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COVID-19 virus, since the detection of the first case in Wuhan in 2019, has caused a worldwide pandemic with significant human, economic and social costs. Fortunately, several vaccines and treatments, both IV and oral, are currently approved against the COVID-19 virus. Paxlovid is an oral treatment option for patients with mild-to-moderate disease, and it effectively reduces disease severity in high-risk patients. Paxlovid is an oral antiviral that consists of a combination of nirmatrelvir and ritonavi. As an oral medication suitable for outpatient treatment, it reduces the cost, hospitalization and mortality associated with COVID-19 infection. The pregnant population is a high-risk category for COVID-19 disease. Given their exclusion in clinical trials, there is limited data regarding Paxlovid use in pregnant and lactating women. Indirect evidence from ritonavir use as part of HAART therapy in the pregnant and lactating population with HIV has shown no significant teratogenicity. Moreover, animal studies on the use of nirmatrelvir do not suggest teratogenicity. This article summarizes the available data on ritonavir and nirmatrelvir use during pregnancy and in ongoing clinical trials. We also review the recommendations of major societies worldwide regarding Paxlovid use in pregnant and breastfeeding patients.

Objective: People with the HLA genotype DRB1*0301-DQA1*0501-DQB1*0201/DRB1*04-DQA1*0301-DQB1*0302 (DR3/4-DQ8) are at the highest risk of developing type 1 diabetes. We sought to find an inexpensive, rapid test to identify DR3/4-DQ8 subjects using two single nucleotide polymorphisms (SNPs).Research Design and Methods: SNPs rs2040410 and rs7454108 were associated with DR3-DQB1*0201 and DR4-DQB1*0302. We correlated these SNPs with HLA genotypes and with publicly available data on 5,019 subjects from the Type 1 Diabetes Genetic Consortium (T1DGC). Additionally, we analyzed these SNPs in samples from 143 HLA-typed children who participated in the Diabetes Autoimmunity Study of the Young (DAISY) using Taqman probes (rs7454108) and restriction digest analysis (rs2040410).Results: With a simple combinatorial rule, the SNPs of interest identified the presence or absence of the DR3/4-DQ8 genotype. A wide variety of genotypes were tested for both SNPs. In T1DGC samples, the two SNPs were 98.5% (1,173 of 1,191) sensitive and 99.7% (3,815 of 3,828) specific for DR3/4-DQ8. In the DAISY population, the test was 100% (69 of 69) sensitive and 100% (74 of 74) specific. Overall, the sensitivity and specificity for the test were 98.57 and 99.67%, respectively.Conclusions: A two-SNP screening test can identify the highest risk heterozygous genotype for type 1 diabetes in a time- and cost-effective manner. [ABSTRACT FROM AUTHOR]

Technology has become available to cost-effectively analyze thousands of single nucleotide polymorphisms (SNPs). We recently confirmed by genotyping a small series of class I alleles and microsatellite markers that the extended haplotype HLA-A1-B8-DR3 (8.1 AH) at the major histocompatibility complex (MHC) is a common and conserved haplotype. To further evaluate the region of conservation of the DR3 haplotypes, we genotyped 31 8.1 AHs and 29 other DR3 haplotypes with a panel of 656 SNPs spanning 4.8 Mb in the MHC region. This multi-SNP evaluation revealed a 2.9-Mb region that was essentially invariable for all 31 8.1 AHs. The 31 8.1 AHs were >99.9% identical for 384 consecutive SNPs of the 656 SNPs analyzed. Future association studies of MHC-linked susceptibility to type 1 diabetes will need to account for the extensive conservation of the 8.1 AH, since individuals who carry this haplotype provide no information about the differential effects of the alleles that are present on this haplotype. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflict of Interest None declared.

Fipronil is a broad-spectrum phenyl pyrazole insecticide that has a high degree of environmental toxicity. Commonly available chilies in the market are treated with fipronil insecticides. Demand for insecticide-free chili has thus been increasing globally. This needs various sustainable and economical methods to remove insecticides from chilies. The present study examined the effectiveness of several cleaning methods to remove pesticide residues in chili fruits. A supervised field trial was conducted in randomized block design at Rajasthan Agricultural Research Institute, Durgapura, Jaipur, India. Chili samples were subjected to seven different household methods. The samples were extracted using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method. The residues were analyzed using a gas chromatograph-electron capture detector and confirmed by GC-MS. Of the seven methods, the acetic acid treatment removes the maximum residue effect of fipronil and its metabolites (desulfinyl [MB046513]), sulfide (MB045950), and sulfone (MB046136) on chili fruits. By contrast, the tap water treatment was the least effective. The Food Safety and Standards Authority of India (FSSAI) have set the maximum residue limit value of 0.001 mg kg -1 for fipronil on green chili., (© 2023 John Wiley & Sons Ltd.)

Neurodegenerative diseases are a significant cause of mortality worldwide, and the blood-brain barrier (BBB) poses a significant challenge for drug delivery. An intranasal route is a prominent approach among the various methods to bypass the BBB. There are different pathways involved in intranasal drug delivery. The drawbacks of this method include mucociliary clearance, enzymatic degradation and poor drug permeation. Novel nanoformulations and intranasal drug-delivery devices offer promising solutions to overcome these challenges. Nanoformulations include polymeric nanoparticles, lipid-based nanoparticles, microspheres, liposomes and noisomes. Additionally, intranasal devices could be utilized to enhance drug-delivery efficacy. Therefore, intranasal drug-delivery systems show potential for treating neurodegenerative diseases through trigeminal or olfactory pathways, which can significantly improve patient outcomes.

