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Summary: Background: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)‐1 system, but the exact pathophysiological pathways remain largely unknown. Objectives: To identify and characterize the pathogenetic players in SchS. Methods: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme‐linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse‐transcriptase polymerase chain reaction and ELISA. Results: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL‐1β (immune cells, fibroblasts) and tumour necrosis factor (TNF)‐α (fibroblasts) were important CCL2 inducers. TNF‐α, but not IL‐17, strengthened the CCL2‐inducing effect of IL‐1β in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF‐α and IL‐1β serum levels in patients with SchS. Therapeutic IL‐1β blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. Conclusions: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS. What's already known about this topic?Schnitzler syndrome (SchS) is a very rare acquired autoinflammatory disease, clinically characterized by urticarial exanthema, arthralgia and osteosclerosis, and episodes of fever.The pathogenesis involves overactivation of the interleukin‐1 system.The exact pathogenetic pathways are mostly unknown, and biomarkers are not available to assess the inflammatory activity in SchS. What does this study add? The chemokine CCL2 is a marker of SchS; its blood levels are significantly upregulated and linked to global disease activity and early therapy response in patients with SchS.While no clear relationship with patients' urticarial exanthema was detected, CCL2 may be involved in bone alterations in these patients.The cellular sources of CCL2 include mononuclear immune cells and fibroblasts.Interleukin‐1β and tumour necrosis factor‐α, blood levels of which correlate with CCL2 levels in patients with SchS, are important CCL2 inducers. What is the translational message? Quantifying CCL2 blood levels may allow the objective estimation of inflammatory disease activity and may help with the therapy decision in patients with SchS.CCL2 may be a key element of the pathogenetic cascades in SchS, especially those important for osteosclerosis. Linked Comment:Kambe and Nguyen. Br J Dermatol 2019; 180:706–707. Respond to this article Plain language summary available online [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the cases of a 73-year-old woman and a 61-year-old woman with notalgia paraesthetica (NP) who both undergo treatment of the disease with an 8% capsaicin patch.

Linked Article: Krause et al. Br J Dermatol 2019; 180:859–868 [ABSTRACT FROM AUTHOR]

Summary: Schnitzler syndrome is a very rare chronic disease, which usually develops in the second half of life. It appears as skin rashes, muscle/skeletal pain and fever episodes. The trigger and molecular processes in the disease are not understood. However, drugs that inhibit the inflammatory molecule called interleukin‐1ß were found to relieve the disease. The authors of this German study wondered which further molecules are involved in Schnitzler syndrome. For this purpose, a range of molecules with inflammatory properties was quantified in the blood of the patients and, as a comparison, in healthy people and patients with other inflammatory diseases. Patients with Schnitzler syndrome were found to have strongly elevated levels of CCL2, a molecule known to attract inflammatory cells to affected tissues and to have a special role in bone alterations. CCL2 levels were particularly high in severely affected patients, especially those with intense bone pain. In the bone, CCL2 is known to be produced by certain bone‐modifying cells. Laboratory experiments revealed that CCL2 was also highly produced by immune cells and connective tissue cells (fibroblasts). Interleukin‐1ß as well as the inflammatory molecule TNF‐α triggered the production of CCL2 by these cells. When patients were treated with an interleukin‐1ß‐blocking drug, health improvement was paralleled by a drop of CCL2 levels. The authors concluded that in Schnitzler syndrome CCL2 is an important player in the inflammation process in bones and other body sites and may be used in the clinic as an indicator of disease severity. Linked Article: Krause et al. Br J Dermatol 2019; 180:859–868 [ABSTRACT FROM AUTHOR]

