Objective Severe myoclonic epilepsy (SMEI; Dravet's syndrome) is a severe form of epilepsy which begins in infancy. The first seizures in Dravet syndrome are often prolonged febrile seizures, the ...course of Dravet syndrome is variable from one child to another. This may delay diagnosis for many months and often years after the onset of seizures. Most children with Dravet syndrome have a mutation in a gene called SCN1A. Methods We present the clinical, laboratory and neuroimaging data of our three SMEI patients, and the importance of genetic diagnosis to treatment decisions. Results First patient has first afebrile atonic episode when she has two months old, then multiple seizure types appeared, sometimes occurring in a daily cluster in spite of various antiepileptic combinations. Extensive neurometabolic and genetic findings including SCN1A gene revealed no abnormalities but due clinical criteria for Dravet syndrome, stiripentol was started with significant improvement in seizures control and development. Second patient presented his first episode of febrile seizures at eight months of age. In following years status epilepticus occurred monthly. At the age of 4 years, a missense mutation was found of the SCN1A gene and treatment with stiripentol was started, seizures stop, and his development is almost normal, but with behavioral disturbances. Third patient has various types of seizures provoked by a febrile state, noise and emotional stimuli. At the age of 12 months DNA diagnostics identified an SCN1A mutation, and then, after various combinations of medications treatment with stiripentol was started. The number of seizures was reduced and developmental delay is minimal. Conclusion The importance is that children with Dravet syndrome can have a genetic diagnosis before the full syndrome has evolved. This will reduce unnecessary diagnostic procedures, enable initiation of appropriate treatment, and thus achieve a better control of seizures and reduce neurological disability.
Propylthiouracil (PTU) could cause lupus or vasculitis-like hypersensitivities thus interfering with some other concomitant diseases.
Clinicians must be aware of the side effects of medications, ...particularly after their introduction and long-term use. Some clinical manifestations may be similar to well-known drug side effects or hypersensitivity. Every unusual clinical scenario related to drug use must be evaluated individually and thoroughly.
Hands and feet skin changes were observed several days after PTU administration in a male patient with severe diffuse toxic goitre. A complete blood count, biochemistry analyses, thyroid function tests and antibodies, and immunology analyses were performed.
As the skin changes were distributed regionally, liver function tests were normal, and there were no signs of clinical deterioration, it was decided to continue PTU treatment and monitor the patient. The initial maculopapular rash quickly turned vesicular, then scaly. After two weeks, the skin changes were wholly restored, with no scarring. Hand, Foot, and Mouth disease (HFMD) was diagnosed after a thorough epidemiological survey and clinical workout.
Our case study demonstrates that skin changes associated with HFMD may resemble those associated with PTU-induced vasculitis.
The repertoire of therapeutic proteins has been substantially augmented by molecular engineering approaches, which have seen remarkable advancement in recent years. In particular, advances in ...directed evolution technologies have empowered the development of custom-designed proteins with novel and disease-relevant functions. Whereas engineered proteins have typically been administered through systemic injection of the purified molecule, exciting progress in gene delivery affords the opportunity to elicit sustained production of the engineered proteins by targeted cells in the host organism. Combining developments at the leading edge of protein engineering and gene delivery has catapulted a new wave of molecular and cellular therapy approaches, which harbor great promise for personalized and precision medicine. This mini-review outlines currently used display platforms for protein evolution and describes recent examples of how the resulting engineered proteins have been incorporated into DNA- and cell-based therapeutic platforms, both in vitro and in vivo. Collectively, the strategies detailed herein provide a framework for synthesizing molecular engineering workflows with gene therapy systems for a breadth of applications in research and medicine.
The interleukin-2 (IL-2) cytokine plays a crucial role in regulating immune responses and maintaining immune homeostasis. Its immunosuppressive effects have been harnessed therapeutically via ...administration of low cytokine doses. Low-dose IL-2 has shown promise in the treatment of various autoimmune and inflammatory diseases; however, the clinical use of IL-2 is complicated by its toxicity, its pleiotropic effects on both immunostimulatory and immunosuppressive cell subsets, and its short serum half-life, which collectively limit the therapeutic window. As a result, there remains a considerable need for IL-2-based autoimmune disease therapies that can selectively target regulatory T cells with minimal off-target binding to immune effector cells in order to prevent cytokine-mediated toxicities and optimize therapeutic efficacy. In this review, we discuss exciting advances in IL-2 engineering that are empowering the development of novel therapies to treat autoimmune conditions. We describe the structural mechanisms of IL-2 signaling, explore current applications of IL-2-based compounds as immunoregulatory interventions, and detail the progress and challenges associated with clinical adoption of IL-2 therapies. In particular, we focus on protein engineering approaches that have been employed to optimize the regulatory T-cell bias of IL-2, including structure-guided or computational design of cytokine mutants, conjugation to polyethylene glycol, and the development of IL-2 fusion proteins. We also consider future research directions for enhancing the translational potential of engineered IL-2-based therapies. Overall, this review highlights the immense potential to leverage the immunoregulatory properties of IL-2 for targeted treatment of autoimmune and inflammatory diseases.
The skin microbiome consists of bacteria, fungi, viruses, and mites, which play a crucial role in maintaining skin health and immune function. Imbalances in this microbial community, known as ...dysbiosis, are implicated in various dermatological conditions. While skincare products are known to influence the skin microbiome, the effects of dermatological procedures have not been extensively studied. Here, we perform a scoping review to outline the studies investigating the impacts of dermatological interventions on the skin microbiome. Phototherapy emerged as the most studied intervention, encompassing UV phototherapy, light therapy, laser therapy, and photodynamic therapy. Chemical interventions, such as chemical peels, micropigmentation, and debridement, have comparatively limited studies describing their impacts on the skin microbiome. To date, no studies have been done on a wide variety of common dermatological procedures such as cryotherapy, skin grafts, and dermabrasion, which may have stronger likelihoods of affecting the skin microbiome. This underscores the need for further research on the influences of dermatological procedures, especially chemical and physical interventions, on the skin microbiome. More comprehensive pre-clinical and clinical studies are essential not only for understanding the long-term consequences of these procedures, but also for optimizing patient outcomes in dermatological care.
Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine’s preferential expansion of immunosuppressive regulatory T cells (Tregs). However, ...off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.
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•Single-chain human interleukin-2/antibody fusion protein (immunocytokine) is designed•F5111 immunocytokine promotes biased Treg activation and expansion•Immunocytokine induces superior Treg bias compared with cytokine/antibody complex•F5111 immunocytokine confers protection in mouse models of autoimmune diseases
VanDyke et al. engineer a single-chain fusion protein composed of the human interleukin-2 cytokine and the anti-cytokine antibody F5111, which induces biased activation and expansion of regulatory T cells in vitro and in vivo. This protein confers protection in animal models of colitis and immune checkpoint inhibitor-induced diabetes mellitus.