Free flap procedure provides an overall success rate of 97%, which decreases to 85% in hypercoagulable states. COVID-19, as a pro-thrombotic disorder, therefore seems detrimental to free flap survival. We encountered a case of unique pattern of free flap partial failure in a young male who underwent extremity reconstruction. The patient was diagnosed as COVID-19 positive on the 3rd day post-reconstruction. The flap survived well for the first 7 days post-operatively, but gradually the skin got necrosed and the subcutaneous fat layer was preserved when debriding. To our knowledge, this is the only case in which the skin of the free flap of a COVID-19 positive patient was necrosed almost entirely subsequently, while the subcutaneous fat was relatively preserved., (Copyright © 2023 Chinese Medical Association. Production and hosting by Elsevier B.V. All rights reserved.)

Polycystic ovarian syndrome (PCOS) develops due to hormonal imbalance and hyperandrogenism. Animal models are widely used to study PCOS because they mimic essential characteristics of human PCOS; however, the pathogenesis of PCOS remains unclear. Different sources of novel drugs are currently being screened as therapeutic strategies to alleviate PCOS and its symptoms. Simplified cell line in-vitro models could be preliminarily used to screen the bioactivity of various drugs. This review describes different cell line models focusing on the PCOS condition and its complications. Therefore, the bioactivity of the drugs could be preliminarily screened in a cell line model before moving to higher animal models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This paper presents a novel method that uses the cold metal transfer based wire arc additive manufacturing process to fabricate functionally graded Inconel 825-SS316L walls. The optical micrograph of Inconel 825 exhibits continuous and discontinuous dendritic structures. The SS316L region comprises 5% of δ-ferrite in primary austenitic (γ) dendrites which was confirmed by the Cr eq /Ni eq ratio of 1.305. The functionally graded interface reveals a partially mixed zone with a transition from the elongated dendrites to fine equiaxed dendrites. The tensile properties of the fabricated wall were determined at room temperature using specimens extracted from Inconel 825, SS316L, and the interface regions. The morphology of the tensile tested specimens revealed significant plastic deformation, indicating ductile failure. The fracture toughness of the wall was experimentally investigated by employing the crack tip opening displacement (CTOD) test. The fracture morphology exhibited a ductile mode of fracture with striations perpendicular to the direction of crack development. Elemental mapping revealed that there was no evidence of elemental segregation on the fractured surfaces, and the elements were uniformly dispersed. The CTOD measures 0.853 mm, 0.873 mm on the Inconel 825 side and the SS316L side respectively. The test results confirm that both the Inconel 825 and SS316L sides have good fracture toughness., (© 2023. The Author(s).)

BACKGROUNDThe free anterolateral thigh (ALTP) and free medial sural artery perforator (MSAP) flaps are time tested donor for head and neck, and extremities defect reconstruction. Proponents of either flap have concluded each as workhorse flap in their large cohort studies. However, we could not find any literature comparing the donor morbidities, or recipient site outcomes of these flaps, objectively.METHODSRetrospective data, such as demographic details, flap characteristics and post operative course, from patients who underwent free thinned ALTP (25 patients) and MSAP flap (20 patients) were included. At follow-up, donor site morbidity and recipient site outcomes were assessed, using previously defined protocols. These were compared in-between the two groups. RESULTSFree thinned ALTP (tALTP) flap had significantly more pedicle length and vessel diameter and harvest time than free MSAP flap (p value<.00). The differences in incidence of hyperpigmentation, itching, hypertrophic scar, numbness, sensory impairment and cold intolerance at the donor site in-between the two groups, were not significant statistically. Scar at free MSAP donor site was considered a significant social stigma (p value=.005). Recipient site cosmetic outcome was comparable (p value=.86), measured using aesthetic numeric analogue.CONCLUSIONSThe free tALTP flap is superior to free MSAP flap in terms of pedicle length, vessel diameter, donor site morbidity, while the latter takes lesser time for harvest.

The abrupt reduction in the human activities during the first lockdown of the COVID-19 pandemic created unprecedented changes in the background atmospheric conditions. Several studies reported the anthropogenic and air quality changes observed during the lockdown. However, no attempts are made to investigate the lockdown effects on the Atmospheric Boundary Layer (ABL) and background instability processes. In this study, we assess the lockdown impacts on the ABL altitude and instability parameters (Convective Available Potential Energy (CAPE) and Convective Inhibition Energy (CINE)) using WRF model simulations. Results showed a unique footprint of COVID-19 lockdown in all these parameters. Increase in the visibility, surface temperature and wind speed and decrease in relative humidity during the lockdown is noticed. However, these responses are not uniform throughout India and are significant in the inland compared to the coastal regions. The spatial variation of temperature (wind speed) and relative humidity shows an increase and decrease over the Indo Gangetic Plain (IGP) and central parts of India by 20% (100%) and 40%, respectively. Increase (80%) in the ABL altitude is larger over the IGP and central parts of India during lockdown of 2020 compared to similar time period in 2015-2019. This increase is attributed to the stronger insolation due to absence of anthropogenic activity and other background conditions. At the same time, CAPE decreased by 98% in the IGP and central parts of India, where it shows an increase in other parts of India. A prominent strengthening of CINE in the IGP and a weakening elsewhere is also noticed. These changes in CAPE and CINE are mainly attributed to the dearth of saturation in lower troposphere levels, which prevented the development of strong adiabatic ascent during the lockdown. These results provide a comprehensive observation and model-based insight for lockdown induced changes in the meteorological and thermo-dynamical parameters., Competing Interests: Declaration of competing interest The authors declare that they don't have any financial interests or personal relationships., (Copyright © 2022 Elsevier B.V. All rights reserved.)

