Specific Drug Therapy Research Articles

Therapeutic potential of plant polyphenols in acute pancreatitis.

Acute pancreatitis is a potentially life-threatening inflammatory disorder of the exocrine pancreas characterized by early activation of pancreatic enzymes followed by macrophage-driven inflammation, and pancreatic acinar cell death. The most common causes are gallstones and excessive alcohol consumption. Inflammation and oxidative stress play critical roles in its pathogenesis. Despite increasing incidence, currently, no specific drug therapy is available to treat or prevent acute pancreatitis, in particular severe acute pancreatitis. New therapeutic agents are very much needed. Plant polyphenols have attracted extensive attention in the field of acute pancreatitis due to their diverse pharmacological properties. In this review, we discuss the potential of plant polyphenols in inhibiting the occurrence and development of acute pancreatitis via modulation of inflammation, oxidative stress, calcium overload, autophagy, and apoptosis, based on the currently available in vitro, in vivo animal and very few clinical human studies. We also outline the opportunities and challenges in the clinical translation of plant polyphenols for the treatment of the disease. We concluded that plant polyphenols have a potential therapeutic effect in the management and treatment of acute pancreatitis. Knowledge gained from this review will hopefully inspire new research ideas and directions for the development and application of plant polyphenols for treating this disease.

Thrombosis in Hemodialysis Tunnelled Central Venous Catheters: From Pathogenesis to Therapeutic Strategies

Central venous catheter-related thrombosis is a frequent non-infectious complication, typically associated with catheter dysfunction and hemodialysis inadequacy. Central venous catheters (CVCs) are categorized into non-tunnelled and tunnelled types, wherein the choice depends on patient's clinical conditions and the diagnostic and therapeutic workup. Tunnelled CVCs (tCVCs) are sought whenever an arteriovenous fistula is unfeasible or as primary access in patients with poor prognosis. Dysfunction is defined as the inability to maintain adequate blood flow within the prescribed dialytic session. Amongst non-infectious complications causing tCVC malfunctioning, thrombosis is the most frequent, and it is further classified into intrinsic (being endoluminal, pericatheter or fibrin sleeve-associated thrombosis) and extrinsic forms (including mural and atrial thrombosis). Diagnosis requires imaging tests like chest X-ray or abdominal X-ray, echocardiography, dynamic catheterography and computed tomography. Pharmacological treatment involves use of local thrombolytic agents. In case of extrinsic thrombosis, systemic anticoagulation is mandatory, occasionally requiring tCVC replacement. Prevention of thrombotic complications includes adequate positioning and appropriate use of the tCVC, with anticoagulant/antimicrobial-based locking solutions playing a crucial role in this context. In cases of extrinsic thrombosis, treatment options vary based on thrombus size, ranging from a conservative approach availing of systemic anticoagulation to surgical interventions like thrombectomy or thrombus aspiration, possibly associated with tCVC removal. In conclusion, late dysfunction of tCVCs is primarily due to thrombosis, thus requiring diagnostic imaging and specific drug therapies. Prevention is crucial to minimize complications.

Restoring CFTR function with Orkambi decreases the severity of alcohol-induced acute pancreatitis.

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100mm) for 12h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.

Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3α, -β, -γ, and -δ), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions.

The importance of physical therapy and occupational therapy on the quality of life and bone health in patients with osteoporosis

This study aims to evaluate. in the course of one year. the role of physical therapy and occupational therapy intervention. in association of specific drug therapy versus only drug therapy. in patients with osteoporosis. The study was carried out between April 2022 and June 2024, on 94 patients with osteoporosis. selected from the Clinical Rehabilitation Hospital in Băile Felix. All subjects signed an informed consent form 46 subjects followed drug therapy, physical therapy and occupational therapy (study group) and 46 subjects had only drug therapy (control group). The following parameters were assessed: the decrease in height. bone mineral density (BMD) - the T score and the Qualeffo test for the quality of life. Between groups analysis showed that in the study group. The post-test values of the total Qualeffo score decrease significantly and showed a smaller decrease in height compared to control group. Regarding BMD there is no significant difference between the study group compared to control group. The results of the study suggest that a specific physiotherapy can cause significant improvements both of quality of life and vertebral static disorders. As far as BMD is concerned rehabilitation has only a limiting effect of braking its decrease.

