Identification of novel genetic variations in ABCB6 and GRN genes associated with HIV-associated lipodystrophy.

Protease inhibitors (PIs) are associated with an incidence of lipodystrophy among people living with HIV(PLHIV). Lipodystrophiesare characterised by the loss of adipose tissue. Evidence suggests that a patient's lipodystrophy phenotype is influenced by genetic mutation, age, gender, and environmental and genetic factors, such as single-nucleotide variants (SNVs). Pathogenic variants are considered to cause a more significant loss of adipose tissue compared to non-pathogenic. Lipid metabolising enzymes and transporter genes have a role in regulating lipoprotein metabolism and have been associated with lipodystrophy in HIV-infected patients (LDHIV). The long-term effect of the lipodystrophy syndrome is related to cardiovascular diseases (CVDs). Hence, we determined the SNVs of lipid metabolising enzymes and transporter genes in a total of 48 patient samples, of which 24 were with and 24 were without HIV-associated lipodystrophy (HIVLD) using next-generation sequencing. A panel of lipid metabolism, transport and elimination genes were sequenced. Three novel heterozygous non-synonymous variants at exon 8 (c.C1400A:p.S467Y, c.G1385A:p.G462E, and c.T1339C:p.S447P) in the ABCB6 gene were identified in patients with lipodystrophy. One homozygous non-synonymous SNV (exon5:c.T358C:p.S120P) in the GRN gene was identified in patients with lipodystrophy. One novelstop-gain SNV (exon5:c.C373T:p.Q125X) was found in the GRN gene among patients without lipodystrophy. Patients without lipodystrophy had one homozygous non-synonymous SNV (exon9:c.G1462T:p.G488C) in the ABCB6 gene. Our findings suggest that novel heterozygous non-synonymous variants in the ABCB6 gene may contribute to defective protein production, potentially intensifying the severity of lipodystrophy. Additionally, identifying a stop-gain SNV in the GRN gene among patients without lipodystrophy implies a potential role in the development of HIVLD.

Maternal smoking, nutritional factors at different life stage, and the risk of incident type 2 diabetes: a prospective study of the UK Biobank.

BACKGROUND: This study aims to investigate potential interactions between maternal smoking around birth (MSAB) and type 2 diabetes (T2D) pathway-specific genetic risks in relation to the development of T2D in offspring. Additionally, it seeks to determine whether and how nutritional factors during different life stages may modify the association between MSAB and risk of T2D. METHODS: This study included 460,234 participants aged 40 to 69 years, who were initially free of T2D from the UK Biobank. MSAB and breastfeeding were collected by questionnaire. The Alternative health eating index(AHEI) and dietary inflammation index(DII) were calculated. The polygenic risk scores(PRS) of T2D and pathway-specific were established, including ß-cell function, proinsulin, obesity, lipodystrophy, liver function and glycated haemoglobin(HbA1c). Cox proportion hazards models were performed to evaluate the gene/diet-MSAB interaction on T2D. The relative excess risk due to additive interaction (RERI) were calculated. RESULTS: During a median follow-up period of 12.7 years, we identified 27,342 cases of incident T2D. After adjustment for potential confounders, participants exposed to MSAB had an increased risk of T2D (HR=1.11, 95%CI:1.08-1.14), and this association remained significant among the participants with breastfeeding (HR= HR=1.10, 95%CI: 1.06-1.14). Moreover, among the participants in the highest quartile of AHEI or in the lowest quartile of DII, the association between MSAB and the increased risk of T2D become non-significant (HR=0.94, 95%CI: 0.79-1.13 for AHEI; HR=1.09, 95%CI:0.99-1.20 for DII). Additionally, the association between MSAB and risk of T2D became non-significant among the participants with lower genetic risk of lipodystrophy (HR=1.06, 95%CI:0.99-1.14), and exposed to MSAB with a higher genetic risk for ß-cell dysfunction or lipodystrophy additively elevated the risk of T2D(RERI=0.18, 95%CI:0.06-0.30 for ß-cell function; RERI=0.16, 95%CI:0.04-0.28 for lipodystrophy). CONCLUSIONS: This study indicates that maintaining a high dietary quality or lower dietary inflammation in diet may reduce the risk of T2D associated with MSAB, and the combination of higher genetic risk of ß-cell dysfunction or lipodystrophy and MSAB significantly elevate the risk of T2D in offspring.