This study evaluated how sampling schedule influenced statistical interpretation of the dietary effects on ruminal pH in lactating cows. Data collected in two published Latin Square studies were utilized (JDS 85:1947: A, JDS 86:2433: B). Ruminal pH was continuously measured in each period for 5 d in A and 3 d in B using indwelling electrodes and averaged by hour such that each cow had 24 observations per day. Average treatment pH, calculated using the hour by treatment least square means within experiment, ranged 0.27 pH units for A and 0.50 pH units for B. In trial A equal portions of TMR were fed every 12 h, where in B 65% of the TMR was fed in the morning and 35% 12 h later. Effect of forage particle size (FPS), grain fermentability (GF) and their interaction were tested in both studies. In both studies an effect of GF was observed (P < 0.05). The effect of FPS was significant in A, but not in B. The GF by FPS interaction was not significant in either study. Data were re-analyzed using 3 abbreviated sampling schedules within day and for 1, 3 or 5 (only for A) consecutive days within period, utilizing rumen pH measured: 1) 8 h post am feeding, 2) every 4 h for 24 h, and 3) and every 2 h for 12 h after the am feeding. Data were analyzed as Latin Square designs utilizing the mixed procedure of SAS with repeated measures. Sampling schedules were compared by the capability to detect a treatment effect (P < 0.05). In study A, sampling for either 3 or 5 d utilizing either of the 3 sampling schedules produced similar results. When only 1 d was utilized in the analysis, sampling every 2 h over a 12 h period detected both treatment effects (P < 0.05). In study B, 3 d of multiple within day samples were required to detect a GF effect (P < 0.05). In contrast to the published analysis, sampling only once a day (1 or 3 d) or every 4 h for 3 d resulted in a GF by FPS interaction (P < 0.05). It is recommended to sample ruminal pH across multiple days and hours. It is important to consider post prandial pattern of ruminal pH when choosing the sampling schedule that will maximize the probability to detect a treatment effect. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder characterized by recurrent weals, angio‐oedema or both. Recent studies have shown that the number of endothelial cells is increased in the skin of patients with CSU, but the underlying mechanisms and clinical implications of this are unclear. Aim: To evaluate whether mast cell (MC) or endothelial cell (EC) numbers correlate with CSU and whether they are relevant for disease duration, disease activity or the presence of clinical features. Methods: We determined the numbers of CD31+ ECs and MCs in nonlesional skin of 30 patients with CSU using quantitative histomorphometry, and assessed their correlation with each other and with clinical features such as disease duration, disease activity and occurrence of angio‐oedema. Results: The numbers of MCs and ECs were high in the nonlesional skin of patients with CSU, but did not correlate with each other. Neither MC number nor EC number correlated with disease duration or disease activity. Interestingly, patients with high numbers of cutaneous CD31+ ECs had higher rates of recurrent angio‐oedema and vice versa. Conclusions: Based on these findings, we speculate that vascular remodelling and MC hyperplasia in patients with CSU occurs independently and via different mechanisms. Targeting of the mechanisms that drive neoangiogenesis in CSU may result in novel therapeutic strategies for the management of patients with angio‐oedema. [ABSTRACT FROM AUTHOR]

A letter to the editor on benefit of doxycycline therapy in patients with chronic cold urticaria is presented.