Far-infrared radiation alleviates steatohepatitis and fibrosis in metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a disease that causes an abnormal accumulation of fat in the liver, triggering inflammation and fibrosis, the mechanism of which is not fully understood and for which there is a lack of specific drug therapy. Far-infrared radiation (FIR) has demonstrated evident therapeutic efficacy across various diseases, and novel nanomaterial graphene patches can emit it through electric heating. This study aimed to investigate the potential protective effects of FIR against MAFLD. Mice were fed with a MCD diet to mimic MAFLD progression, and histopathology analysis, biochemical analysis, RT-qPCR, and Western blotting analysis were performed to assess the effect of FIR on MAFLD in vivo. The effect of FIR treatment on MAFLD in vitro was investigated by biochemical analysis and gene expression profiling of hepatocytes. Mice subjected to the MCD diet and treated with FIR exhibited reduced hepatic lipid deposition, inflammation, fibrosis and liver damage. The therapeutic effect exerted by FIR in mice may be caused by the enhancement of AMPK phosphorylation and inhibition of the TGFβ1-SMAD2/3 pathway. Besides, FIR intervention alleviated MAFLD in hepatocytes in vitro and the results were verified by gene expression profiling. Our results revealed a promising potential of FIR as a novel therapeutic approach for MAFLD.

Features of the formation of bone regenerate and metabolism of bone formation markers in a patient with type 1 diabetes mellitus and diabetic neuroosteoarthropathy (Charcot foot)

Background: Surgical treatment of diabetic neuroosteoarthropathy is a complex area in traumatology — orthopedics not only because of severe biomechanical disorders and gross deformations of the distal segment of the lower limb, but also because these phenomena are accompanied by many disorders of the somatic status. Of particular importance is a pronounced decrease in bone mineral density. This case is intended to illustrate the features of the treatment of this pathology. Clinical case description: A clinical case of treatment of a 34-year-old young female patient with type 1 diabetes mellitus, development of diabetic neuroosteoarthropathy (Charcot foot), and aseptic necrosis of the talus of the right foot is presented. From 2019–2020 conservative and surgical treatment was carried out aimed at stopping the active stage of Charcot foot, correcting deformity and stabilizing the distal segment of the limb (calcaneotibial arthrodesis). A satisfactory treatment result was achieved, complete activation 8 months after the operation. However, in 2021 The patient suffered a closed low-energy fracture of the distal metaphysis of the right tibia. Regarding this episode, the patient comes in at the stage of consolidation of a displaced fracture and complaints of recurrence of varus deformity, even greater shortening of the limb, and swelling of the ankle joint. The fact of injury is denied, which allows us to regard the existing fracture of the tibia as pathological. In this regard, an operation was performed: osteotomy of the fibula and tibia in the area of consolidation of the pathological fracture in order to correct the deformity and compensate for the existing shortening of the limb due to the formation of a distraction regenerate. During the treatment, malnutrition and delayed formation of bone regenerate were noted, which required prolonged use of an external fixation device and specific drug therapy aimed at stimulating osteogenesis and improving bone mineral density. At the end of the course, there was an increase in the mineral density of the tissue, the density of the regenerate radiologically and laboratory (control of bone formation markers) and a satisfactory functional result. CONCLUSION: A successful result in this clinical case was achieved by combining orthopedic surgical and conservative treatment with specific drug therapy in a comorbid patient with reduced bone mineral density and a high probability of complications in a multidisciplinary approach.

Социологическое исследование оценки врачами-онкологами и врачами-радиотерапевтами изменений доступности противоопухолевой терапии при реализации федерального проекта «Борьба с онкологическими заболеваниями».

