Visceral Symptoms Research Articles

Anti-nociceptive effect of STW 5-II in rodent models of stress and post-inflammatory visceral hypersensitivity

AimsVisceral hypersensitivity is a therapy-resistant hallmark of irritable bowel syndrome (IBS). Many IBS patients’ symptoms develop following an acute colitis, and most report that stress worsens symptoms. STW 5-II, a combination of six herbal extracts, is a clinically proven treatment for IBS, but the mechanism is uncertain. Here, we employ two well-characterized rodent models to test the hypothesis that STW 5-II attenuates chronic colonic hypersensitivity. Main methodsSeparate cohorts of male rats were used for each model of colonic hypersensitivity. The first model used repeated water avoidance stress (1hr/day for 10 days), while the second model used intracolonic trinitrobenzene sulfonic acid to induce a short-lived colitis followed by post-inflammatory visceral hypersensitivity. Both models used sham treatment controls. Colonic sensitivity was quantified as the number of abdominal contractions to graded pressures (20–60 mmHg) of isobaric colorectal distension (CRD). Phosphorylation of extracellular signal-regulated kinase (pERK) was assessed via immunohistochemistry in the brain, spinal cord, and dorsal root ganglion (DRG). STW 5-II (10 ml/kg, p.o.) or vehicle (p.o.) was administered for 7 days, prior to CRD and pERK expression. Key findingsRats exposed to either model developed significant colonic hypersensitivity. Both models enhanced CRD-evoked pERK in DRGs, spinal cord, and brain. STW 5-II decreased colonic hypersensitivity and reduced CRD-evoked brain, spinal, and DRG pERK. SignificanceBoth models induced colonic hypersensitivity and enhanced pERK expression. STW 5-II inhibited colonic hypersensitivity and decreased noxious neuronal activation in both models, which could explain its clinically proven efficacy in relieving visceral hypersensitivity-related symptoms in IBS.

Quantum Medicine and Irritable Bowel Syndrome-Associated Chronic Low-Back Pain: A Pilot Observational Study on the Clinical and Bio-Psycho-Social Effects of Bioresonance Therapy.

Background and Objectives: Irritable bowel syndrome (IBS) is an invasive and potentially disabling syndrome characterized by a multitude of symptoms capable of reducing the quality of life of patients. Among the most disabling symptoms of IBS is certainly physical pain, which manifests itself mainly at the abdominal level but can also appear in other areas of the body, particularly in the form of chronic low-back pain (CLBP). Among the non-invasive methods of treating organ-specific pathologies and organ-related musculoskeletal problems, the use of Bioresonance Therapy (BT)-based on the administration of self-modulating Extremely Low-Frequency Electromagnetic Fields, capable of determining a rebalance of bio-electrical and metabolic activity in the presence of various functional alterations-is currently gaining acceptance. Therefore, we decided to monitor results obtained from patients suffering from IBS and CLBP subjected to a cycle of treatments with BT. Materials and Methods: We monitored 20 patients (12 women and 8 men, average age of 51 years) suffering from CLBP and other visceral symptoms related to IBS. Patients were monitored through the use of the Bristol Stool Form Scale (BSFS), the Fecal Calprotectin test and the Short-Form Health Survey 36 (SF-36), collected before (T0) and after (T1) the execution of the cycle of treatments. They undertook a treatment protocol consisting of eight sessions of BT carried out over about a month. Results: At the end of the treatments with BT, it was possible to observe a general and significant improvement in all the parameters observed, as well as a close inversely proportional correlation between the Calprotectin values detected and the quality of life experienced by the patients in relation to their perceived IBS symptoms. Conclusions: Overall, our pilot study would seem to suggest a potential beneficial effect of BT in modulating organic and musculoskeletal symptoms derived from IBS.