East Asian dust episodes have a multitude of impacts, including on human health, environment, and climate over near-source and receptor regions. However, the mechanistic understanding of the synoptic conditions of these outbreaks at different altitude layers, and their eventual environmental impacts are less studied. The present study analyzed the synoptic transport patterns of East Asian dust during multiple dust generation episodes that occurred over only a few days apart in northern China, and which eventually delivered high PM 10 concentrations to surface level and high-altitude locations in Taiwan. Whether the dust plume was uplifted ahead of or behind the 700 hPa trough over East Asia determined its trajectory and eventual impact on the environment downwind. The total dust (iron) deposition over the ocean surface preceding arrival to Taiwan was 2.4 mg m -2 (0.95 μg m -2 ) for the episode impacting the surface level and 5.0 mg m -2 (4.6 μg m -2 ) for the episode impacting high-altitude Taiwan. Dust deposition in marine areas east of China was more intense for the higher altitude transport event that was uplifted behind the 700 hPa trough and resulted in twice higher marine Chl-a concentrations. Furthermore, we estimated a dust-induced direct radiative effect over a high mountainous region in Taiwan of -6.2 to -8.2 W m -2 at the surface, -1.9 to -2.9 W m -2 at the top of the atmosphere and +3.9 to +5.3 W m -2 in the atmosphere. This dust-induced atmospheric warming and surface cooling are non-negligible influences on the atmospheric thermal structure and biogeochemical cycle over the western North Pacific. Overall, this study highlights the significant impacts of dust particles on the marine ecosystem and atmospheric radiation budget over the downwind region, thus lays the foundation for linking these impacts to the initial synoptic conditions in the source area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In this study, the genetic diversity of local mango (Mangifera indica L.) germplasm including 14 genotypes were evaluated by using morphological, biochemical markers and DNA barcoding technique. Morphological characterization is the first step towards utilizing these germplasm in crop improvement studies. The advanced chloroplast based DNA barcode method can be utilized to assess the genetic diversity and phylogenetic structure in such populations., Methods: The study was carried out during 2018-2019 years to evaluate local mango germplasm including 14 diverse genotypes based on a number of morphological and biochemical traits and chloroplast DNA barcoding as well. The experiment was laid out in one way ANOVA design with fourteen germplasm indicated with indigenous collection number., Results: Among local mango germplasm, IC 589756 was found to be the most promising with respect to high magnitudes of fruit length, fruit width, fruit weight, pulp weight, soluble solid content (SSC)/Acidity ratio, pH and low acidity followed by IC 589746 exhibiting the highest pulp percentage and SSC accompanied with lowest stone weight and stone percent as compared to the other genotypes. Further, the dendrogram and cluster analyses based on sequencing of chloroplast marker i.e., trnH- psbA and trnCD depicted the relationship among mango genotypes and clearly clustered them into two main clusters at a similarity coefficient 0.035 and 0.150, respectively. The first cluster includes only one genotype and cluster-II contains 13 genotypes., Conclusions: Particularly results revealed that DNA barcoding of local mango germplasm can assist not only in molecular identification but also help in elucidation of their phylogenetic relationship and thus important in maintaining biodiversity inventories., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Next-Generation Sequencing allows for quick and precise sequencing of multiple genes concurrently. Recently, this technology has been employed for the identification of novel gene mutations responsible for disease manifestation among breast cancer (BC) patients, the most common type of cancer amongst Arabian women, and the major cause of disease-associated death in women worldwide. Genomic DNA was extracted from the peripheral blood of 32 Saudi Arabian BC patients with histologically confirmed invasive BC stages I-III and IV, as well from 32 healthy Saudi Arabian women using a QIAamp ® DNA Mini Kit. The isolated DNA was quantified using a Qubit™ dsDNA BR Assay Kit with a Qubit 2.0 Fluorometer. Ion semiconductor sequencing technology with an Ion S5 System and AmpliSeq™ Cancer Hotspot Panel v2 were utilized to analyze ~2,800 mutations described in the Catalogue of Somatic Mutations in Cancer from 50 oncogenes and tumor suppressor genes. Ion Reporter Software v.5.6 was used to evaluate the genomic alterations in all the samples after alignment to the hg19 human reference genome. The results showed that out of the 50 genes, 26 mutations, including 17 (65%) missense point mutations (single nucleotide variants), and 9 (35%) frameshift (insertion/deletion) mutations, were identified in 11 genes across the cohort in 61 samples (95%). Mutations were predominantly focused on two genes, PIK3CA and TP53, in the BC genomes of the sample set. PIK3CA mutation, c.1173A>G located in exon 9, was identified in 15 patients (46.9%). The TP53 mutations detected were a missense mutation (c.215C>G) in 26 patients (86.70%) and 1 frameshift mutation (c.215_216insG) in 1 patient (3.33%), located within exon 3 and 5, respectively. This study revealed specific mutation profiles for every BC patient, Thus, the results showed that Ion Torrent DNA Sequencing technology may be a possible diagnostic and prognostic method for developing personalized therapy based on the patient's individual BC genome., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Messaoudi et al.)

