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Generalized Pustular Psoriasis (GPP) is a dermatological autoinflammatory disease that rarely occurs in children and is associated with complex genetic factors. GPP pathogenesis has been associated with mutations in IL36RN gene, which encodes an interleukin-36 receptor antagonist. GPP usually occurs without a history of psoriasis in the patients or their family members. This case report describes the clinical course of a 3-year-old toddler with GPP. The diagnosis of GPP was confirmed through a comprehensive series of examinations, and genetic testing revealed an IL36RN mutation, providing further insight into the genetic basis of the condition. This case highlights the importance of a genetic perspective for diagnosing GPP, particularly in children.

This study investigated the association between the pre-miRNA146a C>G rs2910164 polymorphism and serum TNF-α in Egyptian patients with IS.

Graft-versus-host disease (GVHD) is a common complication in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized as either acute or chronic based on symptomatology and histopathological findings. Despite advancements in disease-targeting therapeutics, steroid-refractory GVHD remains a significant contributor to mortality in HSCT recipients, highlighting the gaps in our understanding of its pathophysiology and treatment strategies. We present the case of a 46-year-old woman diagnosed with acute undifferentiated leukemia, who exhibited persistently elevated levels of serum total bilirubin (T.Bili), alkaline phosphatase (ALP), and liver function tests (LFTs) beginning on [day +201] post-haploidentical peripheral blood stem cell (PBSC) transplantation. The patient received fludarabine/total body irradiation (Flu/TBI) as a myeloablative conditioning regimen and post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as GVHD prophylaxis. A liver biopsy confirmed the diagnosis of GVHD, while other possible etiologies were excluded by corresponding tests. Initial treatment with prednisone and tacrolimus, and the later addition of ruxolitinib, all showed poor response indicated by worsening T.Bili, ALP, and LFTs at the same time. Based on a multidisciplinary comprehensive assessment, we decided to administer 1,000 mg/m 2 (1,600 mg) of cyclophosphamide ("pulse Cy"), which resulted in a dramatic improvement in T.Bili and transaminases starting from the very next day. A durable response to pulse cyclophosphamide was observed, as all indicators normalized ("complete response") within 55 days without relapses. The patient remains in good health with no recurrence of hepatic GVHD. To our knowledge, this is the first case in which Grade IV hepatic GVHD, refractory to multiple agents including steroids, tacrolimus, and ruxolitinib, demonstrated a complete response to pulse cyclophosphamide. The success highlights the potential therapeutic role of cyclophosphamide, a potent and cost-effective chemotherapy agent, in treating multi-agent-refractory GVHD. Large-scale clinical trials are warranted to validate its efficacy in this setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cai, Ali, Filler, Bayati, Toma, Zaki, Yaghmour, Ladha, Woan, Tam and Chaudhary.)

