Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 12, 2021

Recent reports of the relationship between nickel, allergy and autoimmunity have been described. However, there remains a lack of information on the concordance between nickel sensitization and potency. Of note, an article by Drenovska et al. recommended a call for increased epidemiologic studies to define the prevalence of autoimmune syndromes induced by adjuvants such as nickel-containing metal implants. Accumulating reports of dermatologic manifestations following medical device implantation highlights the need for consideration regarding the potential sequelae following metal implantation. Considering the medical and the functional necessity of certain device materials, the authors agree calling for further epidemiological studies are needed to prevent metal-related autoimmunity, and additionally discover novel testing strategies.

Presently the world is witnessing the most devastating pandemic in the history of mankind caused by Severe Acute Respiratory Syndrome or SARS-CoV-2. This dreaded pandemic is responsible for escalated mortality rates across the globe and this is the worst catastrophe in the history of mankind. Since its outbreak, substantial scientific explorations focusing on the formulation of novel therapeutical and/or adjunct intervention against the disease are continuously in the pipeline. However, till date, no effective therapy has been approved and hence the present alarming situation urges the necessity of exploring novel, safe and efficient interventional strategies. Functionally, terpenoids are a class of secondary plant metabolites having multi facet chemical structures and are categorically documented to be the largest reservoir of bioactive constituents, predominant in nature. Intriguingly, very little is scientifically explored or reviewed in regards to the anti-CoV-2 attributes of terpenoids. The present article thus aims to revisit the antiviral efficacy of terpenoids by reviewing the current scientific literature and thereby provide an opinion on the plausibility of exploring them as potential therapeutical intervention to deal with ongoing CoV-2 pandemic.

Targeting inhibitory receptors on T cells in the tumor sites can promote effective anti-tumor immunity in bladder cancer. Unfortunately, the main dilemma is that a large number of patients remain refractory to CTLA-4, PD-1, and PD-L1 blockade therapies. T-cell immunoglobulin and mucin domain 3 (Tim-3) is an inhibitory receptor expressed on T cells and innate immune cells. Both in vivo and in vitro data from patients with advanced cancers support the role of Tim-3 inhibition in satisfactory anti-tumor immunity. In bladder cancer, the expression level of Tim-3 significantly increases with advanced pathological grade and T stage. Therefore, rationality implies that designing novel monoclonal antibodies reactive with Tim-3 alone or in combination with other checkpoint inhibitors may indicate a favorable response in bladder cancer. Here, we aimed to investigate the possibility of targeting Tim-3 as a novel anti-cancer treatment for bladder cancer.

Background: The improvement of beta thalassaemia treatments has led to an increase in life expectancy. This implies the emergence of new comorbidities. Amongst others, endocrine glands are extremely sensitive to iron overload. Objective: We aimed to understand the impact of the endocrine conditions on the patient’s quality of life (QOL). Results: Hypogonadism may present with lack or delay of pubertal development, sexual dysfunctions and impaired fertility, which impact QOL in both sexes. Early recognition and treatment, as well as choosing the most appropriate therapy, according to patient’s needs (fertility, pubertal development, psychological concerns, comorbidities), are advisable. Osteoporosis affects QOL irrespective of symptoms. Growth hormone deficiency may occur both in childhood and in adulthood, and it affects different aspects of QOL. In adults, it could be difficult to examine if the symptoms are due to GHD, and a trial of GH replacement could be useful to identify benefits and needs. Glucose metabolism impairment is common in thalassaemic patients and early recognition is mandatory because long-term complications can have a detrimental impact on QOL (as blindness or dialysis). Although the incidence of adrenal insufficiency seems to be rare in thalassaemic patients, when it occurs, it has a severe impact on QOL. Conclusion: Limited data is available on QOL in thalassaemic patients, and is even less related to endocrinopathies. We can speculate that endocrinopathies have an impact on everyday life. More studies are needed to allow our patients to achieve not just a longer life but also a better quality of life.