The diagnostic and prognostic utility of circulating cell-free DNA (cfDNA) in breast cancer (BC) patients was recently reported. Here, we investigated the use of cfDNA to examine microsatellite instability (MSI) and loss of heterozygosity (LOH) for early BC diagnosis. cfDNA and genomic DNA from 41 female BC patients and 40 healthy controls were quantified using NanoDrop spectrophotometry and real-time PCR. The stability of genomic and cfDNA was assessed using a high-resolution AmpFlSTR MiniFiler human identification kit. Significant increases in cfDNA plasma concentrations were observed in BC patients compared to controls. The genotype distribution of the eight autosomal short tandem repeat (STR) loci D7S820 , D13S317 , D21S11 , D2S1338 , D18S51 , D16S539 , FGA , and CSF1PO were in Hardy-Weinberg equilibrium. Significant differences in the allele frequencies of D7S820 allele-8, D21S11 allele-29, allele-30.2, allele-32.2, and CSF1PO allele-11 were seen between BC patients and controls. LOH and MSI were detected in 36.6% of the cfDNA of patients compared to genomic DNA. This study highlights the utility of plasma-derived cfDNA for earlier, less invasive, and cost-effective cancer diagnosis and molecular stratification. It also highlights the potential value of cfDNA in molecular profiling and biomarkers discovery in precision and forensic medicine.

In this article, we describe reconstruction of a McCauley's Grade I postburn anterior neck contracture with extensive scarring in a 34-year-old woman using a free thin anterolateral thigh (ALT) flap. To our knowledge, this is the first case of reconstruction of Grade I neck contracture using a thin ALT flap that has been reported. By selecting the correct patient, adhering to recommended standards of microvascular technique, and implementing appropriate postoperative nursing care, we achieved a near-normal neck contour in this patient in a single-staged procedure., Competing Interests: Conflict of Interest: None declared., (Copyright © 2022 International Society of Plastic and Aesthetic Nurses. All rights reserved.)

Background: X-chromosome short tandem repeat (X-STR) markers are important in forensic identity investigations and kinship analysis., Subject and Methods: In the current study, the distribution of 12 X-STR loci located in four linkage groups was evaluated using Investigator ® Argus X-12 Amplification Kit in 200 unrelated healthy individuals (105 males and 95 females) from the central region of Saudi Arabia in order to develop an allelic frequency database for the markers included in the kit., Results: DXS10146 locus was the most informative with 21 alleles, while DXS8378 locus was the least with five alleles. Forensic parameters showed that all X-STRs loci, either as individual markers or as linkage groups, provide genetic information with high discrimination that is appropriate for forensic purposes with polymorphism information content (PIC), power of exclusion (PE), and paternity index (PI) varying from 0.61211 to 0.917979, 0.38722 to 0.842949, and 0.038416 to 0.16367, respectively. The pairwise genetic distance fixation index (Fst) results showed that the Saudi population is genetically closer to the Egyptian and Emirati populations and distant to the Turkish population., Conclusion: The current study revealed that Investigator ® Argus 12 X-STR kit would support the forensic application, kinship testing involving female offspring, and human identification in the Saudi population.

The use of biological traces recovered from touched or handled items increased with the advance of the forensic analysis system. Thus, DNA profiles obtained from touch DNA became a useful tool in forensic investigation. However, a chimeric person with more than one chromosomal population can be challenging for a forensic analyst. We investigated the genetic profile in blood, buccal swab, and skin swabs from twenty-four recipients aged 21-63 years who underwent a matched sibling allogeneic hematopoietic stem cell transplantation with no sign of skin graft versus host disease. Autosomal short tandem repeats genotyping was performed to evaluate chimerism status at 15 loci along with gender marker Amelogenin. According to our results, donor chimerism was detected in all recipient's blood samples, while in buccal swabs, five recipients showed no presence of donor-derived cells in their genotype. Epithelial cells swabbed from hand fingertips were not devoid of donor-derived cells since all recipients showed high chimerism (39.69%-96.66%) in their genotypes. A significant change in chimerism was seen among various types of biological samples (p<0.05). No correlations were observed between chimerism and recipient age, gender, or time after transplant (p> 0.05). The loci D21S11, D8S1179, and FGA were the most informative, whereas D13S317, Vwa, and TOPX were the least informative STR markers. We concluded that touch DNA from a person who has undergone a successful allogeneic HSCTs should not be considered as reliable evidence for human identifications. Therefore, necessary precautions must be taken to avoid false identification and miscarriage of justice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The Clavien-Dindo (C-D) classification is a simple and feasible grading system of postoperative complications. The aim of the present study was to apply this system to retrospectively classify all types of post-pancreaticoduodenectomy (PD) complications (PPCs) and to systematically identify associated risk factors. Between January 2009 and December 2014, the C-D classification was applied to retrospectively classify PPCs for 1,056 patients who had undergone PD at the West China Hospital. Univariate and multivariate analyses were performed to link perioperative parameters and mortality with the severity of PPCs, which were subdivided into overall PPCs (Grade I-V), severe PPCs (Grade III-V) and mortality (Grade V). The number of patients with Clavien-Dindo grade I, II, IIIa, IIIb, IVa, IVb and V complications was 185 (17.5%), 128 (12.1%), 50 (4.7%), 25 (2.4%), 35 (3.3%), 19 (1.8%) and 33 (3.1%), respectively. A total of 475 (45.0%) patients experienced overall PPCs; 168 (15.9%) patients experienced severe PPCs; and 33 patients succumbed to mortality following PD. The following risk factors were identified following PD: Preoperative hypoproteinemia was correlated with all three subdivisions; obstructive jaundice was associated with severe PPCs and mortality; and older age was revealed to be an independent risk factor of mortality. A large retrospective study was performed in the present study and PD was correlated with a high occurrence of PPCs. The Clavien-Dindo system represents a broad applicable and feasible approach to evaluating PPCs in patients following PD. The independent risk factors of PPCs that were identified in the present study require further validation using the Clavien-Dindo classification in additional prospective studies.