Prevalence and risk factors of metabolic syndrome in Ethiopia: describing an emerging outbreak in HIV clinics of the sub-Saharan Africa - a cross-sectional study.

OBJECTIVES: HIV-induced chronic inflammation, immune activation and combination antiretroviral therapy (cART) are linked with adverse metabolic changes known to cause cardiovascular adversities. This study evaluates the prevalence of lipodystrophy, and metabolic syndrome (MetS), and analyses risk factors in HIV-infected Ethiopians taking cART. METHODS: A multicentre cross-sectional study was conducted at tertiary-level hospitals. Eligible participants attending the HIV clinics were enrolled. Sociodemographic, anthropometric, clinical, HIV treatment variables, lipid profile, fasting blood glucose level, risk factors and components of MetS, also lipodystrophy, were studied. Data were analysed by SPSS statistical package V.25 with descriptive and analytical statistics. For multivariable analysis of risk factors, a logistic regression model was used. Results were presented in frequency and percentages, mean±SD, or median+IQR. Statistical significance was taken as p<0.05. RESULTS: Among 518 studied participants, two-thirds were females, and the mean age of the study population was 45 years (SD=11). The mean duration of cART was 10 years (SD=4). Median CD4 count was 460 cells/mm3. The prevalence of MetS according to the Adult Treatment Panel III (2005) criteria was 37.6%. In multivariable analysis, independent risk factors for MetS were age >45 years (aHR 1.8, 95% CI 1.2 to 2.4), female sex (aHR 1.8, 95% CI 1.1 to 2.8), body mass index (BMI)>25 kg/m2 (aHR 2.7, 95% CI 1.8 to 4.1), efavirenz-based cART (aHR 2.8, 95% CI 1.6 to 4.8) and lopinavir/ritonavir-based cART (aHR 3.7, 95% CI 1.0 to 13.3). The prevalence of lipodystrophy was 23.6%. Prior exposure to a stavudine-containing regimen was independently associated with lipodystrophy (aHR 3.1, 95% CI 1.6 to 6.1). CONCLUSION: Our study revealed 38% of the participants had MetS indicating considerable cardiovascular disease (CVD) risks. Independent risk factors for MetS were BMI≥25 kg/m2, efavirenz and lopinavir/ritonavir-based cART, female sex and age ≥45 years. In addition to prevention, CVD risk stratification and management will reduce morbidity and mortality in people with HIV infection.

Juvenile dermatomyositis: association between nail fold capillary end row loop- area under the curve- and disease damage indicators.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare autoimmune disease characterized by skin and muscle inflammation. The loss of nail fold capillary end row loops (ERL) is evidence of small vessel involvement in JDM. This study aimed to examine the specific association of ERL over the disease course with evidence of JDM disease damage. METHODS: We analyzed data from 68 initially treatment-naïve JDM children who had been observed for at least five years with multiple ERL density assessments. The JDM disease course were categorized into monocyclic short, monocyclic long, polycyclic, and chronic. The ERL capillary count was cumulatively evaluated using the area under the curve (AUC) method. RESULTS: The mean ERL density for the treatment-naive JDM was significantly lower than that of their healthy age-matched controls (4.8 ± 1.6 /mm vs. 7.9 ± 0.9 /mm; p < 0.0001). The ERL AUC was significantly lower in children with a chronic disease course compared to those with a monocyclic short (p = 0.001) or monocyclic long disease course (p = 0.013). JDM patients with lipodystrophy had lower ERL AUC than those without lipodystrophy (p = 0.04). There was no association between ERL AUC and calcifications or fractures. CONCLUSION: Persistently decreased ERL capillary density, reflected by low ERL AUC, is associated with a chronic disease course and lipodystrophy in JDM. Despite medical therapy, the mean ERL count remained below normal even after five years, particularly in polycyclic and chronic cases. It is not clear that restoring normal capillary density is currently feasible in children with JDM.