Anomalies of Midbrain/Hindbrain Development and Related Disabilities: Pontocerebellar Hypoplasia, Congenital Disorders of Glycosylation, and Cerebellar Hemisphere Hypoplasia

AbstractRecent progress in developmental biology, molecular genetics, and neuroimaging has enabled a more profound comprehension of developmental disorders affecting the embryonic midbrain and hindbrain, which manifest clinically. The purpose of this review is to describe anomalies of the midbrain/hindbrain such as pontocerebellar hypoplasia (PCH), congenital disorders of glycosylation (CDG), cerebellar hemisphere hypoplasia. PCH is a group of disorders that is both clinically and genetically diverse. These disorders are identified by the hypoplasia and degeneration of the cerebellum and ventral pons. A total of 18 distinct clinical subtypes of PCH, each linked to pathogenic variants in 19 different genes, have been documented, like mutations in TSEN54 (coding a subunit of tRNA splicing endonucleases complex) and TBC1D23 which display moderate-to-severe intellectual disability (ID) and microcephaly. CDG represent a set of inherited conditions marked by impaired glycosylation of proteins and lipids. The most prevalent subtype among CDG is PMM2-CDG, inherited in a recessive manner, causing reduced activity of phosphomannomutase. Its phenotype varies from mild to severe, involving the central nervous system and affecting many other organs as well. Patients who are severely affected also exhibit visceral symptoms alongside severe ID and other neurological manifestations. Cerebellar hypoplasia (CH) is characterized by a cerebellum of diminished volume while maintaining its shape. CH exhibits a diverse range of neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental involvement. Cerebello–oculo–facio–genital syndrome is linked to a recessive MAB21L1 mutation. Jubert's syndrome, associated with a rare autosomal recessive mutation, is identified on magnetic resonance imaging by cerebellar worm hypoplasia and midbrain malformations. The rhombencephalosynapsis, characterized by vermian agenesis or hypogenesis with the fusion of the cerebellar hemispheres, emerges during embryogenesis. It can manifest alone or in conjunction with other and/or extracerebral abnormalities.

VISCERAL SYMPTOMS IN ABDOMINAL WALL PAIN

Abstract Purpose Anterior Cutaneous Nerve Entrapment Syndrome (ACNES) is characterized by neuropathic pain in a predictable, circumscript abdominal area. The diagnostic delay is long, with half of ACNES-affected individuals reporting next to pain, also nausea, bloating, or loss of appetite mimicking some kind of visceral disease. The aim of this study was to describe these phenomena and to determine whether treatment could successfully reverse the visceral symptoms. Methods This was a prospective observational study. Adult patients who fulfilled published criteria for ACNES and reported at least one visceral symptom at intake were eligible for the study. A self-developed Visceral Complaints ACNES Score (VICAS) questionnaire that scores several visceral symptoms (minimum 1 point, maximum 9 points) was completed before and after therapy. The success of treatment was defined as at least 50% reduction in pain. Results Data from 100 selected (at least one visceral symptom) patients (86 females) aged 39 ± 5 years were available for analysis. Frequently reported symptoms were abdominal bloating (78%), nausea (66%) and altered defecation (50%). Successful pain treatment significantly reduced the number of visceral symptoms, with a VICAS before of 3 (range 1–8) and after of 1 (range: 0–6) (p < 0.001). A low baseline VICAS was associated with successful treatment outcome (OR: 0.738, 95% CI: 0.546–0.999). Conclusion Patients with ACNES may report a variety of visceral symptoms. Successful treatment substantially reduces these visceral symptoms in selected patients, indicating a segmental relation between the abdominal wall and the viscera.

Emotional disorders in the structure of psychoorganic pathology in tumors of the diencephalon