An acceptable area for collecting DNA reference sample is a part of the forensic DNA analysis development. The aim of this study was to evaluate skin surface cells (SSC) as an alternate source of reference DNA sample. From each volunteer (n = 10), six samples from skin surface areas (forearm and fingertips) and two traditional samples (blood and buccal cells) were collected. Genomic DNA was extracted and quantified then genotyped using standard techniques. The highest DNA concentration of SSC samples was collected using the tape/forearm method of collection (2.1 ng/μL). Cotton swabs moistened with ethanol yielded higher quantities of DNA than swabs moistened with salicylic acid, and it gave the highest percentage of full STR profiles (97%). This study supports the use of SSC as a noninvasive sampling technique and as a extremely useful source of DNA reference samples among certain cultures where the use of buccal swabs can be considered socially unacceptable., (© 2017 American Academy of Forensic Sciences.)

Aims: To analyze the incidence of and risk factors for post-pancreatoduodenectomy (PD) hemorrhage (PPH) and to evaluate the outcomes of reinterventions for PPH., Methods: All PDs between January 2009 and December 2014 were retrospectively evaluated. PPH was evaluated according to the criteria of the International Study Group of Pancreatic Surgery. Both univariate and multivariate analyses of risk factors for PPH and mortality were performed. Reinterventions were also evaluated., Results: Of the 1,056 PDs during the study period, 78 (7.4%) developed PPH, including 36 with grade B and 42 with grade C. Of these 78 patients, 24 (30.8%) died of PPH-related causes. Multivariate analysis showed that older age, higher total bilirubin concentration, and postoperative pancreatic fistula (POPF) were independent risk factors for PPH. Patients who died of PPH were significantly older and had lower preoperative hemoglobin and albumin concentrations than patients who did not die of PPH. Of the 78 patients with PPH, 58 underwent reintervention, including 27 who underwent angiography, 24 who underwent endoscopy, 24 who underwent re-laparotomy, and 15 who underwent more than one reintervention., Conclusions: Older age, total bilirubin, and POPF are independent risk factors for PPH. Higher mortality are associated with advanced PPH and poor nutritional conditions., (© 2017 S. Karger AG, Basel.)

While elevated blood pressure is a recognized risk factor for cardiovascular disease, the prevalence of hypertension still remains unclear for most populations. A door-to-door survey was conducted using modified WHO STEPS questionnaire in a group of villages under the Thavanampalle Mandal of Chittoor District in the state of Andhra Pradesh of South India. Data were collated and analyzed for 16,636 individuals (62.3% females and 37.7% males) above 15 years of age. Overall, prevalence of hypertension (as per JNC-7 classification) was found to be 27.0% (95% CI, 26.3, 27.7) in the surveyed community with 56.7% of the total hypertensives being diagnosed for the first time during the survey. An additional 39.1% had their blood pressure readings in the prehypertensive range. Among the known Hypertensives on treatment only 46.2% had a blood pressure recording within acceptable limits, with 31.2% in the prehypertensive range and only 15.0% in the normal range. Systolic blood pressure (SBP) of the surveyed population showed a continuous linear increase with age, but diastolic blood pressure (DBP) peaked and started reducing in early fifth decade in males. Male gender, increasing age, higher body mass index (BMI), increased waist-hip ratio, increased body weight, family history of hypertension, death of spouse, and diabetes were found to be positively correlated with hypertension. Risk factors of alcohol intake, use of ground nut/palm oil, and family history of diabetes lost their independent predictive ability for hypertension on multivariate logistic regression analysis. The level of physical activity was also not found to be a significant predictor of hypertension in the study population.

Ovarian hyperstimulation syndrome is a disorder associated with ovulation induction and is rarely seen in pregnant women. Very few cases of spontaneous ovarian hyperstimulation syndrome have been reported in a woman who is neither pregnant nor undergoing ovulation therapy. This case report describes how spontaneous ovarian hyperstimulation syndrome is associated with primary hypothyroidism in a 25-year-old, nonpregnant woman who is not on ovulation induction therapy. Imaging and laboratory findings confirmed the diagnosis of this rare entity, which aided the clinicians in providing prompt management and in preventing further complications.

DiGeorge syndrome is a congenital genetic disorder that affects the endocrine system, mainly the thymus and parathyroid glands. The syndrome produces different symptoms, which vary in severity and character between patients. It manifests with craniofacial dysmorphism and defects in the heart, parathyroid, and thymus. Patients can present with a palatal deformity and nasal speech. This rare entity is caused mainly due to deletion of chromosome 22q11.2. Radiographic evaluation of DiGeorge syndrome is necessary to define aberrant anatomy, evaluate central nervous system, craniofacial abnormalities, musculoskeletal system, and cardiothoracic contents. It also helps in planning surgical procedures and surgical reconstructions. We report a case of DiGeorge syndrome in a 4-month-old neonate and discuss the clinical, imaging, and cytogenetic findings that helped in the diagnosis of this rare entity.

Arc of Riolan is a collateral channel that connects the proximal superior mesenteric artery (SMA) or its middle colic branch and the proximal inferior mesenteric artery or its left colic branch in case of stenosis of either of the arteries. A 65-year-old diabetic female presented with vague abdominal pain. Ultrasonography showed a large aneurysm within the abdomen in the left lumbar region. Computed tomography (CT) angiography done showed severe diffuse atherosclerotic calcification of the abdominal aorta with complete occlusion of the celiac trunk and mild stenosis of SMA origin. The arc of Riolan was seen between the middle colic artery and the ascending branch of the left colic artery, with a large saccular aneurysm in its mid section. No evidence of rupture or hematoma was visible. Another saccular aneurysm was also seen involving the gastro-duodenal and the pancreatico-duodenal collateral arcade. As far as we know, this is the first case of arc of Riolan artery aneurysm to be reported in English literature.