Cancer, a set of diseases characterized by abnormal cell growth resulting from alteration in the expression pattern of diverse genes, is one of the prominent causes of mortality and morbidity worldwide. This modification of various genes leads to altered signalling cascades and changes in the molecular network. These changes eventually give rise to cellular dysfunction and then to systemic failure causing death. Of the several pathways that are aberrantly activated in cancer, Notch signalling pathway is a prominent one. Notch signalling pathway is a juxtracrine signalling pathway which activates the genes associated with cell proliferation, survival and angiogenesis. Notch signalling pathway components are seen to be upregulated in several types of cancer. Oral squamous cell carcinoma (OSCC) is a predominant category of oral cancer where aberrant activation of Notch signalling causes tumour progression and metastasis. In this review, we discuss the Notch signalling pathway, its components, forms and its role in the progression and metastasis of oral squamous cell carcinoma.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging group of therapeutic agents that show their tremendous glucose lowering activity without producing hypoglycemia, which is one of the major drawbacks of existing antidiabetic therapy. Comprehensive literature was searched in English using electronic databases including PubMed, ScienceDirect, Medline, Scopus and Embase. SGLT2 inhibitors reduce blood glucose levels by producing glucosuria via insulin-independent pathway. The major mechanism by which SGLT2 inhibitors are involved in glucose homeostasis is to prevent the reabsorption of glucose in the proximal convoluted tubule and increase glucose excretion in the urine. Deterioration of β-cells, impairment of functions and development of insulin resistance do not affect the efficacy of SGLT2 inhibitors. SGLT2 inhibitors significantly reduce HbA1c, ameliorate glycemic control and control body weight. SGLT2 inhibitors can block Na+/H+ exchanger (NHE) 1 and play a significant role in treatment of heart failure especially in diabetic patients. They have also positive effects on different metabolic syndromes which cumulatively ameliorate the risk factors for cardiovascular diseases in diabetic patients. SGLT2 inhibitors can improve kidney function by reducing inflammation and improving renal microvasculature up to its original state. The increase in triglyceride level has a strong relationship with coronary artery disease in diabetic patients when combined with other indicators of metabolic disorders while SGLT2 inhibitors cause a significant reduction in plasma triglyceride level in diabetic patients. We have comprehensively summarized the features, mechanism of action of SGLT2 inhibitors and their impact on various metabolic syndrome traits, including diabetic condition, renal dysfunctioning, arterial stiffness, hypertension, lipid profile and cardiovascular diseases. The aim of this review to examine the safety, efficacy and therapeutic properties of SGLT2 inhibitors in renal and diabetic patients.

Background: Based on a common belief among people, narcotic substances and psychoactive drugs may help to reduce blood glucose and lipid profile leading to reduced risk of cardiovascular diseases. This hypothesis has been verified in several studies; however, there is no conclusive agreement on the reducing effects of opium and other opioid derivatives on blood glucose and lipids. In the present review, we collected all related literature to evaluate the effects of opioids and psychoactive drugs abuse in altering blood glucose and lipid profile, and discuss their longterm effects. Methods: A systematic literature search was performed in January 2021 using “lipid profile”, “glucose”, and “opium” including all their equivalents, main derivatives and similar terms. The data were then extracted and reported qualitatively. Results: Overall, 46 articles with 37407 participants were included after several step–by-step procedures of article selection. Findings of this study suggested that opioids may reduce blood glucose and low-density lipoproteins, while increasing triglyceride. However, these effects are temporary, and long-term substance abuse exacerbates glucose and lipid-associated diseases such as diabetes and atherosclerosis. Conclusion: Although there are many confounding factors that may affect the results of the included literature; however, based on the findings of these studies, the long-term beneficial effects of opioids on lipid profile and blood glucose cannot be accepted.

Background: In Covid-19 infection, leukopenia, inflammation, and elevated liver enzymes are found in most patients. Also, vitamin D deficiency attenuates the immune system and predisposes a person to being more susceptible to infection. In this context, we aimed to evaluate vitamin D, electrolytes, complete blood count, liver enzymes, urea, creatinine, albumin, CRP and ESR levels in patients with Covid-19. Methods: We conducted a cross-sectional study on 118 patients with Covid-19 who were hospitalized from 2020/2/19 to 2020/4/3 in ICU. Serum levels of electrolytes, liver enzymes, blood factors, urea, creatinine, CRP and ESR, as well as anthropometric parameters and serum vitamin D concentration, were measured. Results: A total of 118 patients (80 male and 38 female) were enrolled in the study (65.05±15.75 years). Only 5.08% of patients had no risk factors and 55.9% had ≥ 2 risk factors. Diabetes (44.1%) and obesity (23.7%) were more common among patients. Laboratory findings showed that 80.50% of patients had hyponatremia, but other electrolytes including K, Mg, Ca and P were normal in the majority of participants as well as CBC, Cr, Urea, Alb, ALT and ALKP. The AST concentration increased in most patients (66.94%). All patients had high levels of inflammatory factors such as CRP and ESR. The mean of 25-hydroxy-vitamin D levels in participants (25.95 ± 14.56 ng/mL) was lower than its levels in the general population. However, it was not statistically significant (P= 0.88). A significant negative correlation was found between vitamin D and ALT (P= 0.02, -0.21) as well as vitamin D and CRP (P= 0.05, -0.17). Conclusion: Due to the regulatory role of vitamin D in the immune system and low levels of vitamin D in Covid-19 infected patients, the evaluation of vitamin D levels and prescribed supplements, if necessary, is suggested.

Aims: The present study was performed in order to find out the anti-depression effect of Erxian Decoction in perimenopausal mice. Background: Erxian Decoction (EXD) has been used in folk medicine for the treatment of perimenopausal syndrome, but it has not been researched on perimenopausal depression. Objective: The present study aimed to evaluate the effect of extraction of Erxian Decoction on perimenopausal depressive mice. Methods: In this study, female ICR mice were randomly divided into 6 groups: Low, medium and high dose of EXD groups (0.5, 1.5, and 4.5 g/kg), soy isoflavones group (250 mg/kg) and Sham group. The mice in the Sham group received sham surgery (within ovaries), and the others were excised with bilateral ovaries and exerted by 28-day chronic mild unpredictable stimulation for the establishment of a perimenopausal depression model. Results: Behavioral tests showed that EXD could relieve depression symptoms and improve spatial memory in mice. Western blotting showed that EXD significantly up-regulated the expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 in hippocampus and estrogen receptors (ERs) in the uterus and adrenals, protecting hippocampal tissue and antagonizing the symptoms of estrogen deficiency in mice, which was further proved within a uterine morphology test. In addition, EXD reduced the serum levels of follicle-stimulating hormone, luteinizing hormone, and interleukin- 6. Conclusion: These results indicated that EXD can regulate hormone secretion and recover hippocampal damage in perimenopausal depressed mice. Besides, it can antagonize the symptoms of ovarian hormone deficiency as well as relieve perimenopausal syndrome.

Aims: To investigate the influence of body mass index (BMI) on the association between psychological stress and physical fitness. Background: Both obesity and psychological stress reduce exercise performance. Objective: It is unknown whether obesity may modify the relationship. Methods: A population of 4,080 military subjects in Taiwan was divided to three groups according to the BMI ≥27.0 kg/m2 (obesity), 24.0-26.9 kg/m2 (overweight) and 18.5-23.9 kg/m2 (normal weight). Normal, slight, and great psychological stress was evaluated by the Brief Symptoms Rating Scale (BSRS-5) score ≤5, 6-9, and ≥10, respectively. Aerobic and anaerobic fitness were respectively evaluated by time for a 3000-meter run and numbers of 2-minute sit-ups and 2-minute push-ups. Analysis of covariance (ANCOVA) with adjustments for age and sex was used to determine the relationship. Results: The mean time (sec) for a 3000-meter run (standard error) under slight and great stress differed from that under normal stress in the normal weight (881.0 (11.0) and 877.9 (5.8) vs. 862.2 (1.7), p=0.089 and 0.0088, respectively) and in the obesity (928.1 (16.8) and 921.8 (10.7) vs. 895.2 (1.6), p=0.054 and 0.016, respectively), while the differences were not significant in the overweight (877.1 (12.7) and 877.5 (7.1) vs. 867.1 (2.1), both p >0.5). The impacts of the BMI on 2-minute sit-ups had a similar pattern with that on a 3000-meter run whereas the impact of the BMI on 2-minute push-ups was insignificant. Conclusions: Mental stress may not affect physical fitness in overweight military personnel. The mechanism is not clear and should be further investigated.

Background and Objective: Decreased nitric oxide (NO) bioavailability contributes to the pathophysiology of type 2 diabetes mellitus (T2DM). This study aims to determine the effects of nitrate (NO3 –) on gene and protein expression of NO synthase (NOS) enzymes in the liver, soleus muscle (SM), and epididymal adipose tissue (eAT) of rats with T2DM. Methods: Twenty-eight male rats were divided into 4 groups: Control, diabetes, control+NO3 –, and diabetes+NO3 – (n = 7/each group). NO3 – was administered for 6 months, and mRNA and protein levels of NOS enzymes were measured at the end of the study. Results: mRNA and protein levels of inducible NOS (iNOS) were higher in the liver (475% and 73%), SM (271% and 43%), and eAT (543% and 24%) of rats with T2DM. In the case of the endothelial NOS (eNOS), diabetic rats had lower mRNA and protein levels in the liver (26% and 24%) and SM (60% and 62%) and lower mRNA level (30%) in eAT. mRNA and protein levels of neural NOS (nNOS) were lower in SM (69% and 73%) and eAT (25% and 31%) of rats with T2DM. NO3 – administration restored disrupted iNOS and eNOS expressions to their near normal values in all the studied tissues; NO3 – also increased nNOS mRNA and protein levels in SM and eAT but decreased nNOS protein level in the liver. Conclusion: Long-term NO3 – administration restored disrupted expression of NOS enzymes in the liver, SM, and eAT of rats with T2DM; these findings partly explain the beneficial metabolic effects of nitrate in T2DM.

Background: Thyrotoxic Hypokalemic Periodic Paralysis (THPP) is a rare neuromuscular disease characterized by recurrent episodes of skeletal muscle weakness associated with hypokalemia. Alterations in protein-encoding genes that are part of ion channels seem to be related to the development of this disease. However, the pathogenic potential of some variants in these genomic regions is not yet fully understood. The aim of this study was to screen genetic alterations in regions coding for calcium (cav1.1), sodium (nav1.4), and potassium (Kir2.6) channels, evaluating its impact on the phenotype of patients with THPP. Methods: Four patients with a diagnosis of THPP followed by the Endocrinology Service of the University Hospital of the Federal University of Maranhão (Brazil) were investigated for the presence of molecular abnormalities in CACNA1S, SCN4A, and KCNJ18 genes. Results: The KCNJ18 analysis revealed at least one polymorphic variant in each patient. Considering the haplotypic classification of R39Q, R40H, A56E, and I249V variants, two cases were named Kir2.6_RRAI and the other two patients were named Kir2.6_QHEV. No patient had point mutations in the regions evaluated for CACNA1S and SCN4A genes. Conclusion: The identification of the Kir2.6_RRAI and Kir2.6_QHEV haplotypes reinforces the existence of two main haplotypes involving these four loci of the KCNJ18gene. On the other hand, point mutations in CACNA1S, SCN4A, and KCNJ18 genes do not seem to be the main mechanism of pathogenesis of THPP, indicating that many questions about this topic still remain unclear. So, the diagnosis of this rare disorder should still be based on clinical and biochemical aspects presented by the patient.

Background: Some endocrinologists were involved in the management of patients with suspected or confirmed COVID-19 during the first wave of the pandemic. This study aims to analyze burnout levels among the Association of Medical Endocrinologists (AME) members before and during the pandemic. Methods: We recruited two AME members samples at two different times: before COVID-19 (n = 811) and during the first wave of the ongoing pandemic (n = 579). Both the samples filled the Maslach Burnout Inventory. We performed MANOVAs to evaluate demographic and COVID-19 related differences in burnout levels and Pearson’s Chi-square test to compare burnout severity before and during the pandemic. Results: Women reported higher Emotional Exhaustion and reduced Professional Accomplishment than men. The oldest physicians had lower levels of Emotional Exhaustion and Depersonalization and higher Professional Accomplishment than younger workers. Independent contractors displayed lower levels of burnout compared to established contractors. Finally, the pandemic, per se, did not lead to changes in burnout levels. Discussion: Women and young physicians are at higher risk of burnout. It is also possible that front- line professionals are at higher risk during a health care crisis. Moreover, it is likely that the length of exposure to the pandemic has not been sufficient to impact burnout levels. Conclusion: Short-term exposure to pandemic-related activities seemed to have a low impact on burnout severity, except for physicians directly involved in managing COVID-19 cases. It is strongly recommended the availability of psychological support in public hospitals.

Background: Neonatal respiratory distress syndrome (RDS) is a common dangerous chest problem that is caused by a lack of surfactant. Aim: The aim of this study was to show the role of zinc as an adjuvant anti-inflammatory therapy in neonatal RDS. Objective: To study the effect of zinc supplementation in cases of neonatal RDS. Methods: A prospective randomized controlled trial (RCT) study was done on 90 neonates suffering from respiratory distress (RD) who had been diagnosed as RDS. The included neonates were classified into two groups: group 1, which received Zinc (Zn) supplementation, and group 2, which received a placebo. Down score, grades of RDS Malondialdehyde (MDA), Superoxide Dismutase (SOD) andInterleukin-8 (IL-8) were estimated on the 1st and 5th day in the presence of incubators. Results: There were statistically significant differences (SSD) in grades of RDS, Down score, MDA, SOD and IL-8 on the 5th day between group 1 and 2(p = 0.001), and between 1st and 5th day in group 1 (p = 0.001) in the presence of an incubator. There was an SSD between groups 1 and 2 in the duration of hospitalization (p = 0.001) and the number of cases that needed mechanical ventilation (MV) (p = 0.049). Conclusion: Zn supplementation is associated with clinical and laboratory improvement in cases of neonatal RDS. Recommendation: Zn supplementation for RDS neonates.

Background: The incidence and mortality of hyperlipidemia are increasing year by year, showing a younger trend. At present, the treatment of hyperlipidemia is mainly dependent on western medicine, but its side effects on liver and kidney function are common in clinics. Therefore, it is necessary to study the treatment of hyperlipidemia by augmenting effective dietary nutrition supplements. Vitamin B6 (VitB6), as an essential cofactor for enzymes, participates in lipid metabolism. The effects of VitB6 on hyperlipidemia, however, have not been reported until now. Aim: The present study was to investigate the influence of VitB6 on hepatic lipid metabolism in hyperlipidaemia rats induced by a High-Fat Diet (HFD). Methods: Male Sprague-Dawley rats were kept on HFD for two weeks to establish the hyperlipidemia model. The rats in low-dosage and high-dosage groups were received 2.00 and 3.00 mg/kg/- day of VitB6 for eight weeks, respectively. Results: The results showed that both doses of VitB6 reduced HFD-induced hepatic Low-Density Lipoprotein Cholesterol (LDL-C); decreased blood cholesterol (TC), triglycerides, LDL-C, atherogenic index (AI), Atherogenic Index of Plasma (AIP), apolipoprotein B (ApoB) and ApoB/apolipoprotein A-1(ApoA1) ratio; increased liver High-Density Lipoprotein Cholesterol (HDL-C) and serum ApoA1; reduced hepatic steatosis and triglyceride accumulation, lowered fat storage, and recovered heart/body and brain/body ratio to a normal level. In addition, VitB6 supplementation markedly decreased HMGR level, increased the mRNA abundance of LDLR and CYP7A1, and protein expression of SIRT1, following the downregulation of SREBP-1 and PPARγ protein expression in the liver of hyperlipidemia rats. Conclusion: In summary, oral VitB6 supplementation can ameliorate HFD-induced hepatic lipid accumulation and dyslipidemia in SD rats by inhibiting fatty acid and cholesterol synthesis, promoting fatty acid decomposition and cholesterol transport.

Background: The currently available bone turnover markers are mostly derived from osteoblasts or osteoclasts. Protein markers derived from osteocytes, the most abundant bone cells that can regulate bone turnover activities by other cells, are less explored. Objective: This study aimed to compare the circulating markers of osteocytes and calcium homeostasis between Malaysian postmenopausal women with and without osteoporosis. Methods: Postmenopausal women with (n=20) or without osteoporosis (n=20) as determined by dual- energy X-ray absorptiometry were randomly drawn from a bone health cohort. Their fasting blood was collected and assayed by a multiplex immunoassay panel. Results: The results showed that osteoprotegerin and sclerostin levels were significantly lower among postmenopausal women with osteoporosis than the normal control. No significant differences in other markers were observed between the two groups. Sclerostin level correlated positively with spine Bone Mineral Density (BMD), while 25-hydroxyvitamin D correlated negatively with hip BMD in the control group. No significant correlation was observed between other markers with spine or hip BMD. Conclusion: These data provide an insight into the possible roles of osteocyte markers, especially osteoprotegerin and sclerostin, in classifying subjects with osteoporosis. However, the lack of association between these markers and BMD indicates that osteoporosis is a complex and multifactorial condition.

Background and Aims: Due to the increasing prevalence of obesity and related disorders, there is an urgent need to examine the relationship between diet quality and public health. The Alternative Healthy Eating Index (AHEI) is one of the indices that is used to assess diet quality. Therefore, we investigated the relationship between AHEI and anthropometric measurements and blood pressure. Methods: In this cross-sectional study, 127 male and female hospital employees were examined. The AHEI was calculated by a 168 items Food Frequency Questionnaire. Body weight, height, Body Mass Index (BMI), Waist Circumference (WC), Waist-to-Hip Ratio (WHR) and blood pressure were measured by skilled nutritionists. Physical activity level was also obtained by International Physical Activity Questionnaire (IPAQ). Results: The mean total AHEI score in participants was reported as 47.1±6.9 (min=31.9, max=60.3). The mean differences of total AHEI score across the obese/non-obese employees were not statistically significant (P>0.05). Furthermore, there was no significant correlation between total AHEI score and BMI (r=0.019), WC (r=0.022), WHR (r=-0.102), systolic (r=-0.133) and diastolic blood pressure (r=-0.040) (P>0.05). The score of nuts and soybeans was inversely related to the WHR (P=0.008) and systolic blood pressure (P=0.030). Cereal fiber score had a negative relationship with BMI (P=0.02), WC (P=0.03), WHR (P=0.004) and systolic (P<0.001) and diastolic blood pressure (P=0.012). Conclusion: Consumption of nuts and soybeans -one serving per day- can be associated with WHR and systolic blood pressure reduction. More studies with a larger scale are needed to examine diet quality.

