Daylight photodynamic therapy with MAL cream for large‐scale photodamaged skin based on the concept of ‘actinic field damage’: recommendations of an international expert group

Conventional PDT (c‐PDT) is a widely used and approved non‐invasive treatment for actinic keratosis (AK). Recent clinical, histological and immunohistochemical observations have shown that c‐PDT with methyl aminolevulinate (MAL) may also partially reverse the signs of photodamage. However, pain and the need for special light source equipment are limiting factors for its use, especially in the treatment of large areas. More recently, daylight PDT (DL‐PDT) has been shown to be similar to c‐PDT in the treatment of AK, nearly painless and more convenient to perform. To establish consensus on recommendations for the use of MAL DL‐PDT in patients with large‐scale photodamaged skin. The expert group was comprised of eight dermatologists. Consensus was developed based on the personal experience of the experts in c‐PDT and DL‐PDT, and results of an extensive literature review. MAL DL‐PDT for large areas of photodamaged skin was evaluated and recommendations based on broad clinical experience were provided. As supported by evidence‐based data from multicentre studies conducted in Australia and Europe, the authors defined the concept of ‘actinic field damage’ which refers to photodamage associated with actinic epidermal dysplasia, and provide comprehensive guidelines for the optimal use of DL‐PDT in the treatment of actinic field damage. The authors concluded that MAL DL‐PDT has a similar efficacy to c‐PDT at 3‐month (lesion complete response rate of 89% vs. 93% in the Australian study and 70% vs. 74% in the European study (95% C.I. = [?6.8;?0.3] and [?9.5;2.4] respectively) and 6‐month follow‐ups (97% maintenance of complete lesion response) in the treatment of AKs. The authors agree that DL‐PDT is not only efficacious but also nearly pain‐free and easy to perform, and therefore results in high patient acceptance especially for the treatment of areas of actinic field damage.     

PAPSS2‐related brachyolmia: Clinical and radiological phenotype in 18 new cases

Brachyolmia is a skeletal dysplasia characterized by short spine‐short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short‐spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over‐faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi‐parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under‐recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.     

Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging

Purpose

A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI).

Methods

Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined.

Results

A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5?±?0.75% larger than designed; n?=?3).

Conclusions

The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.

     

Secondary immunodeficiency in lymphoproliferative malignancies

Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti‐inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease‐ and treatment‐related factors. Supportive treatment, including early vaccination, anti‐infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John Wiley & Sons, Ltd.     

Presentation of cytosolic glycosylated peptides by human class I major histocompatibility complex molecules in vivo.

Antigens presented by class I major histocompatibility complex (MHC) molecules for recognition by cytotoxic T lymphocytes consist of 8-10-amino-acid-long cytosolic peptides. It is not known whether posttranslationally modified peptides are also presented by class I MHC molecules in vivo. Many different posttranslational modifications occur on cytoplasmic proteins, including a cytosolic O-beta-linked glycosylation of serine and threonine residues with N-acetylglucosamine (GlcNAc). Using synthetic glycopeptides carrying the monosaccharide O-beta-GlcNAc substitution on serine residues, we have shown that glycopeptides bind efficiently to class I MHC molecules and elicit a glycopeptide-specific cytotoxic T lymphocyte response in mice. In this study, we provide evidence that peptides presented by human class I MHC molecules in vivo encompass a small, significant amount of glycopeptides, constituting up to 0.1% of total peptide. Furthermore, we find that carbohydrate structures present on glycopeptides isolated from class I MHC molecules are dominated by the cytosolic O-beta-GlcNAc substitution, and synthetic peptides carrying this substitution are efficiently transported by TAP (transporter associated with antigen presentation) into the endoplasmic reticulum. Thus, in addition to unmodified peptides, posttranslationally modified cytosolic peptides carrying O-beta-linked GlcNAc can be presented by class I MHC molecules to the immune system.     

The low-power laser in the treatment of tinnitus

The purpose of this study was to evaluate the low-power laser on the treatment of tinnitus. In a randomized, prospective, double-blind, placebo-controlled trial, either active or placebo low-power laser irradiation was given through the external acoustic meatus of the affected ear towards the cochlea. The active laser applied 50mW (cw, 830 nm) over a period of 10 min per session. Forty-nine patients with severe, chronic uni- or bilateral tinnitus were studied. The main outcome was measured using psychoacoustical match of tinnitus loudness and pitch, Visual Analogue Scale (VAS) ratings of subjective loudness, annoyance and attention involved, scores on the Tinnitus Handicap Inventory (THI), the Tinnitus Coping Style Questionnaire (TCSQ), and a number of psychosocial questionnaires. The results showed only moderate (18%) subjective improvement with no statistically significant differences between the effects of the active laser and placebo treatments. Also, there were no statistically significant differences in prepost measurements of tinnitus loudness, VAS scores, THI scores, or TCSQ scores for patients treated with active laser compared with those treated with placebo. We conclude that low-power laser treatment is not indicated in the treatment of tinnitus. Reports of significant benefits of this treatment in previous, mostly uncontrolled or single-blinded studies may be explained by the placebo effect.