A subtype of laminopathies: Generalized lipodystrophy-associated progeroid syndrome caused by LMNA gene c.29C>T mutation.

The term laminopathies refers to a group of congenital diseases characterized by accelerated degeneration of human tissues. Mutations in LMNA, LMNB, ZMPSTE24, and other genes lead to structural and functional abnormalities associated with lamins. One subtype of laminopathy is the generalized lipodystrophy-associated progeroid syndrome (GLPS), which occurs in patients with heterozygous mutations of the LMNA gene c.29C>T(p.T10I). This paper reports the first case of GLPS in China and compares the clinical features of other GLPS patients with literature reports. A 16-year-old male patient was treated for diabetic ketoacidosis, presenting with premature aging appearance, systemic lipodystrophy, severe fatty liver, and decreased bone density. After peripheral blood DNA extraction and second-generation sequencing, a heterozygous mutation of exon 1 of the LMNA gene c.29C>T(p.T10I) was detected. This case of GLPS may provide a diagnostic and therapeutic basis for potential patients.

Lipohypertrophy and Insulin: An Old Dog That Needs New Tricks.

OBJECTIVE: To review the current status of practical knowledge related to insulin-associated lipohypertrophy (LH) - an accumulation of fatty subcutaneous nodules commonly caused by repeated injections and/or infusions of insulin into the same site. METHODS: Review of published literature with additional contributions from leading multidisciplinary experts with the emphasis on clinical aspects including pathophysiology, clinical and economic consequences, diagnosis, prevention and treatment. RESULTS: LH is the most common dermatologic complication of insulin therapy. Risk factors for the development of lipohypertrophy include repeated delivery of large amounts of insulin into the same location over time, repeated injection trauma to the skin and subcutaneous tissue, and multiple injections using the same needle. Subcutaneous insulin injection in skin areas with lipohypertrophy is associated with reduced pain; however, this problem can interfere with insulin absorption, thereby increasing the likelihood of glucose variability, hypo- and hyperglycemia when a site is changed. Modern visualization technology of the subcutaneous space with ultrasound can demonstrate lipohypertrophy early in the course of its development. CONCLUSIONS: The physiological and psychological consequences of developing insulin lipohypertrophy can be prevented and treated with education focusing on insulin injection techniques.

Delayed Presentation of Berardinelli-Siep Lipodystrophy in an Adolescent Female.

Berardinelli-Siep syndrome (BSS) is a form of congenital generalized lipodystrophy that disrupts the pathways of lipid metabolism. It presents with physical exam findings, including muscular hypertrophy and lipoatrophy as well as serious metabolic consequences such as diabetes mellitus, hypertriglyceridemia, acute pancreatitis, hepatomegaly, and hepatic steatosis. Diagnosis generally occurs soon after birth or in childhood. The case presented is significant for a delayed diagnosis of suspected BSS Type 1 which is rather uncommon in a developed country. Due to the detrimental complications of BSS, such as hypertrophic cardiomyopathy, pancreatitis, and liver disease, early diagnosis and intervention are crucial. Pediatric providers must be knowledgeable about physical features of BSS and common presentations such as new onset diabetes, hypertriglyceridemia, or pancreatitis throughout early childhood and adolescence in order to avoid delayed diagnoses.

Subcutaneous tissue involvement in idiopathic inflammatory myopathies: Systematic literature review including three new cases and hypothetical mechanisms.