The federal project «Fight against oncological diseases» is aimed at increasing the availability of cancer care that meets clinical guidelines. The purpose is to study the degree of use of clinical guidelines by oncologists and radiotherapists, the attitude to changes in the payment system for antitumor treatment by diagnosis-related group (DRG) of diseases and the opinion on the availability of antitumor therapy. M a t e r i a l s a n d m e t h o d s . A survey of 436 oncologists and radiotherapists was conducted. Results. Oncologists and radiotherapists actively use clinical guidelines in their practice. The majority of respondents positively assessed the changes in the payment system for antitumor drug therapy for DRG starting in 2018 (the inclusion of specific drug therapy regimens in DRG) and radiation therapy starting in 2019. Oncologists are 2 times more likely to face restrictions on the allocation of volumes of medical care in the «oncology» profile for antitumor drug therapy both in round-the-clock and day hospitals than for surgical treatment and radiation therapy. At the same time, 2/3 of the respondents noted that medical care for patients with solid tumors has become more accessible.

Tripled likelihood: polypharmacy increases the occurrence of drug therapy problems in hospitalized pediatric patients.

A drug therapy problem (DTP) is any undesirable event experienced by a patient that accompanies drug therapy, prevents the patient from achieving their desired therapeutic goals, and requires expert judgment to resolve. Pediatric populations are at a higher risk of DTP than adults due to their immature organ systems, including the liver and kidneys, which play crucial roles in drug metabolism and excretion. Most previous studies have focused on only one element of DTP. Therefore, by considering all elements of DTP, we aimed to assess the prevalence of DTP and associated factors among pediatric patients admitted to the Wolaita Sodo University Comprehensive Specialized Hospital. An institution-based cross-sectional study was conducted among pediatric patients admitted to Wolaita Sodo University Comprehensive Specialized Hospital from 8 July 2020, to 7 July 2021. A simple random sampling technique was employed to select study participants. Cipolle's and Strand's classification method of drug therapy problems was used to identify and categorize DTP. Data were obtained by reviewing the patient's medical records using a data abstraction checklist, entered into Epi data version 4.6, and exported to SPSS version 25 for analysis. Binary logistic regression analysis was performed to identify independent predictors of DTP. Medical records of 369 pediatric patients were reviewed, and the overall prevalence of DTP was 60.2% (95% CI:55.2%, 65.2%) with a total of 281 identified DTPs. Among them, 164 (74.2%) had only one DTP. Need additional drug therapy was the most common (140 [49.8%]) DTP identified. The number of disease conditions (AOR = 2.13, 95% CI:1.16, 3.92), polypharmacy (AOR = 3.01, 95% CI:1.70, 5.32), and duration of hospital stay (AOR = 1.80, 95% CI:1.04, 3.10) were independent predictors of DTP among admitted pediatric patients. The prevalence of DTP in pediatric patients in the current setting was high. The number of disease conditions, polypharmacy, and duration of hospital stay were independent predictors of DTP. Enhancements to pharmaceutical care services, optimized dosage practices, improved deprescribing by clinicians, and efficient, comprehensive diagnostic procedures have the potential to significantly reduce specific drug therapy problems in hospitalized pediatrics.

Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients

BackgroundCeliac disease (CD) is a chronic immuno-mediated enteropathy caused by dietary gluten in genetically susceptible individuals carrying HLA (Human Leukocytes Antigen) genes that encode for DQ2.5 and DQ8 molecules. TRAFD1 (TRAF-type zinc finger domain 1) is a gene recently found associated with CD and defined as a master regulator of IFNγ signalling and of MHC class I antigen processing/presentation. There is no specific drug therapy and the only effective treatment is the gluten-free diet (GFD). The great majority of celiac patients when compliant with GFD have a complete remission of symptoms and recovery of gut mucosa architecture and function. Until now, very few studies have investigated molecular differences occurring in CD patients upon the GFD therapy. MethodsWe looked at the expression of both HLA DQ2.5 and TRAFD1 risk genes in adult patients with acute CD at the time of and in treated patients on GFD. Specifically, we measured by qPCR the HLA-DQ2.5 and TRAFD1 mRNAs on peripheral blood mononuclear cells (PBMC) from the two groups of patients. ResultsWhen we compared the HLA-DQ mRNA expression, we didn't find significant variation between the two groups of patients, thus indicating that GFD patients have the same capability to present gliadin antigens to cognate T cells as patients with active disease. Conversely, TRAFD1 was more expressed in PBMC from treated CD subjects. Notably, TRAFD1 transcripts significantly increased in the patients analyzed longitudinally during the GFD, indicating a role in the downregulation of gluten-induced inflammatory pathways. ConclusionOur study demonstrated that HLA-DQ2.5 and TRAFD1 molecules are two important mediators of anti-gluten immune response and inflammatory process.

