Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.     

Sea-blue histiocyte syndrome in bone marrow secondary to total parenteral nutrition including fat-emulsion sources: a clinicopathologic study of seven cases

Bone marrow examination revealed a lipid-laden histiocytosis in seven patients undergoing long-term total parenteral nutrition necessitated by extensive short-bowel surgical resection. Clinical abnormalities occurred during this treatment which required bone marrow examination. These included hepatosplenomegaly and peripheral blood cytopenia; the median time to the detection of these abnormalities was 64 months.   The most striking change within the bone marrow was the presence of many pigment-laden histiocytes which had the typical morphology of sea-blue histiocytes seen in the so-called idiopathic sea-blue histiocyte syndrome. The occurrence of sea-blue histiocytosis in the bone marrow in association with long-term parenteral nutrition for short-bowel syndrome has not, to our knowledge, been reported previously and should now be considered in the differential diagnosis of bone marrow sea-blue histiocytosis.     

Type II Achalasia Is Increasing in Prevalence

Background

Three manometric subtypes of achalasia were defined in the Chicago Classification approximately 10 years ago: type I (aperistalsis), type II (pan-pressurization), and type III (spastic). Since the widespread use of this classification scheme, the evolving prevalence of these subtypes has not been elucidated. We aim to determine the prevalence of each subtype a decade after the adoption of the Chicago Classification.

Methods

This is a retrospective cohort analysis of patients diagnosed with achalasia on high-resolution manometry (HRM) at two major academic medical centers between 2015 and 2018. Patients were excluded if they had a diagnosis of another esophageal motility disorder, previously treated achalasia, or foregut surgery. Demographic data, manometric subtype, and esophageal dilatation grade on endoscopy were obtained. Prevalence of achalasia subtypes was compared with a published historical control population (2004–2007). Fischer’s exact and t tests were used for analysis.

Results

Of 147 patients in the contemporary cohort and 99 in the historical control cohort, the prevalence of type I achalasia was 8% versus 21%, type II 63% versus 50%, and type III 29% versus 29%, respectively (p?=?0.01). The mean age in our population was 58 years compared to 57 years in the historical control, and the proportion of men 48% versus 47%, respectively (p?=?0.78). Mean endoscopic dilatation grade in the contemporary cohort was 1.5 for type I patients, 0.9 for type II, and 0.4 for type III, compared with 1.5, 0.6, and 0.4, respectively. Overall mean dilatation grade was 0.8 in our cohort versus 0.7 in the historical control (p?=?0.58).

Conclusion

The prevalence of type II achalasia was significantly greater and prevalence of type I significantly less in our patient population compared to our predefined historical control. Other characteristics such as age and sex did not appear to contribute to these differences. Histopathological evidence has suggested that type II achalasia may be an earlier form of type I; thus, the increased prevalence of type II achalasia may be related to earlier detection of the disease. The adoption of HRM, widespread use of the Chicago Classification, and increased disease awareness in the past decade may be contributing to these changes in epidemiology.

     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

In vivo treatment with recombinant IL-12 protects C57BL/6J mice against secondary alveolar echinococcosis

Using an experimental model of hepatic Echinococcus multilocularis infection in C57BL/6J mice, intraperitoneal administration of 0.8 μg of recombinant IL-12 to mice with an established infection was shown to reduce the parasite burden as soon as two weeks after the end of treatment. At that time, in vitro Echinococcus multilocularis -induced spleen T cell proliferative responses as well as IFN-γ and IL-5 production were higher in IL-12 treated mice than in untreated mice. Administration of 0.8 μg of IL-12 at the time of infection was shown to be without effect on the parasite establishment. However, this treatment greatly inhibited the subsequent metacestode development. Indeed, ten weeks after infection, it induced a complete healing in 37.5% of mice. At that time, the development of metastases was inhibited in 68.75% of IL-12-treated mice. This reduction of parasite burden was mainly associated with a strong proliferation of spleen cells to E. multilocularis antigen and with a high IFN-γ production. Altogether, our results show that IL-12 is of crucial importance in inhibiting the larval growth after the metacestode establishment in the liver and suggest that this cytokine could be of potential value in the treatment of human alveolar echinococcosis .     

RP-HPLC法测定β-司他夫定的有关物质

目的:建立了β-司他夫定原料有关物质的RP-HPLC测定方法和水解破坏制备系统适用性试验溶液方法。方法:采用Agilent 1100型高效液相色谱仪,使用SUPELCOSIL LC-18-DB(4.6 mm×250 mm,5μm)色谱柱,以0.01 mol·L-1醋酸铵溶液-乙腈(96.5∶3.5)和0.01 mol·L-1醋酸铵溶液-乙腈(75∶25)为流动相,梯度洗脱,检测波长254 nm,柱温25℃。结果:β-司他夫定和4种已知杂质及其他未知杂质均能达到有效分离;经水解破坏产生的α-司他夫定与β-司他夫定的分离度均达2.8;β-司他夫定、胸腺嘧啶、β-胸苷与5-O’-苯甲酰-司他夫定线性范围分别为0.51~26μg·m L-1(r=1.000)、0.13~27μg·m L-1(r=1.000)、0.50~25μg·m L-1(r=1.000)、1.7~6.3μg·m L-1(r=1.000),已知杂质胸腺嘧啶、β-胸苷与5-O’-苯甲酰-司他夫定的平均加样回收率(n=9)分别为102.8%(RSD=1.5%)、100.6%(RSD=0.9%)、101.9%(RSD=2.1%);β-司他夫定与3种已知杂质的最小检出量均在2.5 ng以下;经水解破坏制备的系统适用性溶液的重复性良好;供试品溶液在4℃下的30 h内基本稳定。结论:本方法灵敏、准确、可靠,专属性强,可用于β-司他夫定原料的有关物质测定。     

EFFECTS OF BICYCLE HELMET LAWS ON CHILDREN'S INJURIES

In recent years, many states and localities in the USA have enacted bicycle helmet laws. We estimate the effects of these laws on injuries requiring emergency department treatment. Using hospital‐level panel data and triple difference models, we find helmet laws are associated with reductions in bicycle‐related head injuries among children. However, laws also are associated with decreases in non‐head cycling injuries, as well as increases in head injuries from other wheeled sports. Thus, the observed reduction in bicycle‐related head injuries may be due to reductions in bicycle riding induced by the laws. Copyright © 2013 John Wiley & Sons, Ltd.