IntroductionThe tumors of the diencephalon region (thalamic-hypothalamic-pituitary system) include a large group: pituitary adenomas, craniopharyngiomas, gliomas, and others. Tumors differ in the histological structure, and manifestations of the clinical symptoms; by hormonal data; by approaches and methods in treatment.Psychic symptoms are revealed in disease in addition to cerebral, neuroendocrine symptoms, neurological disorders. Psychoorganic syndrome is represented by emotional, motivational, personal, cognitive impairments, inversion of the sleep-wake cycle, seizures.Disorders of mental activity are detected in all tumors of this localization in varying degrees, according to the different authors from 20 to 100%; affective pathology varies from 2 to 80% by the literature.ObjectivesTo study the emotional disorders in the structure of psychoorganic pathology in tumors of diencephalon regionMethods290 patients (18-78 years old, mean age 38+2): pituitary adenomas (PA), as the most common – 170 (58,6%), craniopharyngiomas (CG), as with the most varied manifestation of mental symptoms – 120 (41,4%). Methods: psychopathological, data from endocrinological, neurological, neuroimaging methods.ResultsEmotional disorders were detected in patients from 30 to 68% of cases, depending on the histology of the tumours: PA with excessive secretion of growth hormone - emotional disorders are in 60%; PA with excessive secretion of adrenocorticotropic hormone - in 50%; PA with excessive secretion of prolactin - in 30%; with excessive secretion of thyroid-stimulating hormone - in 40%; non-functioning PA - in 16%; CG - in 68%.Emotional disorders were more often represented by changeable mood, depression, apathy, sleep disturbance, and visceral symptoms. Symptoms differed depending on the histology of the tumor (type and level of hormones), the volume of the lesion and direction of growth, and concomitant hypertensive-hydrocephalic symptoms. Emotional disturbances often include memory impairment, personality and behavior changes.ConclusionsEmotional disorders are detected in patients in 30-68% of cases in the structure of psychoorganic pathology with damage to the diencephalon region (in particular, with pituitary adenomas and craniopharyngiomas); are determined by the topography of the tumor and histology with the involvement of the corresponding structures and nuclei in the pathological process.Disclosure of InterestNone Declared

Gaucher Disease: A Glance from a Medicinal Chemistry Perspective.

Rare diseases are particular pathological conditions affecting a limited number of people and few drugs are known to be effective as therapeutic treatment. Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, belongs to this class of disorders, and it is considered the most common among the Lysosomal Storage Diseases. The two main therapeutic approaches are the Enzyme Replacement Therapy (ERT) and the Substrate Reduction Therapy (SRT). ERT, consisting in replacing the defective enzyme by administering a recombinant enzyme, is effective in alleviating the visceral symptoms, hallmarks of the most common subtype of the disease whereas it has no effects when symptoms involve CNS, since the recombinant protein is unable to significantly cross the Blood Brain Barrier. The SRT strategy involves inhibiting glucosylceramide synthase (GCS), the enzyme responsible for the production of the associated storage molecule. The rational design of new inhibitors of GCS has been hampered by the lack of either the crystal structure of the enzyme or an in-silico model of the active site which could provide important information regarding the interactions of potential inhibitors with the target, but, despite this, interesting results have been obtained and are herein reviewed.

Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a rare progressive lysosomal lipid storage disorder that manifests with a heterogeneous spectrum of clinical syndromes, including visceral, neurological and psychiatric symptoms. This monogenetic autosomal recessive disease is largely caused by mutations in the NPC1 gene, which controls intracellular lipid homeostasis. Vesicle-mediated endo-lysosomal lipid trafficking and non-vesicular lipid exchange via inter-organelle membrane contact sites are both regulated by the NPC1 protein. Loss of NPC1 function therefore triggers intracellular accumulation of diverse lipid species, including cholesterol, glycosphingolipids, sphingomyelin and sphingosine. The NPC1-mediated dysfunction of lipid transport has severe consequences for all brain cells, leading to neurodegeneration. Besides the cell-autonomous contribution of neuronal NPC1, aberrant NPC1 signalling in other brain cells is critical for the pathology. We discuss here the importance of endo-lysosomal dysfunction and a tight crosstalk between neurons, oligodendrocytes, astrocytes and microglia in NPC pathology. We strongly believe that a cell-specific rescue may not be sufficient to counteract the severity of the NPC pathology, but targeting common mechanisms, such as endo-lysosomal and lipid trafficking dysfunction, may ameliorate NPC pathology. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Abdominal viscera in the thoracic cavity: a case of large Bochdalek hernia in an adult

