Association of Piebaldism,Multiple Café‐au‐lait Macules,and Intertriginous Freckling: Clinical Evidence of a Common Pathway between KIT and Sprouty‐Related,Ena/Vasodilator‐Stimulated Phosphoprotein Homology‐1 Domain Containing Protein 1 (SPRED1)

Abstract: Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5‐year‐old boy who had the white forelock and leukoderma of piebaldism, but the presence of many café‐au‐lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty‐related, Ena/vasodilator‐stimulated phosphoprotein homology‐1 domain containing protein 1 (SPRED1) mutations that also has multiple café‐au‐lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that café‐au‐lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1.     

Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy

Purpose

Individualizing gastric-resistant tablets is associated with major challenges for clinical staff in hospitals and healthcare centres. This work aims to fabricate gastric-resistant 3D printed tablets using dual FDM 3D printing.

Methods

The gastric-resistant tablets were engineered by employing a range of shell-core designs using polyvinylpyrrolidone (PVP) and methacrylic acid co-polymer for core and shell structures respectively. Filaments for both core and shell were compounded using a twin-screw hot-melt extruder (HME). CAD software was utilized to design a capsule-shaped core with a complementary shell of increasing thicknesses (0.17, 0.35, 0.52, 0.70 or 0.87 mm). The physical form of the drug and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC.

Results

A shell thickness ≥0.52 mm was deemed necessary in order to achieve sufficient core protection in the acid medium. The technology proved viable for incorporating different drug candidates; theophylline, budesonide and diclofenac sodium. XRPD indicated the presence of theophylline crystals whilst budesonide and diclofenac sodium remained amorphous in the PVP matrix of the filaments and 3D printed tablets. Fabricated tablets demonstrated gastric resistant properties and a pH responsive drug release pattern in both phosphate and bicarbonate buffers.

Conclusions

Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient’s needs.

     

Direct Crosstalk Between Cancer and Osteoblast Lineage Cells Fuels Metastatic Growth in Bone via Auto‐Amplification of IL‐6 and RANKL Signaling Pathways

The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin‐6 (IL‐6) stimulates receptor activator of NF‐κB ligand (RANKL) expression in bone cells, and serum IL‐6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor‐derived IL‐6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune‐deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL‐6 expression by cancer cells in vitro and in vivo. We then disrupted of IL‐6 signaling in vivo either via knockdown of IL‐6 in tumor cells or through treatment with specific anti‐human or anti‐mouse IL‐6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage‐derived RANKL upregulates secretion of IL‐6 by breast cancers in vivo and in vitro. IL‐6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL‐6 release. Disruption in vivo of this auto‐amplifying crosstalk by knockdown of IL‐6 or RANK in cancer cells, or via treatment with anti‐IL‐6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL‐6 mediate direct paracrine‐autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone. © 2014 American Society for Bone and Mineral Research.     

Management of superior subperiosteal orbital abscess

A superior subperiosteal orbital abscess (SSPOA) is a collection of purulent material between the periorbit and the superior bony orbital wall, and is typically a complication of frontal sinusitis. SSPOA is characteristically managed by classic external surgical drainage. The aim of our study was to assess the role of surgical intervention in SSPOA. A retrospective medical chart review of patients diagnosed with SSPOA secondary to rhinosinusitis between the year 2005 and 2013 was conducted. Collected data included age, gender, co-morbidity, clinical presentation, prior antibiotic management, CT scans, surgical approach, outcome and complications. Six patients were included in our study, three males and three females with a mean age of 22.8 (range 9–58). Two patients were treated with amoxicillin clavulanic acid for 3 days prior to admission. Only the youngest patient with the smallest abscess responded successfully to conservative treatment, while the rest were managed surgically: three patients were treated successfully by the endonasal endoscopic approach and two patients were treated by utilizing the combined endonasal endoscopic and external approach. In patients who underwent the combined approach, the abscess was located in a more antero-lateral position than those treated endonasal endoscopically only. The location of a SSPOA dictates the surgical approach. The most antero-lateral SSPOAs should be drained by the combined approach, while more posterior abscesses should be approached endoscopically. Furthermore, a small SSPOA is first to be reported to resolve with conservative treatment. Level 4 (case series).     

A systematic review and meta‐analysis of the impact of the left atrial appendage closure on left atrial function

BackgroundLeft atrial (LA) appendage closure (LAAC) is effective in patients with atrial fibrillation who are not candidates for long‐term anticoagulation. However, the impact of LAAC on LA function is unknown. The aim of this study is to evaluate the impact of LAAC on atrial function.MethodsThis meta‐analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. A search strategy was designed to utilize PubMed/Medline, EMBASE, and Google scholar for studies showing the effect of LAAC on the LA function from inception to November 20, 2021. The standardized mean difference (SMD) was calculated from the means and standard deviations.ResultsOf 247 studies initially identified, 8 studies comprising 260 patients were included in the final analysis. There was a significant increase in LA emptying fraction following LAAC compared with preoperative function (SMD: 0.53; 95% confidence interval [CI]: 0.04–1.01; p = .03; I ² = 75%). In contrast, there were no significant differences in LA volume (SMD: −0.07; 95% CI: −0.82–0.69; p = .86; I ² = 92%) peak atrial longitudinal strain (SMD: 0.50; 95% CI: −0.08–1.08; p = .09; I ² = 89%), peak atrial contraction strain (SMD: 0.38; 95% CI: −0.22–0.99; p = .21; I ² = 81%), strain during atrial contraction (SMD: −0.24; 95% CI: −0.61–0.13; p = .20; I ² = 0%), strain during ventricular systole (SMD: 0.47; 95% CI: −0.32–1.27; p = .24; I ² = 89%), strain during ventricular diastole (SMD: 0.09; 95% CI: −0.32–0.51; p = .66; I ² = 65%).ConclusionLAAC is associated with improvement in the left atrial emptying fraction, but did not significantly influence other parameters.     

Hepatitis B virus DNA in serum of 'anti-HBc only'-positive healthy Lebanese blood donors: significance and possible implications

Transmission of HBV infection through transfusion of HBsAg-negative blood has been documented. It is evident that low levels of HBV-DNA remain detectable in serum and liver tissue of some patients who clear HbsAg, and that the detection rate is highest in individuals who are 'anti-HBc positive alone'. This study was designed to assess the frequency and clinical significance of 'anti-HBc alone' in Lebanese blood donors. A total of 5511 blood donor samples from three major hospitals representing most regions of the country were tested for anti-HBc, amongst other screening tests. Samples positive for 'anti-HBc alone' were then tested for HBV-DNA and any positive for HBV-DNA were then genotyped and investigated for hepatitis B viral load. The study showed that 203 (3.7%) of randomly selected Lebanese blood donors were confirmed as 'anti-HBc alone'. Of these, 11 (5.4%) were HBV-DNA positive as detected by nested PCR. All samples had HBV-DNA levels below 400 copies/ml and all were genotype D. It can be concluded that HBV was present, although the circulating amount of virus was below the detectable limit for the assay used. Therefore, routine screening for anti-HBc may be required in Lebanese blood donation centres as an additional preventive measure for controlling transmission of HBV via blood transfusion.