Background/aims: This randomized, placebo-controlled trial was analyzed in order to compare different methods of somatostatin administration in postoperative pancreatic fistula (POPF) and other postoperative complications following pancreaticoduodenectomy (PD)., Methodology: Patients were randomized to a control group (n=32) and an experimental group (n=35). The primary endpoint was the incidences of POPF and other postoperative complications. The definition of POPF was classified as described by the International Study Group of Pancreatic Surgery. In the experimental group, the initial somatostatin was infused 1 day before operation and continued for 7 days after surgery., Results: The incidences of POPF did not show a significant difference between the 2 groups (11/30, 36.7% vs. 14/30, 46.7%; p>0.385). However, blood transfusion volume was 1.7±1.53U in the experimental group and 2.7±2.2U in the control group (p=0.034). Furthermore, the abdominal amylase concentration was significantly lower in the experimental group (p=0.038 and p=0.043, respectively) in both Postoperative Day (POD) 3 and POD 7., Conclusions: Preoperative prophylactic use of somatostatin cannot decrease the incidence of POPF and other complications after PD compared to postoperative use. However, the amylase concentration of the abdominal drainage and the blood transfusion volume seems to be decreased. Further experimental investigations are needed to estimate the value of preoperative use of somatostatin and clear the concrete mechanism.

Castleman's disease (CD) is a relatively rare and benign disorder. Pancreatic localization of CD is even more rare and is usually indistinguishable from pancreatic neoplasms. We report three cases of CD in which pancreas was all involved. One located in the tail of the pancreas, who accepted distal pancreatectomy, and the others in the head accepted enucleation. In addition, we review current data on its pathogenesis, imaging findings, diagnosis, differential diagnosis, and treatment.

Purpose: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose., Methods: De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements., Results: The powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates., Conclusion: Cohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.

Purpose: The purpose of this study was to assess the effectiveness of three commercial capsule-based dry powder passive inhalers [Rotahaler® (RH), Monodose Inhaler® (MI) and Handihaler® (HH)] in de-agglomerating salbutamol sulphate (SS) and micronized lactose (LH300) powders and their sensitivity to air flow rate changes and air flow resistance., Methods: Aerosolisation was assessed in real-time using a laser diffraction method: this approach was possible as only single-component formulations were tested. Volume percent of the aerosolised particles with diameter less than 5.4 μm at air flow rates from 30 to 180 l min−1 was obtained with the RH, MI and HH and provided a parameter, relative de-agglomeration (RD), as a measure of de-agglomeration. The pressure drops across the device at various flow rates were obtained from a differential pressure meter., Results: The relationship between RD of SS and LH300 and air flow rate appeared substantially different between the devices. It was surprisingly found that in some cases RD dropped at the highest air flows: this indicates a device specific maxima in RD occurs, and this may in part be attributed to changes in capsule motion. It is proposed that this relationship between RD and pressure drop provides a patient focussed simple way to assess RD performance. This assessment indicated that MI was the most efficient relative de-agglomerator at lower pressure drops, while HH increases its effectiveness at higher pressure drops., Conclusion: The approach of measuring RD as a function of pressure drop revealed instructive variations in the aerosolisation performances of different devices. This new approach helps compare device performances with different powders, and hence improve optimisation and consistency of performance.

Acacia nilotica proteinase inhibitor (AnPI) was isolated by ammonium sulphate precipitation followed by chromatography on DEAE-Sephadex A-25 and resulted in a purification of 10.68-fold with a 19.5 percentage yield. Electrophoretic analysis of purified AnPI protein resolved into a single band with molecular weight of approximately 18.6+1.00 kDa. AnPI had high stability at different pH values (2.0 to 10.0) except at pH 5.0 and are thermolabile beyond 80 degree C for 10 min. AnPI exhibited effective against total proteolytic activity and trypsin-like activity, but did not show any inhibitory effect on chymotrypsin activity of midgut of Helicoverpa armigera. The inhibition kinetics studies against H. armigera gut trypsin are of non-competitive type. AnPI had low affinity for H. armigera gut trypsin when compared to SBTI. The partially purified and purified PI proteins-incorporated test diets showed significant reduction in mean larval and pupal weight of H. armigera. The results provide important clues in designing strategies by using the proteinase inhibitors (PIs) from the A. nilotica that can be expressed in genetically engineered plants to confer resistance to H. armigera.