Introduction: Bochdaleck hernias (BH) are a congenital defect in the diaphragm's postero lateral part that may cause the abdominal viscera's protrusion into the chest cavity. This type of hernia is rare in adults. Most cases are referred to the emergency department with gastrointestinal obstruction and visceral strangulation symptoms. Case presentation: A 50-year-old man was referred to the emergency department complaining of abdominal pain in the left upper quadrant, intermittent vomiting, and pain in the left hemithorax from one day ago. We found a large diaphragmatic hernia on the left side during evaluation, which causes intra-abdominal organ shift to the left hemithorax. The patient underwent surgery for diaphragmatic herniorrhaphy. Conclusion: Congenital diaphragmatic Bochdaleck hernias are rare and are associated with nonspecific symptoms in adults. They may be symptom-free during the patient's life as in our case. It is necessary to investigate more cases and long-term follow-ups of patients, to improve the diagnosis and treatment of these patients.

Ocular manifestation of an adult Niemann-Pick disease type B

Niemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick disease type B as a child, focusing on the ophthalmic manifestation of the disease. During the examination of the patient, fundus photographs and fundus autofluorescence imaging were taken, and optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and visual field (perimetry) examinations were performed. The characteristic macular halo and the cherry-red spot in the fovea were clearly visible during ophthalmoscopy and on the fundus photographs. The OCT images showed focal thickening with high reflectivity in the ganglion cell layer corresponding to the macular halo, and the area of the foveola was spared. With visual field examination, an intact field of vision was found on both eyes. Similar to the presented patient, symptoms in patients with the B subtype are milder, and besides the visceral symptoms, there are no neurological symptoms, and the specific ophthalmic abnormalities do not cause visual impairment. Currently, Niemann-Pick disease is considered a rare disease, and the diagnosis of the patients is often delayed or even missed due to non-specific or mild symptoms. Through consultation between medical specialties, ophthalmological examination can also contribute to the correct diagnosis in cases with mild general symptoms. Timely diagnosis can potentially lead to mitigation of symptoms thanks to the ever-expanding therapeutic options, stabilization of the disease progression, and increase of the patients' life expectancy. Orv Hetil. 2023; 164(46): 1838-1844.

Assessment of Cross-Reactivity of Chimeric Trypanosoma cruzi Antigens with Crithidia sp. LVH-60A: Implications for Accurate Diagnostics.

This study focuses on developing accurate immunoassays for diagnosing Chagas disease (CD), a challenging task due to antigenic similarities between Trypanosoma cruzi and other parasites, leading to cross-reactivity. To address this challenge, chimeric recombinant T. cruzi antigens (IBMP-8.1, IBMP-8.2, IBMP-8.3, and IBMP-8.4) were synthesized to enhance specificity and reduce cross-reactivity in tests. While these antigens showed minimal cross-reactivity with leishmaniasis, their performance with other trypanosomatid infections was unclear. This study aimed to assess the diagnostic potential of these IBMP antigens for detecting CD in patients with Crithidia sp. LVH-60A, a parasite linked to visceral leishmaniasis-like symptoms in Brazil. This study involved seven Crithidia sp. LVH-60A patients and three Leishmania infantum patients. The results indicated that these IBMP antigens displayed 100% sensitivity, with specificity ranging from 87.5% to 100%, and accuracy values between 90% and 100%. No cross-reactivity was observed with Crithidia sp. LVH-60A, and only one L. infantum-positive sample showed limited cross-reactivity with IBMP-8.1. This study suggests that IBMP antigens offer promising diagnostic performance, with minimal cross-reactivity in regions where T. cruzi and other trypanosomatids are prevalent. However, further research with a larger number of Crithidia sp. LVH-60A-positive samples is needed to comprehensively evaluate antigen cross-reactivity.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Visceral symptoms in patients with anterior cutaneous nerve entrapment syndrome (ACNES): expression of viscerosomatic reflexes?

