei). The desert ecozone revealed unique species in cluster 9 (Streptomyces sp.) and cluster 10 (S. griseomycini). Whereas, the savanna ecozone revealed unique species in cluster 4 (Streptomyces sp.), cluster 5 (S. albogriseolus/ S. griseoincarnatus), cluster 6 (S. djakartensis), and cluster 8 (Streptomyces sp.). Streptomycetes are widely distributed in both desert and the savanna ecozones and many of these require full descriptions. Extending knowledge on Streptomyces communities and their dynamics in different ecological zones and their potential antibiotic production is needed.

The Saccharomyces cerevisiae actin-related protein Arp2 is involved in the actin cytoskeleton.

Arp2p is an essential yeast actin-related protein. Disruption of the corresponding ARP2 gene leads to a terminal phenotype characterized by the presence of a single large bud. Thus, Arp2p may be important for a late stage of the cell cycle (Schwob, E., and R.P. Martin, 1992. Nature (Lond.). 355:179-182). We have localized Arp2p by indirect immunofluorescence. Specific peptide antibodies revealed punctate staining under the plasma membrane, which partially colocalizes with actin. Temperature-sensitive arp2 mutations were created by PCR mutagenesis and selected by an ade2/SUP11 sectoring screen. One temperature-sensitive mutant that was characterized, arp2-H330L, was osmosensitive and had an altered actin cytoskeleton at a nonpermissive temperature, suggesting a role of Arp2p in the actin cytoskeleton. Random budding patterns were observed in both haploid and diploid arp2-H330L mutant cells. Endocytosis, as judged by Lucifer yellow uptake, was severely reduced in the mutant, at all temperatures. In addition, genetic interaction was observed between temperature-sensitive alleles arp2-H330L and cdc10-1. CDC10 is a gene encoding a neck filament-associated protein that is necessary for polarized growth and cytokinesis. Overall, the immunolocalization, mutant phenotypes, and genetic interaction suggest that the Arp2 protein is an essential component of the actin cytoskeleton that is involved in membrane growth and polarity, as well as in endocytosis.

Suppression of mutations in mitochondrial DNA by tRNAs imported from the cytoplasm.

Mitochondrial import of a cytoplasmic transfer RNA (tRNA) in yeast requires the preprotein import machinery and cytosolic factors. We investigated whether the tRNA import pathway can be used to correct respiratory deficiencies due to mutations in the mitochondrial DNA and whether this system can be transferred into human cells. We show that cytoplasmic tRNAs with altered aminoacylation identity can be specifically targeted to the mitochondria and participate in mitochondrial translation. We also show that human mitochondria, which do not normally import tRNAs, are able to internalize yeast tRNA derivatives in vitro and that this import requires an essential yeast import factor.

Fungal peritonitis caused by Pichia kudriavzevii following sleeve gastrectomy.

A 23-year-old female, who had undergone a sleeve gastrectomy two weeks earlier, presented with abdominal complaints. A CT scan showed portal vein thrombosis, bowel ischemia, and intra-abdominal sepsis. Anastomosis and antibiotic therapy were not successful, and the patient went into multi-organ failure and died. Multiple cultures revealed a yeast fungus confirmed as Pichia kudriavzevii using rRNA gene sequencing. We report the first case of peritonitis in association with P kudriavzevii. In addition to the abdominal complications and surgical interventions, the yeast was found to have significantly contributed to the patient's death. SIMILAR CASES PUBLISHED: None. CONFLICT OF INTEREST: None.

Antimicrobial Efficiency of Essential Oils from Traditional Medicinal Plants of Asir Region, Saudi Arabia, over Drug Resistant Isolates.

Antimicrobial resistance (AMR) is a recurring global problem, which constantly demands new antimicrobial compounds to challenge the resistance. It is well known that essential oils (EOs) have been known for biological activities including antimicrobial properties. In this study, EOs from seven aromatic plants of Asir region of southwestern Saudi Arabia were tested for their antimicrobial efficacy against four drug resistant pathogenic bacterial isolates (Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Streptococcus typhimurium) and one fungal isolate (Candida albicans). Chemical compositions of EOs were determined by gas chromatography-mass spectrometry (GC-MS). The results revealed that EOs from Mentha cervina, Ocimum basilicum, and Origanum vulgare proved most active against all isolates with inhibitory zone range between 17 and 45 mm. The lowest minimum inhibitory concentration (MIC) of 0.025mg/ml was observed for Staph. aureus and Streptococcus pyogenes with EO of Origanum vulgare. All the three EOs showed significant anticandida activity. The results related to EOs from Mentha cervina, Ocimum basilicum, and Origanum vulgare demonstrated significant antimicrobial efficacy against drug resistant microorganisms.

Anomalous right subclavian artery and coarctation-related aneurysm repaired with bilateral subclavian-to-carotid transposition and exclusion stent-grafting.