Objective: Patients with liver cirrhosis suffer from hyperinsulinemia, hyperglucagonemia and a certain degree of insulin resistance, and portosystemic shunts may be involved in the etiology. A transjugular intrahepatic portosystemic shunt (TIPS) as a treatment for the complications of portal hypertension leads to hemodynamic changes. The objective of the present study is to evaluate whether TIPS can also affect glycometabolism in cirrhosis patients., Methods: Forty-six liver cirrhosis patients (experimental group [EG]) without diabetes who underwent TIPS were evaluated. Portal venous pressure (PVP), cardiac output (CO) and blood flow in the shunt (BFS) were measured or calculated before TIPS, after 15 minutes and, finally, after 90 days. Twenty-five liver cirrhosis patients without diabetes and without TIPS were included as the control group (CG). Oral glucose tolerance tests (OGTTs) were carried out at 0, 1, 7, 30 and 90 days after TIPS or after inclusion in the study. Indices related to glycometabolism and liver function, which included biochemical values, were also investigated., Results: PVP changed immediately from 39.43 ± 1.29 cmH(2)O to 21.43 ± 1.42 cmH(2)O and remained stable thereafter. A pronounced increase in CO was observed after TIPS, while BFS did not change significantly. Also, glycosylated hemoglobin A(1c) (HbA(1c)), fasting plasma glucose (FPG), fasting plasma C-peptide (FPC), glucagon-like peptide-1 (GLP-1) and 2-h post-challenge plasma glucose (2 hPG) were non significantly increased after the shunt. Statistically significant hyperinsulinemia and hyperglucagonemia persisted for 90 days after TIPS. In addition, TIPS was followed by an increase in insulin resistance (IR) and β-cell function. Thirty-four patients in the EG and 15 in the CG were diagnosed with diabetes or prediabetes after 90 days. No significant differences in biochemical values were observed 90 days after the shunt., Conclusion: In addition to causing hemodynamic changes, TIPS augments hyperglucagonemia because of increased secretion and decreased clearance of glucagon in the liver, whereas IR deteriorates after the procedure. However, glycemic control does not worsen after TIPS, and the procedure is not associated with a higher risk of diabetes largely because of the simultaneous increase in insulin., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Purpose: The purpose of the current investigation is to understand the kinetics of de-agglomeration (k(d)) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180l min(-1)) from three dry powder inhaler devices (DPIs), Rotahaler (RH), Monodose Inhaler (MI) and Handihaler (HH)., Results: Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 μm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k(d)), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k(d)vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k(d) was highest from RH and lowest from MI. Differences in k(d) between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure., Conclusion: This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations., Methods: An additional 2717 case and 1315 control chromosomes have been analyzed from the T1DGC, with human leukocyte antigen (HLA) typing and data for 2837 SNPs across the MHC region., Results: We confirmed the association of rs1233478 (new data only: P=2.2E-5, OR=1.4). We also found two additional SNPs nearby that were significantly associated with Type 1 diabetes (new data only rs3131020: P=8.3E-9, OR=0.65; rs1592410: P=2.2E-8, OR=1.5). For studies of Type 1 diabetes in the MHC region, it is critical to account for linkage disequilibrium with the HLA genes. Logistic regression analysis of these new data indicated that the effects of rs3131020 and rs1592410 on Type 1 diabetes risk are independent of HLA alleles (rs3131020: P=2.3E-3, OR=0.73; rs1592410: P=2.1E-3, OR=1.4). Haplotypes of 12 SNPs (including the three highly significant SNPs) stratify diabetes risk (high risk, protective, and neutral), with high-risk haplotypes limited to approximately 20,000 bp in length. The 20,000-bp region is telomeric of the UBD gene and contains LOC729653, a hypothetical gene., Conclusions: We believe that polymorphisms of the telomeric MHC locus LOC729653 may confer risk for Type 1 diabetes., (© 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

Context: Autoimmune Addison's disease (AD) is the major cause of primary adrenal failure in developed nations. Autoantibodies to 21-hydroxylase (21OH-AA) are associated with increased risk of progression to AD. Highest genetic risk is associated with the Major Histocompatibility region (MHC), specifically human leukocyte antigen (HLA)-DR3 haplotypes (containing HLA-B8) and HLA-DR4., Objective: The objective of the study was the further characterization of AD risk associated with MHC alleles., Design, Setting, and Participants: MHC genotypes were determined for HLA-DRB1, DQA1, DQB1, MICA, HLA-B, and HLA-A in 168 total individuals with 21OH-AA (85 with AD at referral and 83 with positive 21OH-AA but without AD at referral)., Main Outcome Measure(s): Genotype was evaluated in 21OH-AA-positive individuals. Outcomes were compared with general population controls and type 1 diabetes patients., Results: In HLA-DR4+ individuals, HLA-B15 was found in only one of 55 (2%) with AD vs. 24 of 63 (40%) 21OH-AA-positive nonprogressors (P = 2 × 10(-7)) and 518 of 1558 (33%) HLA-DR4 patients with type 1 diabetes (P = 1 × 10(-8)). On prospective follow-up, none of the HLA-B15-positive, 21-hydroxylase-positive individuals progressed to AD vs. 25% non-HLA-B15 autoantibody-positive individuals by life table analysis (P = 0.03). Single nucleotide polymorphism analysis revealed the HLA-DR/DQ region associated with risk and HLA-B15 were separated by multiple intervening single-nucleotide polymorphism haplotypes., Conclusions: HLA-B15 is not associated with protection from 21OH-AA formation but is associated with protection from progression to AD in 21OH-AA-positive individuals. To our knowledge, this is one of the most dramatic examples of genetic disease suppression in individuals who already have developed autoantibodies and of novel dominant suppression of an autoimmune disease by a class I HLA allele.

Objective: The objective of this study was to test if the proportion of new-onset diabetic subjects with the HLA-DR3/4-DQB1*0302 genotype is decreasing over time., Research Design and Methods: We analyzed HLA class II genotype frequencies over time in two large populations with type 1 diabetes diagnosed at ≤18 years of age. There were 4,075 subjects from the Type 1 Diabetes Genetics Consortium (T1DGC) and 1,675 subjects from the Barbara Davis Center (BDC)., Results: Both T1DGC and BDC cohorts showed a decrease of the highest-risk HLA-DR3/4-DQB1*0302 genotype over time. This decrease was greatest over time in T1DGC subjects with age of onset ≤5 years (P = 0.004) and onset between ages 6 and 10 years (P = 0.002). The overall percent of HLA-DR3/4-DQB1*0302 was greater in the T1DGC population compared with the BDC population. There was an increased percent over time of other HLA genotypes without HLA-DR3 or -DR4 in T1DGC new onsets (P = 0.003), and the trend was similar in BDC subjects (P = 0.08). Analyzing time trend, there appears to be a large stepwise decrease in percent DR3/4 in the 1980s in T1DGC subjects with onset age <5 years (P = 0.0001)., Conclusions: The change in frequency of multiple different genotypes and a possible stepwise decrease in percent DR3/4 suggest a change in genetic risk factors and environmental determinants of type 1 diabetes. Larger studies are needed to confirm the changing pattern of genetic risk because a stepwise change may have direct bearing on defining critical environmental determinants of type 1 diabetes.