In Silico Analysis of Inhibitor Potential of Punicalagin Compound in Pomegranate (Punica granatum) Against NS5 DENV-3 Protein

Indonesia is one of the Dengue Virus (DENV) endemic areas which are dominated by DENV-2 and DENV-3. Until now, no specific drug therapy has been found to cure Dengue Virus Infection (DVI). Punicalagin is one of the active compounds that have the potential to be used as an antiviral. Unfortunately, not many studies have used punicalagin as a DENV antivirus. This study aims to determine the inhibitory potential of punicalagin compounds against NS5 DENV-3 protein through molecular docking. Molecular docking was performed using AutoDock Tools, ChemDraw, and Discovery Studio Visualizer. The target protein used is NS5 DENV-3 protein with PDB ID code: 4V0Q. The ribavirin compound was used as a positive control. The results obtained show that the punicalagin compound has the ability to attach to target receptors in the C-Terminal domain complex. This docking produces a bond free energy (ΔG) of -6.39 kcal/mol. This result is better than the ΔG of the control compound. Punicalagin's Inhibition Constant (Ki) value also showed better results than ribavirin. So it can be seen that the compound punicalagin effectively inhibits DENV replication and has the potential as a DENV drug candidate.

Icariin suppresses nephrotic syndrome by inhibiting pyroptosis and epithelial-to-mesenchymal transition.

Nephrotic syndrome(NS) has emerged as a worldwide public health problem. Renal fibrosis is the most common pathological change from NS to end-stage renal failure, seriously affecting the prognosis of renal disease. Although tremendous efforts have been made to treat NS, specific drug therapies to delay the progression of NS toward end-stage renal failure are limited. Epimedium is generally used to treat kidney disease in traditional Chinese medicine. Icariin is a principal active component of Epimedium. We used Sprague Dawley rats to establish NS models by injecting doxorubicin through the tail vein. Then icariin and prednisone were intragastric administration. Renal function was examined by an automatic biochemical analyzer. Pathology of the kidney was detected by Hematoxylin-Eosin and Masson staining respectively. Furthermore, RT-PCR, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Western Blot and Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling staining were employed to detect the proteins related to pyroptosis and EMT. HK-2 cells exposed to doxorubicin were treated with icariin, and cell viability was assessed using the MTT. EMT was assessed using Enzyme-Linked Immunosorbent Assay and Western Blot. The study showed that icariin significantly improved renal function and renal fibrosis in rats. In addition, icariin effectively decreased NOD-like receptor thermal protein domain associated protein 3,Caspase-1, Gasdermin D, Ly6C, and interleukin (IL)-1β. Notably, treatment with icariin also inhibited the levels of TGF-β, α-SMA and E-cadherin. It is confirmed that icariin can improve renal function and alleviate renal fibrosis by inhibiting pyroptosis and the mechanism may be related to epithelial-to-mesenchymal transition. Icariin treatment might be recommended as a new approach for NS.

Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. SIGNIFICANCE STATEMENT: Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.

Structural Analyses of An Epidermal Growth Factor Receptor-Specific Single-Chain Fragment Variable via An In Silico Approach.

