Late-phase urticaria Update

In ordinary urticaria, individual lesions disappear within 24 hours. However, we sometimes encounter patients whose eruptions last longer than 24 hours, but without evidence of vasculitis or a history of exposure to pressure. In these patients, histology reveals a perivascular infiltration, predominantly of eosinophils, depending on the timing of the biopsy. Unlike urticarial vasculitis, no immunoglobulins, complement deposition, or endothelial fibrinoid degeneration is observed. The peripheral eosinophil counts and serum complement levels appear within normal range. No protein urea or joint pain is observed, and the lesions can be controlled only by systemic glucocorticoids. We recognize such a urticarial reaction as a different clinical entity than usual urticaria, which is presumably mediated by latephase inflammatory reaction in immediate hypersensitivity.     

Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance

J Oral Pathol Med (2012) 41 : 444–451 Background: Stromal cells are believed to affect cancer invasion and metastasis. The purpose of this study was to evaluate the distribution of cancer‐associated fibroblasts (CAFs) and the incidence of tumor‐associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC), focusing on clinicopathological factors and patient prognosis, as well as cancer invasion. Methods: The study included 108 patients with OSCC. Anti‐α‐smooth muscle actin, CD68, and CD163 antibodies were used to identify CAFs and TAMs. CAFs were divided into 4 grades on the basis of staining intensity: negative (0), scanty (1), focal (2), and abundant (3). The most intensive areas of macrophage concentration in each tumor invasive stroma were also evaluated. Results: The cancer specimens were divided into Grade 0/1, Grade 2, and Grade 3 on the basis of CAF grade. In addition, they were divided into low‐ and high‐grade groups on the basis of the number of CD68‐positive and CD163‐positive macrophages. The latter were significantly increased in the Grade 2 CAF group compared to the Grade 0/1 group (P = 0.009). Kaplan–Meier and multivariate survival analyses revealed that Grade 2 CAFs (P = 0.003) and high CD163‐positive macrophage levels (P = 0.007) significantly correlated with a poor outcome in patients with OSCC, and that a high CD163‐positive macrophage level was a significant and an independent prognostic factor (P = 0.045). Conclusions: Cancer‐associated fibroblasts and CD163‐positive macrophages may be potential prognostic predictors of OSCC.     

Flow pattern and perforating vessels in three different phases of myopic choroidal neovascularization seen by swept-source optical coherence tomography angiography

Graefe's Archive for Clinical and Experimental Ophthalmology - To compare the choroidal neovascularization (CNV) flow patterns and the relationship between perforating vessels (PVs) and CNV in...     

Unilateral nephrectomy for young infants with congenital nephrotic syndrome of the Finnish type

Clinical and Experimental Nephrology - The management of congenital nephrotic syndrome of the Finnish type (CNF) is challenging. It is difficult to withdraw intravenous albumin infusions, resulting...     

Impact of omalizumab on medical cost of childhood asthma in Japan

Omalizumab is effective in children with severe asthma, but its impact on medical cost in Japan is not clear. We evaluated the impact of omalizumab on medical cost by comparing the pre‐ vs post‐omalizumab‐initiation medical costs of 12 children with severe asthma who received omalizumab for 2 years, and calculating incremental cost‐effectiveness ratio for omalizumab therapy. Health outcome was measured as hospital‐free days (HFD). The median total medical costs and medication fee per patient increased significantly after omalizumab initiation because of the high cost of omalizumab. The median hospitalization fee per patient, however, decreased significantly after omalizumab initiation due to reduction in hospitalization. Omalizumab led to an estimated increase of 40.8 HFD per omalizumab responder patient per 2 years. The cost was JPY 20 868 per additional HFD. Omalizumab can therefore reduce hospitalization cost in children with severe asthma in Japan.     

Dietary l-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.Medial vascular calcification is common in aging, diabetes, and CKD.^1–4 Because the presence of vascular calcification is strongly associated with increased cardiovascular morbidity and mortality, several studies in both animals and humans have sought ways to reduce the extent of vascular calcification.^5–10 However, satisfactory therapies have not yet been established.¹¹Adenine-induced renal failure is one of the commonly used animal models for studying the development of vascular calcification, but the prevalence of vascular calcification in this model is not very high. Indeed, Price et al. reported that vascular calcification was detected in only 30% of rats with adenine-induced chronic renal failure (adenine rats) fed a normal-protein diet.⁵ These authors speculated that consistent vascular calcification might require a longer period of adenine feeding. On the basis of this idea, they designed a low-protein (LP) diet in an attempt to reduce the nitrogen load and thus enable the rats to thrive on the adenine diet for longer periods. As a result of this attempt, Price et al. unexpectedly found that adenine rats fed a LP diet had extensive vascular calcification without a longer feeding period.⁵ All 13 adenine rats fed the LP diet had uniform alizarin red staining of the aorta, whereas only 3 of the 11 adenine rats fed a normal-protein diet had partial calcification.⁵ These findings indicated that dietary protein deficiency correlates with the extent of vascular calcification.Proteins are usually made from 20 kinds of amino acids. On the basis of nutritional requirements, these amino acids can be divided into two groups: essential amino acids (EAAs) and non-EAAs. Because restriction of dietary protein results in a shortage of EAAs, the level of dietary EAAs may be relevant to the extent of vascular calcification. Among nine EAAs, this study focused on l-lysine (l-Lys) based on the following three reasons. First, l-Lys is the first-limiting amino acid in most cereal grains.¹² Second, the safety of l-Lys supplementation has been verified in the area of animal husbandry. l-Lys has long been added to feed grains in order to improve the utility of feed proteins.¹³ Third, several studies have demonstrated that dietary supplementation with l-Lys protects bones from osteoporosis, a pathologic condition that often coexists with vascular calcification.^14,15 These points prompted us to hypothesize that supplementation with l-Lys would ameliorate vascular calcification. Therefore, in this study, we tested this hypothesis using adenine rats.     

Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms—Workshop Report

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.     

Population-Specific ACE2 Single-Nucleotide Polymorphisms Have Limited Impact on SARS-CoV-2 Infectivity In Vitro

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), employs host-cell angiotensin-converting enzyme 2 (ACE2) for cell entry. Genetic analyses of ACE2 have identified several single-nucleotide polymorphisms (SNPs) specific to different human populations. Molecular dynamics simulations have indicated that several of these SNPs could affect interactions between SARS-CoV-2 and ACE2, thereby providing a partial explanation for the regional differences observed in SARS-CoV-2 infectivity and severity. However, the significance of population-specific ACE2 SNPs in SARS-CoV-2 infectivity is unknown, as no in vitro validation studies have been performed. Here, we analyzed the impact of eight SNPs found in specific populations on receptor binding and cell entry in vitro. Except for a SNP causing a nonsense mutation that reduced ACE2 expression, none of the selected SNPs markedly altered the interaction between ACE2 and the SARS-CoV-2 spike protein (SARS-2-S), which is responsible for receptor recognition and cell entry, or the efficiency of viral cell entry mediated by SARS-2-S. Our findings indicate that ACE2 polymorphisms have limited impact on the ACE2-dependent cell entry of SARS-CoV-2 and underscore the importance of future studies on the involvement of population-specific SNPs of other host genes in susceptibility toward SARS-CoV-2 infection.