PurposeAnterior cutaneous nerve entrapment (ACNES) is characterized by neuropathic pain in a predictable, circumscript abdominal area. The diagnostic delay is long, with half of ACNES-affected individuals reporting nausea, bloating, or loss of appetite mimicking visceral disease. The aim of this study was to describe these phenomena and to determine whether treatment could successfully reverse the visceral symptoms.MethodsThis prospective observational study was conducted between July 2017 and December 2020 at SolviMáx, Center of Excellence for Chronic Abdominal Wall and Groin Pain, Máxima Medical Center, Eindhoven. Adult patients who fulfilled published criteria for ACNES and reported at least one visceral symptom at intake were eligible for the study. A self-developed Visceral Complaints ACNES Score (VICAS) questionnaire that scores several visceral symptoms (minimum 1 point, maximum 9 points) was completed before and after therapy. The success of treatment was defined as at least 50% reduction in pain.ResultsData from 100 selected patients (86 females) aged 39 ± 5 years were available for analysis. Frequently reported symptoms were abdominal bloating (78%), nausea (66%) and altered defecation (50%). Successful treatment significantly reduced the number of visceral symptoms, with a VICAS before of 3 (range 1–8) and after of 1 (range 0–6) (p < 0.001). A low baseline VICAS was associated with successful treatment outcome (OR 0.738, 95% CI 0.546–0.999).ConclusionPatients with ACNES may report a variety of visceral symptoms. Successful treatment substantially reduces these visceral symptoms in selected patients.

Sacral Tarlov cysts: Neurophysiology abnormalities and correlation with pelvic sensory and visceral symptoms.

Recent studies suggest a possible association between Tarlov cysts (TCs), usually considered as incidental radiological findings, and neurological symptoms such as pain, numbness and urogenital complaints. The aim was to explore the relationship between TCs and sacral nerve root functions using pelvic neurophysiology tests, and to correlate changes with clinical symptoms and magnetic resonance imaging (MRI) findings. Consecutive patients with sacral TCs, referred for pelvic neurophysiology testing and presenting with at least one symptom related to the pelvic area, participated in a cross-sectional review of symptoms using validated questionnaires. Findings of pelvic neurophysiology (pudendal sensory evoked potentials, sacral dermatomal sensory evoked potentials, external anal sphincter electromyography) and urodynamics testing were collected retrospectively. The relationship between neurophysiology, MRI findings and patients' symptoms was assessed using Fisher and ANOVA tests. Sixty-five females were included (mean age 51.2 ± 12.1 years). The commonest symptom was pain (92%). Urinary (91%), bowel (71%) and sexual (80%) symptoms were also frequently reported. Thirty-seven patients (57%) had abnormal neurophysiology findings reflecting sacral root dysfunction. No association was seen between MRI findings (size, location of the cysts, severity of compression) and neurophysiology. A negative association was observed between neurophysiology abnormalities and occurrence of urgency urinary incontinence (p = 0.03), detrusor overactivity (p < 0.01) and stress urinary incontinence (p = 0.04); however, there was no association with voiding difficulties. Contrary to current understanding, TCs are associated with injury to the sacral somatic innervation in the majority of patients with presumed symptomatic cysts. However, urinary incontinence is unlikely to be related to TC-induced nerve damage.

Acute Intermittent Porphyria's Symptoms and Management: A Narrative Review.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis in the liver that is caused by the accumulation of toxic heme metabolites aminolevulinic acid (ALA) and porphobilinogen (PBG) due to a deficiency in the enzyme hydroxymethylbilane synthase(HMBS). The prevalence of AIP is found to commonly affect females of reproductive age (ages 15-50) and people of Northern European descent. The clinical manifestations of AIP include acute and chronic symptoms that can be outlined into three phases: the prodromal phase, the visceral symptom phase, and the neurological phase. Major clinical symptoms involve severe abdominal pain, peripheral neuropathy, autonomic neuropathies, and psychiatric manifestations. Symptoms are often heterogeneous and vague, which can lead to life-threatening signs if not treated and managed appropriately. Whether treating AIP in its acute or chronic form, the cornerstone of treatment consists of the suppression of the production of ALA and PBG. The mainstay of managing acute attacks continues to comprise discontinuing porphyrogenic agents, adequate caloric support, heme treatment, and the treatment of symptoms. In recurrent attacks and chronic management, prevention is key with the consideration of liver transplantation and/or renal transplantation. In recent years, there has been great interest in emerging treatments that focus on a molecular level such as enzyme replacement therapy, ALAS1 gene inhibition, and even liver gene therapy (GT), which has changed the way of traditionally managing this disease and will pave the way for innovative therapies to come.

Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results.

Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.

PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases

Mutations in GBA1, encoding glucocerebrosidase (GCase), cause Gaucher disease (GD) and are also genetic risks in developing Parkinson's disease (PD). Currently, the approved therapies are only effective for directly treating visceral symptoms, but not for primary neuronopathic involvement in GD (nGD). Progranulin (PGRN), encoded by GRN, is a novel modifier of GCase, but the impact of PGRN in GBA1 mutation-associated pathologies invivo remains unknown. Herein, Grn-/- mice crossed into Gba9v/9v mice, a Gba1 mutant line homozygous for the Gba1 D409V mutation, generating Grn-/-Gba9v/9v (PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to Grn-/- and Gba9v/9v mice. Moreover, PG9V mice also displayed PD-like phenotype. Mechanistic analysis revealed that PGRN deficiency caused severe neuroinflammation with microgliosis and astrogliosis, along with impaired autophagy associated with the Gba1 mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts exvivo. Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in Gba9v/null and PG9V mice. Collectively, this study not only provides the first line of invivo but also exvivo evidence demonstrating the crucial role of PGRN in GBA1/Gba1 mutation-related pathologies, as well as a clinically relevant mouse model for mechanistic and potential therapeutics studies for nGD and PD. Importantly, a BBB penetrant PGRN-derived biologic was developed that may provide treatment for rare lysosomal storage diseases and common neurodegenerative disorders, particularly nGD and PD.

Хвороба Німана-Піка тип С: симптоми, діагностика, лікування

Among all inborn errors of metabolism lysosomal storage diseases occupy an important place, because they have a diverse clinical symptoms, manifest at different ages and are disguised as different diseases, which makes the diagnosis of these diseases quite difficult and long-term. Niemann-Pick disease, a rare inherited neurodegenerative disease caused by a disruption of intracellular lipid metabolism, is one such disease. The clinical manifestations of this disease are quite nonspecific, including neurological, visceral, or psychiatric symptoms, and can appear both in childhood and adulthood, which complicates diagnosis. Although this disease belongs to orphan diseases, doctors of many specialties may encounter such a patient - general practitioners, pediatrician, neonatologist, neurologist, gastroenterologist, hepatologist, hematologist and psychiatrist. Due to the specifics of the clinic, insufficient awareness of this disease, referral to a medical geneticist is late and patients remain unrecognized for years. The purpose - to provide up-to-date data on Niemann-Pick type C disease, clinical manifestations, diagnostic difficulties, and information on disease treatment options to increase awareness and awareness of the disease among physicians of various specialties. The article discusses the features of clinical manifestations, basic information about the possibilities of laboratory diagnostics, tools for early detection of the disease and achievements in the treatment of the disease. Management of patients with Niemann-Pick disease is complex, requires a multidisciplinary approach, and can only slow the progression of the disease. That is why early diagnosis of the disease is critically important, because specific treatment started as early as possible gives a chance to slow down the development of complications. Spreading knowledge about this disease will shorten the path to diagnosis and improve the provision of medical care to patients. No conflict of interests was declared by the authors.

Acute Intermittent Porphyria – A Rare Case with Neurovisceral Symptoms

Acute intermittent porphyria (AIP) is an autosomal dominant disorder resulting from partial deficiency of the porphobilinogen deaminase affecting the production of heme. It produces acute neurovisceral symptoms. The diagnosis of AIP is difficult. Symptoms are often nonspecific.As the penetrance is low in AIP, positive family history of disease may be absent. So high index of suspicion is required to diagnose AIP. Combination of neurologic and visceral symptoms gives clue to the diagnosis. In December 2018, we have diagnosed a case of Acute intermittent porphyria who presented with acute abdomen, hypertension, tachycardia and convulsion. His urine colour turned to purple red on exposure to sunlight. He had hyponatremia. MRI of brain revealed features of Posterior Reversible Encephalopathy Syndrome (PRES) and EEG was suggestive of focalseizure. Urine porphoblinigen was positive. He was treated with IV glucose, DNS, high carbohydrate diet, newer antiepileptic drug, opioid analgesic, antihypertensive medication and other supportive and symptomatic measures. Ultimately his condition improved gradually and discharged with advice to continue medicine and periodic follow up. JAFMC Bangladesh. Vol 18, No 1 (June) 2022: 94-96

Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome.

Symptoms of irritable bowel syndrome (IBS) have been associated to altered colonic motility and sensation. Smoking affects pain perception and is a risk factor in the development of post-infectious IBS, but its effect on abdominal pain and colonic transit remains to be elucidated in IBS. Forty patients with IBS-C and 28 with IBS-M were selected based on Rome IV criteria. Colonic transit time was studied and smoking habit was recorded. Presence of mild or severe abdominal pain and the prevalent pain characteristics (diffuse or localized, chronic or acute, with cramps or gradually distending) were recorded. Data were analyzed by univariate and stepwise multiple logistic regression analysis to verify the risk association between pain and all other variables. IBS-C patients had a longer transit time in the right colon and scored more chronic pain than IBS-M patients. When severity of abdominal pain was used as discriminating factor, a significant number of subjects reporting severe pain were males and smokers (16/30 vs. 4/38 and 20/30 vs. 4/38, both ƿ<0.001). Multivariate analysis confirmed that smoking was an independent factor associated with severe abdominal pain (OR 14.3, CI 2-99, p=0.007). Smoking was not associated with colonic transit times and colonic transit was not associated with IBS symptoms' severity (both ƿ=N.S.). Smoking was the only factor independently associated with severe abdominal pain. As smoking does not seem to affect colonic transit time, we suggest that smoking may influence visceral perception and symptoms severity in IBS patients.

CRISPR-Cas9-Mediated NPC1 Gene Deletion Enhances HEK 293T Cell Adhesion by Regulating E-Cadherin.

NPC1 gene encodes a transmembrane glycoprotein on the late endosome/lysosomal membrane. Its mutation leads to a rare and aggravated autosomal recessive neurovisceral condition, termed Niemann-Pick disease type C1 (NPC1), which is characterized by progressive neurodegeneration, visceral symptoms, and premature death. To investigate the influence of NPC1 gene deletion on cell morphology, adhesion, proliferation, and apoptosis, CRISPR-Cas9 technology was used to knockout the NPC1 gene in HEK 293T cells. Sanger sequencing, western blotting, and immunofluorescence were used to confirm successful NPC1 ablation. Filipin staining results indicated that deletion of NPC1 gene led to accumulation of unesterified cholesterol in HEK 293T cells. Phalloidin staining results revealed cell aggregation, synapse shortening, nuclear enlargement, and cytoskeleton filamentous actin thinning in HEK 293T cells with NPC1 gene mutation. Furthermore, NPC1 gene mutated HEK 293T cell showed enhanced cell adhesion, inhibited cell proliferation, and increased cell apoptosis. In addition, NPC1 gene mutations significantly increased the protein expression levels of E-cadherin and γ-catenin and significantly decreased the protein expression levels of Wnt 3a, c-Myc, and cyclin D1. These results suggest that NPC1 may regulate cell adhesion by affecting the cadherin-catenin complex through E-cadherin, and that the classical Wnt signaling pathway may be inhibited by restricting β-catenin from entering the nucleus to inhibit cell proliferation.