Single-chain fragment variable (scFv) antibodies were previously constructed of variable light and heavy chains joined by a (Gly4-Ser) 3 linker. The linker was created using molecular modeling software as a loop structure. Here, we introduce a protocol forin silico analysis of a complete scFv antibody that interacts with the epidermal growth factor receptor (EGFR). The homology modeling, with Pyrx of protein-protein docking and molecular dynamic simulation of the interacting scFv antibody and EGFR First, the authors used a protein structure modeling program and Python for homology modeling, and the antibody scFv structure was modeled for homology. The investigators downloaded Pyrx software as a platform in the docking study. The Molecular dynamic simulation was run using modeling software. Results show that when the MD simulation was subjected to energy minimization, the protein model had the lowest binding energy (-5.4 kcal/M). In addition, the MD simulation in this study showed that the docked EGFR-scFv antibody was stable for 20-75 ns when the movement of the structure increased sharply to 7.2 Å. In conclusion, in silicoanalysiswas performed, and the molecular docking and molecular dynamics simulations of the scFv antibody proved the effectiveness of the designed immune-therapeutic drug scFv as a specific drug therapy for EGFR.

Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling.

Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its pathogenesis is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by CYP (cytochrome P450) enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by sEH (soluble epoxide hydrolase), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3β (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-β production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.

Exercise therapy and basic treatment for osteoporosis

Physical training is an important component in the prophylaxis of osteoporosis and the prevention of fractures. Physical training not only has adirect effect on muscle strength and muscular performance, but also on the risk of falling and the fear of falling. Therefore, physical training is also an integral part of the basic treatment for osteoporosis. The recommendations for basic treatment are an adequate intake of nutrients, including protein in particular. The intake of calcium and vitaminD in sufficient quantities is also important and, in the case of specific drug therapy, also to avoid side effects and to ensure the therapeutic effect. This article summarizes the recommendations of the updated S3guideline on the diagnosis and treatment of osteoporosis and explains the background for the recommendations included.

A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity.

Monogenic obesity generally results in severe early-onset obesity associated with abnormal feeding behavior and endocrine disorders. We report here an extremely severe case of early-onset obesity associated with hyperphagia in an 11-month-old boy without other signs of a syndromic obesity. He developed severe obstructive sleep apnea, dyslipidemia, hepatic steatosis with cytolysis, and acanthosis nigricans with insulin resistance in the first months of life. Laboratory investigations showed an elevated serum leptin level (80.03 ng/mL, normal range 2.45-6.55 ng/mL). Next-generation sequencing of obesity genes panel identified a novel homozygous intronic variant in leptin receptor gene (LEPR), c.703 + 5G>A, predicting affected splicing that resulted in a frameshift, premature stop, and truncation of the protein beyond the cytokine receptor homology domain 1. The child died at 27 months of age in the absence of available specific drug therapy.

Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria

BackgroundPrimary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase.MethodsA survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group “Rare Forms of Nephrolithiasis and Nephrocalcinosis” of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy.ResultsForty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants.ConclusionsThe data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.Graphical abstract

Large-scale metabolomic profiling and incident non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032UK Biobank participants. We identified several metabolic factors associated with NAFLD risk in observational and MR analyses including triglyceride-rich and high-density lipoprotein particles composition, as well as the ratio of polyunsaturated fatty acids to total fatty acids. This study, is one of the largest to investigate incident NAFLD, provides concordant observational and genetic evidence that therapies aimed at reducing circulating triglycerides and increasing large HDL particles, as well as interventions aimed at increasing polyunsaturated fattyacid content may warrant further investigation into NAFLD prevention and treatment.

Should We Change the Target of Therapy in Pulmonary Hypertension?

Despite the evolution of drug therapy in pulmonary arterial hypertension and the more aggressive treatment approach according to the guidelines, patients continue to have unacceptable mortality rates. Furthermore, specific drug therapy alone in chronic thromboembolic pulmonary hypertension also does not seem to have any beneficial impact on survival. As the function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension, the treatment strategy should focus on modifying factors involved in RV dysfunction. Although some previous reports demonstrated that the survival of patients with pulmonary hypertension was associated with mPAP, nevertheless, mPAP is still not considered as a target of therapy. There are many examples of effective mPAP lowering with early and aggressive drug therapy in pulmonary arterial hypertension, or with interventions in chronic thromboembolic pulmonary hypertension. This effective mPAP reduction can lead to reverse RV remodeling, and thus, improvement in survival. In this article, the importance of mPAP lowering is stated, as well as why the change of our current strategy and considering mPAP reduction as the target of therapy could make pulmonary hypertension a chronic but not fatal disease.