Genomic variants in the coding region of neuronal nitric oxide synthase (NOS1) in infantile hypertrophic pyloric stenosis

Background

Infantile hypertrophic pyloric stenosis (IHPS) is a common childhood pathology affecting 1 to 5:1000 newborns, with a genetic background suggested by familial occurrence. Neuronal nitric oxide synthase (NOS1) is a candidate gene owing to its role in the relaxation of smooth musculature and the association of the −84g>a variant of NOS1 with IHPS.

Methods

We investigated NOS1 through sequencing of the complete NOS1 coding region in DNA from 43 patients with IHPS compared the genotype frequencies to 47 controls using the Cochran-Armitage trend or Fisher exact tests.

Results

We found 19 polymorphisms in the coding region of NOS1. The variants c.3827-42_3827-43 del_insTA and c.+276 c>t were more frequent in IHPS with statistically significant exact P values (P = .010 and P = .039, respectively) yet failed to show significance after Bonferroni adjustment for multiple testing. We have also found a marginally significant occurrence of the variants c.−460A (P = .065) and c.2823+15G (P = .076). There was a significant correlation between the variants c.2706C>T ? c.2823+15A>G, (r² = 1.00) and c.3258 C>T ? c.3235+31A>G (r² = 1.00).

Conclusions

We conclude that NOS1 variants are present in patients with IHPS yet show no significant statistical association with the IHPS phenotype, suggesting at best an adjuvant role for NOS1 in IHPS.     

In vitro and in vivo properties of BAL30376, a β-lactam and dual beta-lactamase inhibitor combination with enhanced activity against Gram-negative Bacilli that express multiple β-lactamases

BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC(90) was ≤ 4 μg/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC(90) for Stenotrophomonas maltophilia was 2 μg/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 μg/ml, and for MDR Acinetobacter and Burkholderia spp. it was 16 μg/ml. The presence of the class C β-lactamase inhibitor BAL29880 contributed significantly to the activity of BAL30376 against strains of Citrobacter freundii, Enterobacter species, Serratia marcescens, and P. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains of Escherichia coli and Klebsiella pneumoniae that produced class A extended-spectrum β-lactamases. The activity of BAL30376 against strains with metallo-β-lactamases was largely attributable to the intrinsic stability of the monobactam BAL19764 toward these enzymes. Considering its three components, BAL30376 was unexpectedly refractory toward the development of stable resistance.     

Localised angiosarcomas: The identification of prognostic factors and analysis of treatment impact. A retrospective analysis from the French Sarcoma Group (GSF/GETO)

BackgroundAngiosarcomas represent less than 2% of all adult soft tissue sarcomas. Prognostic factors and the role of (neo-) adjuvant treatments in the management of localised angiosarcomas require further investigation.MethodsWe have conducted a retrospective multicenter study (June 1980 to October 2009) of 107 patients with localised angiosarcomas. All of the cases were centrally reviewed by a certified pathologist. Univariate and multivariate analyses were conducted to identify independent poor prognostic factors (PF). Overall survival (OS) and Local Recurrence-Free Survival (LRFS) were estimated using the Kaplan–Meier method. The effect of treatments was explored using the Cox model after adjusting for the PF.ResultsThe median age was 71 years. 22.4% and 62.6% developed an angiosarcoma in pre-existing lymphoedema and within irradiated tissue respectively. The median OS, LRFS and Disease Recurrence-Free Survival (DRFS) were 38.8, 27 and 36.1 months, respectively. In multivariate analysis, the following parameters influenced the OS: lymphoedema (Hazard ratio (HR) = 2.0) and size >5 cm (HR = 1.5). After adjustment to these PF, R0 margins was the only treatment parameter that improving the OS (HR = 0.2). In the multivariate analysis, the LRFS was influenced by an age >70 (HR = 1.8) and pre-existing lymphoedema (HR = 2.0). After adjustment for these PF, R0 margins (HR = 0.5) and adjuvant radiotherapy (HR = 0.3) improved the LRFS.ConclusionsOur results suggest the following points: (i) pre-existing lymphoedema, tumour size and age >70 are probably the major prognostic factors in patients with localised angiosarcomas; (ii) the achievement of R0 margins is probably of major importance for improving the patient outcome and (iii) adjuvant radiotherapy probably decreased the risk of local recurrence.     

Active Immunological Profile Is Associated with Systemic Sj?gren��s Syndrome

Background

The aim of this paper was to study the evolution of primary Sjögren??s syndrome (pSS) immunological profile, its impact on pSS activity and long-term evolution in a bicentric cohort of French patients with pSS (n?=?445, mean age 53.6?±?14 years, mean follow-up 76.1?±?51 months).

Methods

This is a retrospective cohort study.

Results

Two hundred twelve patients were Sjögren??s syndrome A (SSA) positive, and 131 were both SSA and Sjögren??s syndrome B (SSB) positive. Sixty-eight patients (15%) had cryoglobulinemia. Active systemic profile (i.e., hypergammaglobulinemia, rheumatoid factor (RF), and anti-Sjögren??s syndrome A (anti-SSA), anti-Sjögren??s syndrome B (anti-SSB) positivity), associated with multisystemic involvement, leads to an increased utilization of corticosteroid and hydroxychloroquine. Multivariate analysis pointed out independent statistical association between hypergammaglobulinemia, anti-SSA, anti-SSB, and RF. Cryoglobulinemia is associated with multi-systemic involvement, lymphoma, and pSS-related death.

Conclusion

The subset of patients with active immunological profile is characterized by systemic complications leading to immunosuppressive drug utilization and polyclonal B-cell activation profile.     