Purpose: The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions., Methods: Aerosolisation of particles less than 5.4μm at air flow rates from 30 to 180 l min(-1) was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler(®). The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters., Results: De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS-LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate., Conclusion: This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Context: Multiple autoimmune disorders (e.g. Addison's disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease., Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison's disease (AD)., Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34., Main Outcome Measures: AD and genotype were measured., Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10(-4)) and 13% of general population controls (P = 3.00 × 10(-19)). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10(-191)). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10(-5)) and type 1 diabetes patients (73%, P = 1.93 × 10(-3)). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A., Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype.

Objective: HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-by-descent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes., Research Design and Methods: We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium., Results: We found evidence for an association with type 1A diabetes (rs1233478, P = 1.6 x 10(-23), allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P = 1.4 x 10(-12)) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P = 0.01)., Conclusions: Polymorphisms in the region of the UBD/MAS1L genes are associated with type 1A diabetes independent of HLA class II and I alleles.

Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.

Objective: A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as >85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403., Research Design and Methods: We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequence-specific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes., Results: By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is approximately 55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P = 0.02) with either protective allele, and the risk is 20 vs. 2% (P = 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies., Conclusions: The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.

We report the prevalence of celiac disease (CD) and its relationship with other autoimmune diseases and HLA haplotypes in a Bedouin kindred. Of 175 individuals sampled and typed for autoantibodies and HLA class II genotypes, six (3.4%) members had CD, and an additional 10 (5.7%) members tested positive for autoantibodies to transglutaminase (TgAA+). Several CD/TgAA+ relatives also had islet cell antigen or adrenal autoimmunity. Affected relatives are more closely related than expected from the pedigree relationships of all family members and were more often the offspring of consanguineous marriages. Individuals with CD or TgAA+ were enriched for DRB1*0301-DQA1*0501-DQB1*0201, a haplotype previously reported as high risk for CD. There was also an increased frequency of DQB1*0201/DQB1*0201 homozygotes among affected relatives. We found no evidence that DRB1*0701-DQA1*0201-DQB1*0201/DRB1*11-DQA1*0501-DQB1*0301 is a high-risk genotype, consistent with other studies of Arab communities. In addition, a nonparametric linkage analysis of 376 autosomal markers revealed suggestive evidence for linkage on chromosome 12p13 at marker D12S364 (NPL = 2.009, p = 0.0098). There were no other significant results, including the HLA region or any other previously reported regions. This could reflect the reduced power of family-based linkage and association analyses in isolated inbred populations.

Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3/4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P = 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR/DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.

Generalized vitiligo is a common autoimmune disorder characterized by white patches of skin and overlying hair caused by loss of pigment-forming melanocytes from involved areas. Familial clustering of vitiligo is not uncommon, and patients and their relatives are at increased risk for a specific complex of other autoimmune diseases. Compared with sporadic vitiligo, familial vitiligo is characterized by earlier disease onset and greater risk and broader repertoire of autoimmunity, suggesting a stronger genetic component, and perhaps stronger associations with specific alleles. To determine whether the major histocompatibility complex (MHC) contributes to the familial clustering of vitiligo and vitiligo-associated autoimmune/autoinflammatory diseases, we performed case-control and family-based association analyses of HLA class II-DRB1 and -DQB1 alleles and haplotypes in affected probands and their parents from 76 European-American Caucasian families with familial vitiligo. Affected probands showed a significantly increased frequency of DRB1*04-DQB1*0301 and a significantly decreased frequency of DRB1*15-DQB1*0602 compared with a large sample of reference chromosomes. Family-based association analyses confirmed these results. Probands with DRB1*04-DQB1*0301 developed vitiligo an average of 13.32 yr earlier than probands with DRB1*15-DQB1*0602. Overall, our results indicate that specific MHC-linked genetic variation contributes to risk of familial vitiligo, although HLA does not completely explain familial clustering of vitiligo-associated autoimmune/autoinflammatory diseases.

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.

We hypothesized that homozygosity for the major histocompatibility complex (MHC) class I chain-related gene A (MIC-A)5.1 allele with premature stop codon would increase diabetes risk of individuals followed from infancy in the DAISY study (Diabetes Autoimmunity Study in the young). Forty five percent (10/22) of relatives (siblings and offspring cohort, SOC) who developed anti-islet autoantibodies were MIC-A5.1/5.1 homozygous. Of SOC individuals without autoantibodies, 12/58 (19%, p = 0.02) were MIC-A5.1 homozygous. By life table analysis of expression of autoantibodies, DR3-DQ2/ DR4-DQ8 more than 50% of MIC-A5.1 homozygous children became autoantibody positive by 7 years of age, compared to delayed development of autoantibodies for non-MIC-A5.1/5.1 DR3-DQ2/ DR4-DQ8 children (p = 0.005). For DR3-DQ2/DR4-DQ8 nonrelatives, the risk of activating anti-islet autoimmunity remained low even with MIC-A5.1 homozygosity suggesting that there are additional factors contributing to the marked risk of relatives compared to the general population with the DR3-DQ2/DR4-DQ8 genotype.

To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk.