A novel stoploss mutation CYB5R3 c.906A>G(p.*302Trpext*42) involved in the pathogenesis of hereditary methemoglobinemia.

Recessive congenital methemoglobinemia (RCM) is a hereditary autosomal disorder with an extremely low incidence rate. Here, we report a case of methemoglobinemia type I in a patient with congenital persistent cyanosis. The condition was attributed to a novel compound heterozygous mutation in CYB5R3, characterized by elevated methemoglobin levels (13.4 % of total hemoglobin) and undetectable NADH cytochrome b5 reductase (CYB5R3) activity. Whole-exome sequencing (WES) revealed two heterozygous mutations in CYB5R3: a previously reported pathogenic missense mutation c.611G>A(p.Cys204Tyr) inherited from the father, and a novel stop codon mutation c.906A>G(p.*302Trpext*42) from the mother, the latter mutation assessed as likely pathogenic according to ACMG guidelines. In cells overexpressing the CYB5R3 c.906A>G mutant construct, the CYB5R3 mRNA level was significantly lower than in cells overexpressing the wild-type (WT) CYB5R3 construct. However, there was no significant difference in protein expression levels between the mutant and WT constructs. Notably, an additional protein band of approximately 55 kDa was detected in the mutant cells. Immunofluorescence localization showed that, compared to wild-type CYB5R3, the subcellular localization of the CYB5R3 p.*302Trpext*42 mutant protein did not show significant changes and remained distributed in the endoplasmic reticulum and mitochondria. However, the c.906A>G(p.*302Trpext*42) mutation resulted in increased intracellular reactive oxygen species (ROS) levels and decreased NAD+/NADH ratio, suggesting impaired CYB5R3 function and implicating this novel mutation as likely pathogenic.

Selenium deficiency exacerbates ROS/ER stress mediated pyroptosis and ferroptosis induced by bisphenol A in chickens thymus.

Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.

Iodine Deficiency as a Risk Factor for Postpartum Depressive Disorder in Women.

Nutritional support is considered as one of the components of disease-modifying therapy for postpartum depressive disorder. Such nutrients include iodine, which is an important trace element in the development and functioning of the central nervous system. The brief review presents updated knowledge about the relationship of iodine deficiency with the development and severity of postpartum depressive disorders in women, based on the analysis and generalization of the results of domestic and international studies.

Rare primary vasculitis: update on multiple complex diseases and the new kids on the block.

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

Late-onset renal TMA and tubular injury in cobalamin C disease: a report of three cases and literature review.

BACKGROUND: Mutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists. CASE PRESENTATION: Here we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered. CONCLUSIONS: The clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease. CLINICAL TRIAL NUMBER: Not applicable.

Anterior pituitary hormone dysfunction among individuals with complete heart block requiring pacemaker.

Background & objectives Neuronal hypoxia associated with conditions like traumatic brain injury and cardiac tachyarrhythmia has been implicated in causing hypopituitarism. Individuals with complete heart block (CHB) may be predisposed to develop anterior pituitary hormone dysfunction in the long term. The objective of this study was to investigate anterior pituitary hormone functions in individuals after CHB. Methods This prospective cohort study included 30 individuals (21 men and 9 women) with CHB requiring pacemaker implantation, who were evaluated at admission and then at a mean follow up of 12.4 ± 2.2 months to look for development of any degree of hypopituitarism. In addition to the measurement of hormones like follicle-stimulating hormone (FSH), luteinising hormone (LH), thyroid stimulating hormone (TSH), total tetra iodothyronines (TT4), free tetraiodothyronines (FT4), cortisol, insulin-like growth factor-1 (IGF-1), testosterone and estradiol, a fixed-dose glucagon stimulation test (GST) was performed to assess growth hormone (GH) and adrenocorticotrophic hormone (ACTH) axis. Results The mean age of the participants was 64.9 ± 11.3 yr. At follow up evaluation, 17 (56.7%) had low serum IGF-1, and among them, seven (23%) had growth hormone deficiency (GHD) (peak GH <1.0 ng/ml after GST). Six participants (20%) had ACTH deficiency (peak cortisol <9 ug/dl after GST) and one had TSH deficiency. None had prolactin (PRL) or gonadotropin deficiency. Overall, hormone deficiencies were observed in nine patients (30%). Interpretation & conclusions This pilot study detected loss of anterior pituitary hormones in a significant number of individuals of CHB at 12 months follow up. Unrecognised hypopituitarism may have resulted in significant morbidity and mortality in these individuals.

Comprehensive model for simultaneous monitoring of primary tumor to metastatic cancer utilizing Prkdc and Il2rg double knockout mice.

Liver cancer is the second leading cause of cancer-related deaths worldwide, motivating major scientific efforts to understand and treat this cancer type. Over 30% of patients with liver cancer progress to metastasis, which reduces the survival rate. Extensive studies on primary tumors have been conducted to improve the prognosis. However, there is a lack of appropriate and accessible models for studying the progression and metastasis of liver cancer. Moreover, conventional metastasis models do not reproduce metastasis as it occurs in patients. To address this lack of an appropriate model for the monitoring of cancer progression and evaluation of anticancer drugs, we established a spontaneous metastatic xenograft model using NSG mice subcutaneously transplanted with SK-Hep-1 cells. Compared to the conventional experimental metastasis model (intravenous transplantation), in which only lung metastasis was observed, the established spontaneous metastatic xenograft model was superior, as it showed both a primary tumor and metastatic patterns similar to those observed in human patients. Additionally, this model was successfully used to assess the antimetastatic efficacy of sorafenib. In conclusion, our results demonstrate that the established spontaneous metastatic xenograft model better reflects liver cancer metastasis and can be utilized to assess the efficacy of anticancer drugs for liver cancer.

Keratin 20 positive SDH-deficient renal cell carcinoma: a case report and literature review.

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up.

The relationship between remnant cholesterol and the risk of testosterone deficiency in US adults: a cross-sectional study based on the NHANES database.

Background: Testosterone deficiency (TD) is an urgent health issue that requires attention, associated with various adverse health outcomes including cardiovascular diseases (CVD) and metabolic syndrome. Remnant cholesterol (RC) has emerged as a potential biomarker for cardiovascular risk, but its relationship with testosterone levels and TD has not been thoroughly investigated. This study aims to explore the association between RC and TD in adult American males using data from the National Health and Nutrition Examination Survey (NHANES). Methods: This cross-sectional study utilized data from three NHANES cycles (2011-2016), including 2,848 adult male participants. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL). TD was defined as total testosterone levels below 300 ng/dL. Multivariable linear and logistic regression analyses, as well as smooth curve fitting and generalized additive models, were performed to assess the associations between RC and total testosterone levels and TD, adjusting for potential confounders. Subgroup analyses were conducted based on age, BMI, smoking status, diabetes, hypertension, CVD, and chronic kidney disease (CKD). Results: Higher RC levels were significantly associated with lower total testosterone levels (ß = -53.87, 95% CI: -77.69 to -30.06, p<0.001) and an increased risk of TD (OR = 1.85, 95% CI: 1.29 to 2.66, p=0.002) in fully adjusted models. When RC was analyzed as quartiles, participants in the highest quartile (Q4) had significantly lower total testosterone levels (ß = -62.19, 95% CI: -93.62 to -30.76, p<0.001) and higher odds of TD (OR = 2.15, 95% CI: 1.21 to 3.84, p=0.01) compared to those in the lowest quartile (Q1). Subgroup analyses revealed consistent associations across different age groups, particularly strong in participants over 60 years, and in never smokers. The associations remained significant in both hypertensive and non-hypertensive groups, as well as in those with and without CKD. No significant interactions were found across subgroups. Conclusion: This study demonstrates a significant inverse association between RC levels and total testosterone levels, along with a positive association with the risk of TD. These findings suggest that RC could serve as a valuable biomarker for early identification of individuals at risk for TD. Future longitudinal studies are needed to confirm these findings and explore the underlying mechanisms.

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms.

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis.

Arginine vasopressin deficiency (central diabetes insipidus) with partial empty sella: a case report.

BACKGROUND: Arginine vasopressin deficiency (central diabetes insipidus) is defined as a reduction in the release of arginine vasopressin (AVP) resulting in a variable degree of polyuria. Partial empty sella refers to an enlarged sella turcica that is not completely filled by pituitary gland. It can be either primary or secondary and its manifestation ranges from asymptomatic cases to isolated posterior pituitary, isolated anterior pituitary or both anterior and posterior pituitary dysfunctions. Diabetes insipidus caused by a partially empty sella is rare. CASE PRESENTATION: The patient, an 18-year-old Ethiopian woman who presented with long standing headache, increased urination, increased thirst, absence of menses and weight loss. Urine and serum osmolality was done and suggested diabetes insipidus. On further workup, brain magnetic resonant imaging was done and partially empty sella was diagnosed. CONCLUSION: Diabetes insipidus secondary to partially empty sella is uncommon. In patients presenting with headache and anterior or posterior pituitary dysfunction, empty sella should be considered, whether partial or complete.

Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis.

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis. Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR).

Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Prevalence of hypogonadism in men with and without chronic obstructive pulmonary disease: A cross-sectional study.

BACKGROUND: Hypogonadism is a common finding of chronic obstructive pulmonary disease (COPD). However, the prevalence of hypogonadism in COPD varies among studies. The aim of this study was to determine and compare the prevalence of hypogonadism in men with and without COPD. METHODS: We conducted a cross-sectional study with 134 patients with stable COPD and 70 age-matched men with non-COPD. Hypogonadism was defined by the presence of symptoms according to the Androgen Deficiency in Aging Males questionnaire, along with total testosterone deficiency (<300ng/dL). RESULTS: Patients had a mean age of 68 years (SD, 6), a body mass index of 28kg/m2 (SD, 6), and 17% were current smokers. The prevalence of hypogonadism was 41.8% in COPD men (N=56, 95%CI, 33-51) and 10.0% in non-COPD men (N=7, 95%CI, 4-20), with a prevalence ratio of 4.2 (95%CI, 2.0-8.7, p<0.001). The prevalence of low total testosterone concentrations (<300ng/dL) were significantly higher in COPD patients vs the control group (47.0% vs 15.7%, p=<0.001). In the COPD group, 89.3% of patients had hypogonadotropic hypogonadism and 10.7%, hypergonadotropic hypogonadism. The prevalence of hypogonadism was higher in severe vs non-severe COPD patients (55.8% vs 35.2%; p=0.024). CONCLUSIONS: The prevalence of hypogonadism was high and greater in COPD vs non-COPD men. This study suggests that COPD patients should be screened for hypogonadism.

[Full-cycle, multidisciplinary and systematic management of citrin deficiency].

Professor Takeyori Saheki's team at Kagoshima University, Japan, published a paper in Nature Genetics in June 1999, pinpointing the pathogenic gene for adult-onset type Ⅱ citrullinemia as SLC25A13 and naming the protein product encoded by this gene as citrin. Over the past 25 years, the researches have made positive progress on the pathophysiological mechanism, clinical phenotype, molecular diagnosis, treatment, and prognosis of citrin deficiency (CD) as an autosomal recessive genetic disease. Currently, three age-dependent clinical phenotypes of CD have been found, namely neonatal intrahepatic cholestasis caused by citrin deficiency, failure to thrive and dyslipidemia caused by citrin deficiency, and adult-onset type Ⅱ citrullinemia. Although relevant internal medicine drugs are being researched and developed while liver transplantation has been used for the treatment of CD patients, scientific dietary therapy remains the foundation, core, and key for the management of this disease. Furthermore, CD management involves the full life cycle of patients, requiring the joint efforts of basic and clinical medicine as well as systematic articulation at multi-levels, such as the parents, family, and society. By full-cycle, multidisciplinary, and systematic management, it is an achievable goal for CD patients to learn, work, and live in a healthy manner.

Impact of 5-Lipoxygenase Deficiency on Dopamine-Mediated Behavioral Responses.

The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses.

Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3-deficient autism model.

Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.