Objectives: When tested in broth, avibactam reverses ceftazidime resistance in many Pseudomonas aeruginosa that express ESBLs. We examined whether similar reversal is observed against intracellular forms of P. aeruginosa .Methods: Strains: reference strains; two engineered strains with basal non-inducible expression of AmpC and their isogenic mutants with stably derepressed AmpC; and clinical isolates with complete, partial or no resistance to reversion with avibactam. Pharmacodynamic model: 24 h concentration-response to ceftazidime [0.01-200 mg/L alone or with avibactam (4 mg/L)] of bacteria in broth or bacteria phagocytosed by THP-1 monocytes, with calculation of ceftazidime relative potency ( C s : concentration yielding a static effect) and maximal relative effect [ E max : cfu decrease at infinitely large antibiotic concentrations (efficacy in the model)] using the Hill equation. Cellular content of avibactam: quantification by LC-MS/MS.Results: For both extracellular and intracellular bacteria, ceftazidime C s was always close to its MIC. For ceftazidime-resistant strains, avibactam addition shifted ceftazidime C s to values close to the MIC of the combination in broth. E max was systematically below the detection limit (-5 log 10 ) for extracellular bacteria, but limited to -1.3 log 10 for intracellular bacteria (except for two isolates) with no effect of avibactam. The cellular concentration of avibactam reflected extracellular concentration and was not influenced by ceftazidime (0-160 mg/L).Conclusions: The potential for avibactam to inhibit β-lactamases does not differ for extracellular and intracellular forms of P. aeruginosa , denoting an unhindered access to its target in both situations. The loss of maximal relative efficacy of ceftazidime against intracellular P. aeruginosa was unrelated to resistance via avibactam-inhibitable β-lactamases. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare heifer growth and reproductive performance following 2 levels of stockpiled fall forage allowance of orchardgrass (30.5%) and tall fescue (14.1%). Spring-born heifers (n = 203 and BW = 246 ± 28.9 kg) of primarily Angus background were allocated to 2 grazing treatments during the fall period (November 12 to December 17 in yr 1, November 7 to January 4 in yr 2, and November 7 to January 14 in yr 3) each replicated 3 times per year for 3 yr. Treatments consisted of daily pasture DM allowance of 3.5% of BW (LO) or daily pasture DM allowance of 7.0% of BW (HI) under strip-grazing management. Throughout the winter feeding period, mixed grass-legume haylage and soybean hulls were fed. Heifers were grazed as 1 group under continuous stocking after the winter period. Heifers in the LO group gained less than heifers in the HI group during the fall grazing period (0.12 vs. 0.40 kg/d; P < 0.0001). For each 1 10 g increase in NDF/kg fall pasture (DM basis), fall ADG decreased 0.14 kg (P = 0.01). During winter feeding, ADG was 0.30 and 0.39 kg/d for LO vs. HI heifers, respectively (P = 0.0008). During the spring grazing period (April 16 to May 24 in yr 1, April 22 to May 26 in yr 2, and April 5 to May 16 in yr 3), LO heifers had numerically greater ADG than HI heifers (1.38 vs. 1.30 kg/d; P = 0.64). Hip height (122.7 vs. 121.4 cm; P = 0.0055), BCS (5.8 vs. 5.6; P = 0.0057), and BW (356 vs. 335 kg; P < 0.0001) at the end of spring grazing was greater for HI than LO heifers. Heifers in the LO group compensated with greater summer ADG than heifers in the HI group (0.74 vs. 0.66 kg/d; P = 0.03). Total ADG from treatment initiation (November) through pregnancy diagnosis (August) was greater for HI than LO heifers (0.61 vs. 0.55 kg/d; P < 0.001) as was BW at pregnancy diagnosis (415 vs. 402 kg; P = 0.0055). Percentage of heifers reaching puberty by the time of AI was 34% for both groups (P = 0.93). Percentage of heifers becoming pregnant to AI tended (P = 0.13) to be greater for HI (44%) than for LO heifers (32%). Fall ADG across treatment groups affected the probability of a heifer becoming pregnant by AI (P = 0.01). Percentage pregnant by natural service (61% for LO vs. 59% for HI; P = 0.80) and final pregnancy rate (74% for LO vs. 77% for HI; P = 0.61) was not different for the 2 groups. These results indicate that altering fall forage allowance may delay the majority of BW gain until late in heifer development without negatively affecting overall pregnancy rates. [ABSTRACT FROM AUTHOR]

Background: The protein p73, the first identified homologue of the tumor suppressor gene p53 (also known as TP53), has been shown to induce apoptosis (programmed cell death), but its function in tumor development has not been established. This study was undertaken to investigate the expression of p73 in liver tissue of patients with hepatocellular carcinoma (HCC) and to determine whether this expression has any impact on prognosis.Methods: In situ hybridization and immunohistochemistry for the detection of p73 RNA transcripts and protein, respectively, were performed in tissues from 193 patients with curatively (R0-) resected HCC. Patients receiving liver transplantation were excluded. The results obtained were analyzed with respect to their association with pathohistologic stage, Edmondson grade, p53 expression status and several histopathologic factors of possible prognostic value, and, finally, with patient survival.Results: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes. Transcripts were also found occasionally in non-neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was confined to the cell nucleus. Univariate survival analysis showed that p73 expression status was statistically significantly related to prognosis (two-sided P<.0001). Patients with p73-positive tumors had a poorer prognosis than those with p73-negative carcinomas. Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors.Conclusion: The protein p73 is overexpressed by a subset of HCCs and could serve as a useful indicator of prognosis in patients with this disease. [ABSTRACT FROM AUTHOR]

The article discusses the use of skin biomarker profiles to distinguish Schnitzler syndrome from chronic spontaneous urticaria. It mentions immunohistochemistry of skin cytokines presented significantly higher numbers of IL-6-positive cells in SchS. It also mentions the need of evaluation of these biomarkers in patients and along with characterization of the role of mast cells and neutrophils in auto inflammatory diseases.