Background: Breast cancer (BC) patients have a higher chance of survival if it is diagnosed at an early stage, which is essential for efficient treatment of the condition. The results of an elevated risk of cancer, including BC, previously associated with the ins/del polymorphism rs145204276 in the promoter region of growth arrest-specific 5 (GAS5) are still up for debate. Thus, this study aimed to appraise the frequency of the GAS5 rs145204276 variant with BC risk and demonstrate the potential impact of the sirtuin 1 (SIRT-1), transforming growth factor-beta (TGF-β), and microRNA-182 (miR-182) expression and their diagnostic value in BC., Methods: Blood samples of 155 patients with BC and fibroadenoma and 80 healthy controls were analyzed for GAS5 rs145204276 single nucleotide polymorphism (SNP), SIRT-1, TGF-β, and miRNA-182 expression levels., Results: Ins/ins genotype and ins allele frequencies for GAS5 rs145204276 were considerably higher in BC patients compared with controls. Patients with BC had significantly greater serum levels of TGF-β, miR-182, and SIRT-1 expression., Conclusions: The SIRT-1, TGF-β, and miR-182 genes provide novel, noninvasive diagnostic biomarkers for BC., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: The purpose of this study was to determine agreement with the American Academy of Orthopaedic Surgery Appropriate Use Criteria (AUC) for distal radius fractures (DRFs), before and after their adoption, and secondarily determine predictors of operative management., Methods: A single-institution retrospective cohort study comparing patients treated either nonoperatively (115 patients) or operatively (767 patients) for DRFs between May 1, 2008, and May 1, 2018, by 8 hand surgeons was performed. Data included demographics, injury characteristics, DRF radiographic measurements, treatment rendered, and their appropriateness according to the AUC. Statistical testing used the Fisher and χ 2 tests, t test, and multiple variable logistic regression, with a significance level of .05., Results: Overall, there was a significant increase in AUC agreement for operatively treated DRFs (82.7%-89.3%, P = .01), but no difference in agreement for nonoperatively treated DRFs (12.5%-10.7%, P = .77). Age <80 years, AO classes other than B, intra-articular displacement >1 mm, radial inclination <18°, high-energy mechanism of injury, and greater than 1 week to treatment were independent predictors of operative treatment. The area under the curve for the validated regression model using the aforementioned predictors was 0.82., Conclusion: Agreement with AUC for DRFs increased after its adoption for operatively treated, but not for nonoperatively treated, fractures. In addition, a predictive model for operative treatment was developed and validated. Future studies may benefit from further model refinement and testing in other patient cohorts.

Background  Due to the commonality of distal radius fractures (DRFs), the potential impact of ulnocarpal abutment (UA) on patient outcomes is significant, whether it developed after or prior to injury. It is, therefore, important to consider whether preexisting UA has any impact on outcomes after an acute DRF. Questions/Purpose  The aims of this study were to determine if differences were present in (1) pain at final follow-up, (2) complications, and (3) unintended operations in patients with DRFs and either without or with preexisting radiographic UA. Methods  A single institution retrospective cohort study comparing patients treated either nonoperatively (43 patients) or operatively (473 patients) for DRFs between 5/1/2008 to 5/1/2018 was performed. Data included demographics, prior wrist pain or surgery, ulnar variance, select treatment data, and presence of pain, complication, or unintended operation by final follow-up. Statistical testing used Fisher's exact test and chi-squared test, with a significance level of 0.05. Results  The prevalence of preexisting UA was 14.0 and 15.6% in the nonoperatively- and operatively treated groups, respectively. In nonoperatively treated patients without or with UA, no differences in pain (37.8 vs. 33.3%, p  = 1.00) or complications were seen (13.5 vs. 50.0%, p  = 0.07). A higher unintended operation rate for nonoperatively treated DRFs with UA, compared with those without, UA was seen (5.4 vs. 50.0%, p  = 0.01). No differences in pain, complications, or unintended operations were seen between those without and with UA in the operatively treated group. Conclusion  Preexisting UA is not associated with pain, complications, or unintended operations after operative treatment of DRFs. Prospective studies further evaluating outcomes in nonoperatively treated DRFs with UA may be beneficial., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