INTRODUCTION: Aortic arch anomalies are common; however, the presence of concomitant pathology may present a complex management problem. REPORT: A 42 year old lady with anomalous right subclavian artery was found to have recurrent coarctation of the aorta and an aneurysm related to the previous repair. Management of the aneurysm was complicated by the proximity of subclavian artery origins. Bilateral subclavian-to-carotid transposition was undertaken to preserve antegrade vertebral artery flow, with subsequent exclusion stent-grafting of the aneurysm and coarctation. DISCUSSION: This case illustrates combined surgical and interventional radiological repair to deal with a complex thoracic aortic clinical problem.

Fungal keratitis caused by a rare ocular pathogen, Gjaerumia minor: A case report.

Fungal keratitis is an important infection of the eye that may cause devastating effects. Keratitis caused by fungi has been described in many parts of the world mainly in tropical countries. The objective of this study is to report a serious eye infection in an adult with a known history of diabetes caused by an uncommon yeast fungus with details of clinical findings and laboratory investigations. Left eye visual acuity was no perception of light due to end stage neovascular glaucoma. The patient was pseudophakic in both eyes. Culture of a corneal scraping showed yeast like organism on Sabouraud dextrose agar. Gjaerumia minor, a rare yeast but with history of a pulmonary infection in the region, was confirmed with 98% similarity in the large subunit ribosomal RNA gene (accession KY690175). Topical Amphotericin B and oral fluconazole were initiated. The patient showed gradual improvement, epithelial defect healed, infiltration steadily regressed and hypopyon disappeared. We report the first case of fungal keratitis caused by G. minor in Saudi Arabia. Fungal Keratitis should be considered in cases where clinical response to the conventional antibacterial antibiotic treatment is not optimal.

Functional expression of kinin B1 and B2 receptors in mouse abdominal aorta.

Previous studies have shown that the vascular reactivity of the mouse aorta differs substantially from that of the rat aorta in response to several agonists such as angiotensin II, endothelin-1 and isoproterenol. However, no information is available about the agonists bradykinin (BK) and DesArg(9)BK (DBK). Our aim was to determine the potential expression of kinin B(1) and B(2) receptors in the abdominal mouse aorta isolated from C57BL/6 mice. Contraction and relaxation responses to BK and DBK were investigated using isometric recordings. The kinins were unable to induce relaxation but concentration-contraction response curves were obtained by applying increasing concentrations of the agonists BK and DBK. These effects were blocked by the antagonists Icatibant and R-715, respectively. The potency (pD(2)) calculated from the curves was 7.0 +/- 0.1 for BK and 7.3 +/- 0.2 for DBK. The efficacy was 51 +/- 2% for BK and 30 +/- 1% for DBK when compared to 1 microM norepinephrine. The concentration-dependent responses of BK and DBK were markedly inhibited by the arachidonic acid inhibitor indomethacin (1 microM), suggesting a mediation by the cyclooxygenase pathway. These contractile responses were not potentiated in the presence of the NOS inhibitor L-NAME (1 mM) or endothelium-denuded aorta, indicating that the NO pathway is not involved. We conclude that the mouse aorta constitutively contains B(1) and B(2) subtypes of kinin receptors and that stimulation with BK and DBK induces contractile effect mediated by endothelium-independent vasoconstrictor prostanoids.

Multidrug resistance Acinetobacter species at the intensive care unit, Aseer Central Hospital, Saudi Arabia: A one year analysis.

OBJECTIVE: To identify and to determine the antimicrobial susceptibility of Acinetobacter baumannii (A. baumannii) clinical isolates from ICU at Aseer Central Hospital. METHODS: The study was conducted in the Intensive Care Unit, Aseer Central Hospital, Saudi Arabia over 13 months period (2014-2015). Acinetobacter species (n = 105) were isolated from various clinical samples. Isolates were identified using selected phenotypic criteria and confirmed using the Vitek 2 automated system. This system was used to determine the susceptibilities of 21 antimicrobial agents. Patients, isolates and drug data were analyzed using the SPSS statistical software package to determine some epidemiological and microbiological patterns. RESULTS: Of the 105 stains, A. baumannii accounted for 49 (46.67%), A. baumannii complex, 19 (18.09%), A. baumannii/haemolyticus 32 (30.47), Acinetobacter haemolyticus 4 (3.81%), Acinetobater lwoffii 1 (0.95%) and unidentified Acinetobater species 2 (1.3%). Of the 105 Acinetobacter strains, 103 (98.1%) were found multidrug resistant (MDR). A. baumannii strain were 100% sensitive to colistin and 74.5% to trimethoprim + sulfamethoxazole. The remaining 19 antimicrobial agents revealed low or no sensitivities: amikacin 16.3%; ampicillin 7.7%; ceftazidime, 7.3%. Distribution of similar sensitivities was shown by other Acinetobacter species. Mean number of isolates from males and females indicates no statistical variation (P = 0.867) whereas age groups showed significant differences (P = 0.008) as it is clear from the high percentage of infected individuals more than 60 years followed by those aged 20-29 years old (19.05%). Upper respiratory tract (30.48%), lower respiratory tract (47.65%) and subcutaneous tissue (9.5%) were the main sources of Acinetobacter spp. but mean numbers of isolates from these specimens indicate no discrepancy between specimens (P = 0.731). CONCLUSIONS: Acinetobacter species including A. baumannii were found MDR (98.1%) according to the current Acinetobacter spp. antimicrobial categorization. Approximately half of these strains were A. baumannii. All Acinetobacter species were 100% sensitive to colistin and to some extent to trimethoprim + sulfamethoxazole (74.5%). ICU-acquired pneumonia among patients over 60 years of age who spend prolong times at artificial ventilations made up the majority of the cases.