INTRODUCTION: Involvement of subcutaneous tissue in idiopathic inflammatory myopathies (IIM) is poorly known. METHODS: We conducted a systematic review of the literature regarding panniculitis and lipodystrophy/lipoatrophy in juvenile and adult IIM via PubMed/Medline, Embase and Scopus databases. Three local observations are included in this review. Epidemiological, clinical, paraclinical and therapeutic data were collected. RESULTS: Panniculitis appears to be more common in adults than in juveniles. It was mainly localised in the upper and lower limbs. Panniculitis improved in most cases with steroids and panniculitis and myositis had a similar course in 83.3% and 72.2% of cases in juveniles and adults, respectively. Lipodystrophy appeared to be more frequent in juveniles and was only observed in dermatomyositis in both juveniles and adults. Lipodystrophy was mainly partial in juveniles and adults. The median time from myositis to the diagnosis of lipodystrophy was 6 years [0-35] and 2.5 years [0-10] in juveniles and adults, respectively. Lipodystrophy was associated with anti-TIF1 gamma auto-antibody positivity, a polycyclic/chronic course of myositis and the occurrence of calcinosis and might be an indicator of poor disease control. CONCLUSION: Adipose tissue involvement, particularly lipodystrophy, occurs almost exclusively in dermatomyositis. The insidious onset and lack of awareness of the diagnosis may underestimate its prevalence. Larger studies are needed to identify possible risk factors in these patients, to better potential underlying pathophysiological process, in order to discuss potential therapeutic targets.

Adipokine profile in long-term juvenile dermatomyositis, and associations with adipose tissue distribution and cardiac function: a cross-sectional study.

OBJECTIVES: In long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease with controls, and explore associations between adipokines and (1) adipose tissue distribution and (2) cardiac function. METHODS: The study cohort included 59 patients with JDM (60% female, mean age 25.2 years, mean disease duration 16.9 years), and 59 age/sex-matched controls. Updated Pediatric Rheumatology International Trials Organization criteria for clinically inactive JDM were used to stratify patients into active (JDM-active) or inactive (JDM-inactive) disease groups. Lipodystrophy was clinically assessed in all patients. In all study participants, we measured adipose tissue distribution by dual-energy X-ray absorptiometry and cardiac function by echocardiography. Serum adipokines (adiponectin, apelin-12, lipocalin-2, leptin, visfatin and resistin) were analysed using ELISA. RESULTS: Patients with JDM had higher leptin levels compared with controls (p≤0.01). In JDM-active, apelin-12 and visfatin were higher compared with JDM-inactive (p≤0.05). In JDM-total and JDM-active, lower adiponectin correlated with lipodystrophy and total fat mass. Also, systolic dysfunction correlated with: lower adiponectin in JDM-total, JDM-inactive and JDM-active, and with lower apelin-12 in JDM-total and JDM-active and resistin in JDM-active (all p≤0.05). Lower adiponectin correlated with diastolic dysfunction in JDM-total and JDM-active. CONCLUSION: After long-term disease, leptin levels were unfavourably regulated in patients with JDM compared with controls, and apelin-12 and visfatin in JDM-active versus JDM-inactive. We found associations between adipokines and both adipose tissue distribution and cardiac systolic function in all patients with JDM, which was most prominent in patients with active disease.

Adipose tissue distribution is associated with cardio-metabolic alterations in adult patients with juvenile-onset dermatomyositis.

OBJECTIVES: Primary aims were to compare adipose tissue distribution in adult patients with juvenile-onset DM (JDM), with matched controls. Secondary aims were to explore how adipose tissue distribution is associated with cardio-metabolic status (cardiac dysfunction and metabolic syndrome) in patients. METHODS: Thirty-nine JDM patients (all aged ≥18 y, mean age 31.7 y and 51% female) were examined mean 22.7 y (s.d. 8.9 y) after disease onset and compared with 39 age/sex-matched controls. In patients, disease activity and lipodystrophy were assessed by validated tools and use of prednisolone noted. In all participants, dual-energy X-ray absorptiometry (DXA) and echocardiography were used to measure visceral adipose tissue (VAT)(g) and cardiac function, respectively. Risk factors for metabolic syndrome were measured and associations with adipose tissue distribution explored. For primary and secondary aims, respectively, P-values ≤0.05 and ≤0.01 were considered significant. RESULTS: Patients exhibited a 2.4-fold increase in VAT, and reduced HDL-cholesterol values compared with controls (P-values ≤ 0.05). Metabolic syndrome was found in 25.7% of the patients and none of the controls. Cardiac dysfunction (systolic and/or diastolic) was found in 23.7% of patients and 8.1% of controls (P = 0.07). In patients, VAT levels were correlated with age, disease duration and occurrence of metabolic syndrome and cardiac dysfunction. Occurrence of lipodystrophy (P = 0.02) and male sex (P = 0.04) tended to be independently associated with cardiac dysfunction. CONCLUSION: Adults with JDM showed more central adiposity and cardio-metabolic alterations than controls. Further, VAT was found increased with disease duration, which was associated with development of cardio-metabolic syndrome.

A likely pathogenic POLD1 variant associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome in a Chinese patient.

BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; OMIM# 615381) is a rare autosomal dominant disorder, with only a few reported cases worldwide. Herein, we describe the clinical features and underlying molecular etiology of MDPL syndrome in an 8-year-old Chinese patient. METHODS: We performed otological, endocrine, ultrasound, and radiological examinations, as well as genetic testing. Additionally, the literature concerning MDPL was reviewed to do a retrospective analysis of the pathogenesis, genotype-phenotype correlation, and clinical management. RESULTS: The proband was diagnosed with MDPL, presenting with mandibular hypoplasia, a characteristic facial appearance, lipodystrophy, and sensorineural hearing loss (SNHL). Whole-exome sequencing and bioinformatics analysis revealed a de novo missense variant in the POLD1 gene, NM_002691.4:c.3185A>G (NP_002682.2:p.(Gln1062Arg)). The retrospective analysis showed wide variation in the MDPL phenotype, but the most frequent features included mandibular hypoplasia, characteristic facial appearance, lipodystrophy, and SNHL. CONCLUSIONS: This study supplements the mutational spectrum of POLD1. The genetic analysis contributes to the diagnosis of syndromic deafness, and it has a vital role in clinical management and future genetic consultation.

Coexistence of Colon Perforation and Congenital Lipodystrophy.

Lipodystrophy (LD) is an acquired or congenital rare condition consisting of hyperlipidaemia, glucose intolerance/ insulin resistance, and almost complete absence and storage of adipose tissue. Colon perforations can be observed in type 4 congenital LD. Here, we aimed to present a case of sigmoid colon perforation which developed in a young woman with the diagnosis of LD. Extensive purulent peritonitis, significant wall thickening, and oedema in the sigmoid colon were detected during surgical exploration. Anterior resection with end colostomy procedure was then performed. Although bowel perforation has been theoretically reported to occur in LD, the presented case is the first adult patient in the literature. These individuals tend to develop colon perforation as a result of histological changes in their gastrointestinal tract. This situation should always be taken into consideration in order to avoid delay in diagnosis, especially in patients who present with abdominal pain and have a history of LD. Key Words: Intestinal perforation, Congenital lipodystrophy, Peritonitis, Sigmoid colon.

The acromegaly lipodystrophy.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are essential to normal growth, metabolism, and body composition, but in acromegaly, excesses of these hormones strikingly alter them. In recent years, the use of modern methodologies to assess body composition in patients with acromegaly has revealed novel aspects of the acromegaly phenotype. In particular, acromegaly presents a unique pattern of body composition changes in the setting of insulin resistance that we propose herein to be considered an acromegaly-specific lipodystrophy. The lipodystrophy, initiated by a distinctive GH-driven adipose tissue dysregulation, features insulin resistance in the setting of reduced visceral adipose tissue (VAT) mass and intra-hepatic lipid (IHL) but with lipid redistribution, resulting in ectopic lipid deposition in muscle. With recovery of the lipodystrophy, adipose tissue mass, especially that of VAT and IHL, rises, but insulin resistance is lessened. Abnormalities of adipose tissue adipokines may play a role in the disordered adipose tissue metabolism and insulin resistance of the lipodystrophy. The orexigenic hormone ghrelin and peptide Agouti-related peptide may also be affected by active acromegaly as well as variably by acromegaly therapies, which may contribute to the lipodystrophy. Understanding the pathophysiology of the lipodystrophy and how acromegaly therapies differentially reverse its features may be important to optimizing the long-term outcome for patients with this disease. This perspective describes evidence in support of this acromegaly lipodystrophy model and its relevance to acromegaly pathophysiology and the treatment of patients with acromegaly.

Lipodystrophy-associated progeroid syndromes.

With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally recovered. As a consequence, an ectopic deposition of lipids frequently occurs, which usually leads to insulin resistance, atherogenic dyslipidemia, and hepatic steatosis. These disorders include certain accelerated aging syndromes or progeroid syndromes. Even though each of them has unique clinical features, most show common clinical characteristics that affect growth, skin and appendages, adipose tissue, muscle, and bone and, in some of them, life expectancy is reduced. Although the molecular bases of these Mendelian disorders are very diverse and not well known, genomic instability is frequent as a consequence of impairment of nuclear organization, chromatin structure, and DNA repair, as well as epigenetic dysregulation and mitochondrial dysfunction. In this review, the main clinical features of the lipodystrophy-associated progeroid syndromes will be described along with their causes and pathogenic mechanisms, and an attempt will be made to identify which of López-Otín's hallmarks of aging are present.

Determination of insulin-related lipohypertrophy frequency and risk factors in patients with diabetes.

INTRODUCTION: Insulin, which is used in the treatment of diabetes mellitus (DM), may lead to the development of lipohypertrophy (LH) which can negatively affect the management of diabetes mellitus. Two common methods to detect LH are palpation and superficial subcutaneous ultrasonography (SSU). We investigated the frequency of non-palpable LH using SSU, as well as examining risk factors. METHOD: We included in our study patients who had been receiving insulin injections at least twice a day for over one year without palpable LH. The epidermis and the subcutaneous tissue thickness of each region were examined using SSU. The presence of LH and associated risk factors for LH were evaluated. RESULTS: We included 136 patients in our study. The mean age of all patients was 52.87±14.93 years, 59.6% were female and 73.5% had type 2 DM. The duration of DM and insulin usage were 15.76±9.20 and 11.42±8.26 years, respectively. The mean body mass index (BMI) of all patients was 30.59±7.40kg/m2. Non-palpable LH was detected in 87.5% (n=116) of the patients using SSU. In the multivariate logistic regression analyses, total cholesterol level, short-acting insulin dose and coronary artery disease (CAD) were associated with LH presence. CONCLUSION: Non-palpable LH can be seen at high rates in patients who have multiple insulin injections. Palpation is likely not enough to detect LH and we believe it would be appropriate to evaluate the presence of LH using SSU, especially for those who need high-dose insulin to control hyperglycaemia.

Lipodystrophy related to HIV-The Brazilian Public Health approach.

BACKGROUND: Lipodystrophy associated with the human immunodeficiency virus (HIV) is an unpleasant disorder found in 6%-80% of patients infected with HIV. Brazil has a universal public health system, an effective program for patients diagnosed with HIV, providing lipodystrophy treatment since 2004. The objective of this article is to describe the Brazilian approach to this complication. METHOD: A search in the Brazilian Health Care Legislation and the Brazilian Health System database was conducted to identify all the inclusion criteria and surgical treatment offered to HIV patients with lipodystrophy, identify all the facilities that offer this, and describe their geographic distribution. In addition, the number of procedures performed was obtained. RESULTS: The inclusion criteria were the following:1 diagnosis of HIV/AIDS and lipodystrophy due to the use of antiretroviral drugs for at least 12 months;2 no response or the impossibility of changing ART;3 clinical stability for six months without clinical manifestations suggestive of immunodeficiency in the last 6 months;4 laboratory results showing CD4 cell count >250 cells/mm3 and viral load <10,000 copies/ml in the last 6 months; and5 stable clinical and laboratory parameters. A total of 4,760 procedures were performed, with the most common procedure being facial filler with polymethylmethacrylate. Eleven hospitals were registered to offer this treatment. CONCLUSION: The Brazilian Health Care System approach to lipodystrophy has an organized plan with universal and integral coverage. All the procedures offered were safe and well-tolerated, according to the literature. However, regional distribution is the main issue and needs to be improved.

Synergic effect of metabolic syndrome and lipodystrophy on oxidative stress and inflammation process in treated HIV-patients.

The aim of this study was to assess the effect of lipodystrophy (LD) associated to metabolic syndrome (MS) on oxidative stress and inflammation in a cohort of 243 HIV-infected patients with MS, all of them under three different antiretroviral regimens. We collected immunovirological, biochemical and metabolic data, as well as anthropometric measurements. In addition, cardiovascular risk was also assessed by means of Atherogenic Index of Plasma (API) and Framingham Risk Score. The MS-LD patient set was characterized by a lower initial lymphocyte CD4 count and CD4/CD8 ratio and a higher initial viral load than the group without LD. We also found worse lipidic and glycaemic profiles (with lower HDL-cholesterol and higher triglyceride and glucose levels) in the MS-LD group. BMI, systolic blood pressure and Framingham score were significantly increased compared to MS-Non LD. In addition, patients with MS and LD had significantly higher levels of carbonylated proteins, lipid peroxidation, IL-6 and IL-8, as well as a significant decrease in the levels of leptin, adiponectin and antioxidant activities of catalase, super oxide dismutase and glutathione associated enzymes. In MS-LD HIV-1 patients, a significant negative correlation was found between Framingham Risk Score and the antioxidant biomarkers, however a positive association was found between API and protein-C reactive and carbonylated proteins. Segregating by ART, the above-mentioned conditions were worse within the MS-LD group whose treatment contained protease inhibitors, such as lopinavir. In conclusion, HIV-1 infected patients treated for at least six months, especially with regimens including PIs, showed a worsening of inflammatory process and oxidative stress.

Berardinelli Seip Syndrome: A rare case report.

Berardinelli Seip Congenital Lipodystrophy (BSCL) or Congenital Generalized Lipodystrophy (CGL) is one of the four subgroups of lipodystrophy syndrome which is characterized by varying degrees of loss of adipose mass in the body. It is an extremely rare autosomal recessive disorder and commonly reported clinical presentations include muscular hypertrophy, gigantism, hepatomegaly, impaired glucose tolerance, acanthosis nigricans, hypertriglyceridaemia, cardiomyopathy, intellectual impairment, bone cysts and phlebomegaly. We present a case of a 4.5 years old male child born to consanguineous parents, presented with pneumonia. There was history of recurrent diarrhea and chest infection in the past. He had acromegaly like features, hirsutism, firm hepatomegaly, a well defined bone cyst in proximal right femur, pancytopenias with normal bone marrow biopsy report, hypertriglyceridemia and selective IgA deficiency. This is the first case of BSCL, reported in Pakistan with a bone cyst and IgA deficiency. Such patients need to be identified and monitored for complications like diabetes mellitus and hypertrophic cardiomyopathy.

Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene.

POLD1 (DNA polymerase delta 1, catalytic subunit) is a protein-coding gene that encodes the large catalytic subunit (POLD1/p125) of the DNA polymerase delta (Polδ) complex. The consequence of missense or nonsynonymous SNPs (nsSNPs), which occur in the coding region of a specific gene, is the replacement of single amino acid. It may also change the structure, stability, and/or functions of the protein. Mutation in the POLD1 gene is associated with autosomal dominant predisposition to colonic adenomatous polyps, colon cancer, endometrial cancer (EDMC), breast cancer, and brain tumors. These de novo mutations in the POLD1 gene also result in autosomal dominant MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy). In this study, genetic variations of POLD1 which may affect the structure and/or function were analyzed using different types of bioinformatics tools. A total of 17038 nsSNPs for POLD1 were collected from the NCBI database, among which 1317 were missense variants. Out of all missense nsSNPs, 28 were found to be deleterious functionally and structurally. Among these deleterious nsSNPs, 23 showed a conservation scale of >5, 2 were predicted to be associated with binding site formation, and one acted as a posttranslational modification site. All of them were involved in coil, extracellular structures, or helix formation, and some cause the change in size, charge, and hydrophobicity.