While retrograde cargo selection in the Golgi is known to depend on specific signals, it is unknown whether anterograde cargo is sorted, and anterograde signals have not been identified. We suggest here that S-palmitoylation of anterograde cargo at the Golgi membrane interface is an anterograde signal and that it results in concentration in curved regions at the Golgi rims by simple physical chemistry. The rate of transport across the Golgi of two S-palmitoylated membrane proteins is controlled by S-palmitoylation. The bulk of S-palmitoylated proteins in the Golgi behave analogously, as revealed by click chemistry-based fluorescence and electron microscopy. These palmitoylated cargos concentrate in the most highly curved regions of the Golgi membranes, including the fenestrated perimeters of cisternae and associated vesicles. A palmitoylated transmembrane domain behaves similarly in model systems., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pseudozyma flocculosa is a fungus very useful and highly efficient as a biocontrol agent against powdery mildew. The reproduction of this fungus occurs exclusively by asexual production of conidia or sporidia that are the most suitable form for agricultural use and seems to be the most resistant to storage conditions. Despite the advantages offered by P. flocculosa in biological control, the use of this fungus use remains largely limited compared to that of chemical fungicides, at least partly due to the difficulty to obtain sporidia resistant to adverse environmental stresses in submerged culture conditions. Under solid-state and submerged-state cultivation, P. flocculosa strain CBS 16788 produced different types of sporidia. The submerged sporidia (SS) appeared relatively uniform in size, which was 15,4 ± 1,6 μm μm long, and 2,8 ± 0.8 μm wide. The aerial sporidia (AS) varied in shape and size, with a mean length of 8,2 ± 3 μm and width of 2,3 ± 0.6 μm. Under scanning and transmission electron microscopy, the cell wall of submerged sporidia was thinner than that of aerial spores, and the surface was smooth in contrast to the aerial sporidia that had a tendency to have verrucous, brittle surface characteristics. The thickness of the aerial sporidia wall is due to the presence of an outer layer rich in melanin. The sporidia germination was compared on YMPD (yeast extract, malt extract, soy peptone, dextrose and agar) coated coverslips. The aerial sporidia did not show germ tubes until 5 h of incubation, while the submerged sporidia showed many germ tubes after the same time. The resistance against the adverse environmental conditions in relation to the type of sporidia of P. flocculosa is discussed., Competing Interests: We confirm that Artechno’s commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).

Background: Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age., Results: Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious., Conclusion: Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Background: With the increasing number of agents active against cancer, advanced cancer patients including metastatic colorectal cancer (mCRC) patients may continue receiving palliative systemic anticancer therapy (PSAT) near the end-of-life. Validated palliative prognostic models, such as the Chuang's prognostic scale (CPS), may be helpful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT., Aim: To test the ability of the CPS to predict the survival of mCRC under treatment with PSAT., Methods: CPS was prospectively assessed in 36 mCRC patients who were receiving PSAT. The scale is based on eight items: ascites, edema, cognitive impairment, liver and lung metastases, performance status, tiredness, and weight loss. The total CPS score ranges from 0 to 8.5 with the higher score indicating worse prognosis., Results: Patients were divided into two groups using a CPS cutoff score of 5, Group 1 with a CPS score ≤5 and Group 2 with a CPS score >5. Using this cutoff value, 3-month mortality was predicted with a positive predictive value of 71%, a negative predictive value of 77%, a sensitivity of 67%, a specificity of 81% and an overall accuracy of 75%. Group 1 patients had a longer median survival of 149 days (95% confidence interval [CI]: 82-216) in comparison to Group 2 patients who had a median survival of 61 days (95% CI: 35-87). The difference in survival was statistically significant (P = 0.01)., Conclusion: CPS may be useful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT.

Purpose: The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy., Methods: Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients., Results: Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months)., Conclusions: These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.

While glyco-engineered monoclonal antibodies (mAbs) with improved antibody-dependent cell-mediated cytotoxicity (ADCC) are reaching the market, extensive efforts have also been made to improve their pharmacokinetic properties to generate biologically superior molecules. Most therapeutic mAbs are human or humanized IgG molecules whose half-life is dependent on the neonatal Fc receptor FcRn. FcRn reduces IgG catabolism by binding to the Fc domain of endocytosed IgG in acidic lysosomal compartments, allowing them to be recycled into the blood. Fc-engineered mAbs with increased FcRn affinity resulted in longer in vivo half-life in animal models, but also in healthy humans. These Fc-engineered mAbs were obtained by alanine scanning, directed mutagenesis or in silico approach of the FcRn binding site. In our approach, we applied a random mutagenesis technology (MutaGen™) to generate mutations evenly distributed over the whole Fc sequence of human IgG1. IgG variants with improved FcRn-binding were then isolated from these Fc-libraries using a pH-dependent phage display selection process. Two successive rounds of mutagenesis and selection were performed to identify several mutations that dramatically improve FcRn binding. Notably, many of these mutations were unpredictable by rational design as they were located distantly from the FcRn binding site, validating our random molecular approach. When produced on the EMABling(®) platform allowing effector function increase, our IgG variants retained both higher ADCC and higher FcRn binding. Moreover, these IgG variants exhibited longer half-life in human FcRn transgenic mice. These results clearly demonstrate that glyco-engineering to improve cytotoxicity and protein-engineering to increase half-life can be combined to further optimize therapeutic mAbs.