Quantitative structural imaging of keratoconic corneas using polarization-resolved SHG microscopy

The human cornea is mainly composed of collagen fibrils aligned together within stacked lamellae. This lamellar structure can be affected in pathologies such as keratoconus, which is characterized by progressive corneal thinning and local steepening. In this study, we use polarization-resolved second harmonic generation (P-SHG) microscopy to characterize 8 control and 6 keratoconic human corneas. Automated processing of P-SHG images of transverse sections provides the collagen orientation in every pixel with sub-micrometer resolution. Series of P-SHG images recorded in the most anterior region of the stroma evidence sutural lamellae inclined at 22° ± 5° to the corneal surface, but show no significant difference between control and keratoconic corneas. In contrast, series of P-SHG images acquired along the full thickness of the stroma show a loss of order in the lamellar structure of keratoconic corneas, in agreement with their defective mechanical properties. This structural difference is analyzed quantitatively by computing the entropy and the orientation index of the collagen orientation distribution and significant differences are obtained along the full thickness of the stroma. This study shows that P-SHG is an effective tool for automatic quantitative analysis of structural defects of human corneas and should be applied to other collagen-rich tissues.     

Compounded topical preparations in plaque psoriasis: Still a place for it in 2018?

Compounded topical preparations (CTP) were used to treat psoriasis until the last century and have disappeared from guidelines. The present authors report two severe psoriasis patients who were treated with CTP. A man had psoriasis with a PASI of 23 and a body surface area (BSA) of 43%. He had been using daily for several weeks a CTP including minoxidil, clobetasol propionate and hydroxyprogesterone formulated in an alcohol based vehicle. A woman suffered from psoriasis with an annular inflammatory pattern and a central healing. The PASI was 20 and the BSA was 30%. She had been using a CTP daily for 4 months including resorcinol, salicylic acid, 0.05% tretinoin cream, bethamethasone dipropionate cream. Until the 1970s, the dermatological textbooks recommended to treat severe psoriasis with CTP. Nowadays, CTP are considered outdated because of the large therapeutic armamentarium. The stability and benefit risks of the CTP used here were not documented. The use of CTP in psoriasis should be regulated and must be evidence based. Strict protocol and stability evaluation for preparations must be confirmed prior to compounding.     

In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

{"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC₉₀s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC₉₀ of meropenem for the same sets of isolates was >32 μg/ml. {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.There is a paucity of new agents acting against Gram-negative organisms, even though the rate of drug resistance among these bacilli continues to increase and resistance occasionally gives rise to organisms causing infections for which no adequate therapeutic options exist (20, 44). Two recent reports from the Infectious Diseases Society of America have addressed the lack of agents for the treatment of infections caused by three categories of Gram-negative bacilli: extended-spectrum cephalosporin-resistant Escherichia coli and Klebsiella spp., multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter spp. (5, 50).Strains of Escherichia coli and Klebsiella pneumoniae that have acquired resistance to the extended-spectrum cephalosporins are emerging as threats in hospitals and in the community in many parts of the world (10, 45, 48). The principal mechanism of β-lactam resistance in these two organisms is the expression of extended-spectrum β-lactamases (ESBL) belonging to Ambler class A (43); but other enzymes, such as class B metallo-β-lactamases, class C cephalosporinases, and ESBL variants of class D oxacillinases, may also play a role (11, 34, 54). In addition, both E. coli and K. pneumoniae are known to acquire alterations in the outer membrane proteins that result in limited influx (e.g., by the mutation or deletion of porins) or accelerated efflux (14, 32). These mechanisms of resistance are also affecting the utility of carbapenems. The ability of these organisms to produce class A carbapenemases, in addition to the mechanisms described above, has now become apparent in some regions of the United States, in Israel, and in Greece (31, 38). Acinetobacter baumannii and P. aeruginosa are both intrinsically resistant to a broad variety of antibiotics and have the ability to acquire further mechanisms to the extent that some strains of these pathogens have expressed resistance to all clinically available compounds (4, 15, 22, 29). Resistance to β-lactams in P. aeruginosa is achieved through various combinations of expression of the chromosomally encoded class C β-lactamase; additional enzymes from the other β-lactamase classes; mutation, deletion, or altered expression of the outer membrane proteins involved in the influx of the drug; overexpression of efflux pumps; and mutation of the target penicillin-binding proteins (4, 21, 23, 36, 40, 41, 49). Similar factors play a role in the resistance of Acinetobacter (16, 18), although the variety of β-lactamases implicated in resistance is different. In particular, the class D oxacillinases with carbapenemase activity have acquired particular significance, causing a number of serious outbreaks in Europe and the United States (11).Monobactams, such as aztreonam (ATM) and carumonam (3, 17, 26, 27), and sulfactams, such as tigemonam (7, 52), make interesting starting points for the development of a new antibiotic targeting Gram-negative bacteria. They have been shown to have potent activity against isolates of the Enterobacteriaceae family and moderate activity against P. aeruginosa (17, 26). In addition, the monocyclic β-lactams are highly resistant to hydrolysis by class B metallo-β-lactamases and are potent inhibitors of class C β-lactamases (3, 27).Numerous attempts have been made to introduce iron-binding functional groups into β-lactams since the 1980s, in order to circumvent the limitations imposed by porin mutation or deletion (37). {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 is a sulfactam, analogous to tigemonam, with a dihydropyridone iron-chelating group (19, 33). We show here that this combination of features unexpectedly confers markedly different antibiotic properties to {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072.