Neurospora crassa mitochondrial transfer RNAs.

Total mitochondrial tRNA from Neurospora crassa was characterized by base composition analysis, one- and two-dimensional gel electrophoreses and reversed-phase chromatography on RPC5. The guanosine + cytidine content was about 43%, as compared to 60% for cytoplasmic tRNA. The modified nucleoside content was low and about the same as that of total yeast mitochondrial tRNA, though the G + C content is very different. We found psi, T, hU, t6A, m1G, M2G, m22G. Neither the eukaryotic "Y" base, nor the prokaryotic s4U were present. On two-dimensional polyacrylamide gel electropherograms about 25 species were separated. One species for phenylalanine, two for leucine and two for methionine could be located. Neurospora crassa mitochondrial tRNA does not hybridize with yeast mitochondrial DNA.

Quantification of pressure gradients across stenotic valves by Doppler ultrasound.

Two-dimensional echocardiography has proven very useful in assessing valvular heart disease, but the technique is limited in certain groups of patients and is unable to quantify a transvalvular pressure gradient. Advances in the Doppler ultrasound techniques have made it possible to noninvasively measure velocity of flow across a stenotic heart valve and to calculate the pressure gradient. A commercially available, continuous and pulse wave Doppler instrument was utilized to assess the transvalvular pressure gradient in patients with mitral and aortic stenosis and the transmitral pressure half-time to calculate mitra valve area. Thirty-five consecutive adult patients with suspected aortic stenosis and 30 adult patients with suspected mitral stenosis underwent Doppler ultrasound examination within 24 hours of cardiac catheterization. An adequate Doppler examination was obtained in 81% of the patients with aortic stenosis, with a correlation between the Doppler-derived transaortic gradient and the catheterization-derived gradient of 0.94. The Doppler-measured gradient accurately separated those patients with significant aortic stenosis (gradients of greater than 50 mm Hg) from those patients with noncritical aortic stenosis. Similarly, an adequate Doppler examination was obtained in 90% of the adult patients with mitral stenosis. There was also close correlation between the mitral valve area and mean pressure gradient measured by the Doppler technique and that obtained at the time of cardiac catheterization (r = 0.87 and 0.85, respectively). The Doppler technique proved to be useful in those patients who had also undergone prior mitral commissurotomy. This study confirms that the combined continuous pulse wave Doppler technique will serve as a valuable addition to the diagnostic capabilities offered by echocardiography.

Arrhythmias before and after anatomic correction of transposition of the great arteries.

Cardiac rhythm has been evaluated using 24 hour ambulatory electrocardiographic (ECG) recordings in 92 survivors of anatomic correction of transposition of the great arteries. A low incidence of arrhythmias was found in preoperative recordings made in 41 patients. Thirty-four (83%) patients showed sinus rhythm exclusively; one (2.4%) patient had supraventricular premature beats and one (2.4%) paroxysmal atrial fibrillation. Six patients (14.6%) had ventricular arrhythmias, five (12.2%) with modified Lown grade 1 ventricular premature beats and one (2.4%) with a modified Lown grade 5 arrhythmia. The incidence of arrhythmias was unchanged after a first stage operation consisting of banding of the pulmonary artery with or without insertion of a systemic to pulmonary shunt. During a mean 3.1 year follow-up, there have been no cases of arrhythmic death or symptomatic arrhythmias requiring treatment. Postoperative recordings in 40 patients have shown a low incidence of important arrhythmias with 62% having recordings free from arrhythmias. There was an increase in the incidence of infrequent supraventricular premature beats from 4.9% preoperatively to 23% postoperatively (p less than 0.05), with no significant change in the incidence of ventricular arrhythmias. One patient has acquired complete heart block but all others had sinus rhythm postoperatively. Preoperative arrhythmias are uncommon in patients with transposition of the great arteries and are similar to those described in normal children. The incidence of important arrhythmias after anatomic correction is low during the medium-term period of follow-up. Further longitudinal studies will be required to determine whether this promising result is maintained.