Objective: To explore and analyze the current status in management of patients with perforated peptic ulcers (PPU)., Methods: A retrospective study carried out at the Surgical Department, Al-Gamhouria Teaching Hospital, Aden, Yemen. Patients admitted with perforated benign peptic ulcers from January 1997 to December 2006 were included in the study., Results: A total of 156 patients, 138 (88.5%) male and 18 (11.5%) female, with an overall mean age of 39.08 years (range 14-75 years) and a higher frequency of PPU was noted in patients 21-40 years (58.3%). The perforated duodenal ulcer and perforated gastric ulcer ratio was 4.38:1. The mean time of presentation was 16.5 hours, and operative intervention after admission was 5.25 hours. Simple perforation closure was used in 91.7% of the patients. Postoperative complication rate was 41% (statistically significant in cases admitted later than 12 hours), wound sepsis making the majority at 55.2%, 6 deaths (3.9%), the correlation with presentation time was not significant. The overall mean post-operative hospitalization period was 12.76 days; 14.7% of the patients stayed more than 3 weeks., Conclusion: Younger patients (21-40 years) were frequently affected. Emphasis should be placed on shortening the time to surgery. Simple closure remains the selected treatment in the majority of patients. Overall post-operative mortality was low (3.9%). Improving the surgical skills, wound care, administrative regulations, hospital environment, and equipment are needed to reduce the high rate of complications.

Background: A proportion of cases with repeated abortion are caused by chromosomal abnormality in one of the parents. Several studies have been done to determine the role of chromosomal abnormalities in couples with repeated fetal loss in various countries. None of these studies was done in the Arab Peninsula., Material and Methods: Cytogenetic study was done for 193 consecutive Saudi couples who presented with repeated abortion at the King Khalid University Hospital in Riyadh, Saudi Arabia., Results: We found that the frequency of chromosomal abnormalities was not significantly different from that reported worldwide. The nature of those abnormalities and their relation to the obstetric history of cases were discussed., Conclusion: This study should help physicians working in the region to realize the contribution of chromosomal abnormalities to cases of repeated fetal loss. It should also help in setting priorities of cytogenetic screening in individual cases.

Background: Studies on fragile X syndrome are scarce in Saudi Arabia and other countries of the Arabian Peninsula. The few studies previously done have either been in the form of case reports or those performed on institutionalized mentally retarded patients. The aim of this study was to determine the prevalence of fragile X syndrome among cases with mental retardation who have been referred to the pediatric neurology clinics of King Khalid University Hospital (KKUH) in Riyadh., Patients and Methods: Cytogenetic studies were performed in 94 cases who were referred to the pediatric neurology clinics of KKUH because of mental retardation and/or delayed milestones of development, from July 1995 to December 1997., Results: Six male probands (6.4%) showed the classic fragile X chromosome and another six (including a four year-old girl) were detected, following extension of the cytogenetic studies to all 32 first-degree relatives. Affection of more than one sibling was ascertained in four families. One family had four brothers with fragile X syndrome, whereas another formed part of a large kindred with twelve males and five females who were mentally retarded. A clinical, physical and psychological screening checklist was applied to the eleven affected males. Large testicular size, long face and short attention span were the most frequent features, and each was detected in nine patients (82%). Pes planus and history of delayed speech were found in eight patients (73%)., Conclusion: The study showed that the fragile X syndrome clinical screening checklist that has been applied in other populations might equally be valuable and applicable among the population of Saudi Arabia. However, the presence of pale blue eyes can be excluded and more weight given to positive family history of mental retardation. The study also highlighted the need for further emphasis on the orientation of primary care physicians to the most common clinical diagnostic features of fragile X syndrome.