Background & Objective: Exercise and dietary interventions are used to control dyslipidemia and depression in obese individuals, whilst rare investigations have examined the concurrent effects of a low-fat diet and moderate-intensity aerobic exercise training (MIAET) on dyslipidemia and depression in obese patients. Hence, we assessed the potential influences of a low-fat diet combined with MIAET on blood lipids and depression in those individuals. Methods: Forty-two obese patients aged 30-50 years have been enrolled in this randomized controlled trial. They have been randomized equally into MIAET group (n=14, 60-70% of the maximum heart rate (Max HR), three sessions a week), a low-fat diet group (n=14, fat, 30% Kcal/day), and a low-fat diet plus MIAET (n=14) for 10 consecutive weeks. Body mass index (BMI), lipid profile, and Hamilton depression rating scale (HDRS) have been assessed on two occasions, pre and post- 10 weeks. Results: It was demonstrated that a low-fat diet group showed an improvement in total cholesterol (T-Ch), p=0.046, with no changes in triglycerides (TGs), p=0.343, low-density lipoproteins (LDLs), p=0.187, and high-density lipoproteins (HDLs), p=0.224; however, MIAET group showed an improvement in TGs, p=0.042, HDLs, p=0.038 with no changes in T-Ch, p=0.126, and LDLs, p=0.368. Regarding the low-fat diet plus MIAET group, significant improvements were identified in TGs, p=0.003, T-Ch, p<0.001, LDLs, p=0.004, and HDLs, p<0.001. For the depression status, all groups showed a significant improvement in HDRS, p<0.001, with a low-fat diet plus MIAET group showing greater advantages, p<0.05. Conclusion: The results of the current trial suggest an important implication for promoting improvement in blood lipids and a reduction in depression status in obese patients with dyslipidemia following 10-week of a concurrent low-fat diet and moderate-intensity aerobic exercise more than low-fat diet or MIAET alone.

Background: In Congenital Disorder of Glycosylation (CDG) type Ia, homozygous mutations of the PMM2 gene cause phosphomannomutase 2 dysfunction. Case presentation: Herein, a 10-month-old girl, is presented with severe hypotonia, along with inappropriately normal mental status and normal facies. High 2-ketoglutaric acid was detected in her urine, therefore, the diagnosis of 2-Ketoglutarate dehydrogenase complex (KDHC) deficiency was made for this patient. A high dose of vitamin B1 was administered because thiamine is considered a co-factor in this inborn error of metabolism. She responded very well to the daily administration of 500 mg/day vitamin B1 and stood up without help 5 months later. She had also experienced a seizure, which responded well to pyridoxine. Then, she grew up into a 3.5-years-old child who could talk and walk normally. Recently, whole-exome sequencing was performed for her, which showed homozygote mutation of PMM2, therefore, the diagnosis was changed from KDHC deficiency to PMM2-CDG. Conclusion: Paying attention to the pathophysiology of inborn errors of metabolism is necessary while considering the defective enzyme co-factor, which may help us to find an option for the treatment of such rare diseases.

Background: We describe the case of an 11-year-old boy affected by chronic granulomatous disease complicated by a Crohn’s like colitis needing prolonged treatment with oral corticosteroids. Case Presentation: His therapy for the control of severe oral mucositis was based on topical clobetasol, which did not decrease once the steroids were discontinued. Two years after the oral interruption of the steroids, cushingoid characteristics persisted, the cause of which, after a thorough investigation, was found to be the persistence of the topical clobetasol oral gel. Conclusion: Several studies investigated the efficacy of topical clobetasol for immuno-related mucositis, but little is known about its pharmacokinetics and side effects. In this report, we have reviewed the literature, defining a maximum putative dose of clobetasol mucosal gel to avoid Cushing syndrome.