Isolated dentinogenesis imperfecta: Novel DSPP variants and insights on genetic counselling.

OBJECTIVE: Dentinogenesis imperfecta (DI) is an inherited dentin defect and may be isolated or associated with disorders such as osteogenesis imperfecta, odontochondrodysplasia Ehler-Danlos and others. Isolated DI is caused mainly by pathogenic variants in DSPP gene and around 50 different variants have been described in this gene. Herein, we report on 19 patients from two unrelated Egyptian families with isolated DI. Additionally, we focused on genetic counselling of the two families. MATERIALS AND METHODS: The patients were examined clinically and dentally. Panoramic X-rays were done to some patients. Whole exome sequencing (WES) and Sanger sequencing were used. RESULTS: WES revealed two new nonsense variants in DSPP gene, c.288T > A (p.Tyr96Ter) and c.255G > A (p.Trp85Ter). Segregation analysis by Sanger sequencing confirmed the presence of the first variant in all affected members of Family 1 while the second variant was confirmed to be de novo in the patient of Family 2. CONCLUSIONS AND CLINICAL RELEVANCE: Our study extends the number of DSPP pathogenic variants and strengthens the fact that DSPP is the most common DI causative gene irrespective of patients' ethnicity. In addition, we provide insights on genetic counseling issues in patients with inherited DSPP variants taking into consideration the variable religion, culture and laws in our society.

A randomized controlled trial of two-doses of vaginal progesterone 400 vs. 200 mg for prevention of preterm labor in twin gestations.

OBJECTIVES: To compare between the effectiveness and safety of two different daily doses of vaginal progesterone (400 vs. 200 mg) in the prevention of preterm labor in twin pregnancy. METHODS: This is a prospective single-blinded randomized controlled trial conducted on 100 primi-gravida who had twin pregnancy and attended the antenatal clinic of a University hospital. They were equally and randomly allocated into two arms each containing 50 patients. Arm 1 received 400 mg and arm 2 received 200 mg vaginal progesterone daily at bed time starting from 14 weeks of pregnancy to 36 weeks. Transvaginal ultrasound was performed for assessment of the length of cervix at 14 and 22 weeks. RESULTS: Both arms of the current study were comparable regarding the cervical length at 14 and 22 weeks, mean gestational age at delivery, incidence of pre-term delivery, birth weight of the first twin. Second twin in addition to the average weight of both twins. No statistical significance differences between two arms regarding incidence of early neonatal death. NICU, mechanical ventilation, length of admission in NICU for the first twin. Second twin as well as both twins. CONCLUSIONS: Vaginal progesterone treatment with different doses was tolerable, but wasn't effective in the prevention of preterm labor in twin pregnancy.

Evaluation of the Anticancer Potential of Crude, Irradiated Cerastes cerastes Snake Venom and Propolis Ethanolic Extract & Related Biological Alterations.

We aimed to evaluate the anticancer potential of crude venom (CV), γ irradiated Certastes cerastes venom (IRRV), and propolis ethanolic extract (PEE). IRRV showed a higher toxicity than CV, while CV-PEE showed higher toxicity than IRRV and CV against lung [A549] and prostate [PC3] cancer cells. Toxicity to [A549] and [PC3] cells was concentration and cell type dependent. In comparison to controls, apoptotic genes showed a significant upregulation of P53 and Casp-3 and a downregulation of Bcl-2. Also, induced elevated DNA accumulation in the [S] phase post PC3 cell treatment with IRRV and CV, as well as a significant DNA accumulation at G2/M phase after IRRV treatment of A549 cells. In contrast, PC3 cells showed a negligible cellular DNA accumulation after PEE treatment. Glutathione reductase [GR] was reduced in case of PC3 and A549 cell treated with IRRV, CV, and PEE compared with its values in untreated cell control. The Malondialdehyde [MDA] values in both cells recorded a significant elevation post IRRV treatment compared to the rest of the treatment regimen and untreated cell control. Similarly, IRRV and CV-PEE mix showed obviously higher reactive oxygen species [ROS] values than PC3 and A549 cell treatments with CV and PEE.

Hospital Prevalence of Colorectal Cancer among Colonoscopy Recipients Attending a Tertiary Hospital in Oman: A Cross-Sectional Study.

PURPOSE: Evidence from industrialized/developed countries showed that colorectal cancer (CRC) incidence rates have significantly dropped due to the widespread use of colonoscopy. In Arab countries, however, the CRC had been reported to have increased. Despite the concerted effort in the primary prevention and widespread use of colonoscopy, to our knowledge, there have been no reports of the prevalence rate of CRC among colonoscopy recipients from Oman. This study aims to explore the CRC prevalence estimates over selected sociodemographic characteristics among colonoscopy-recipients at a tertiary hospital in Oman over five years of follow-up. The regional variations in Oman were also examined in this study. METHODS: This hospital-based cross-sectional study reviewed reports of colonoscopies performed over 5-years of retrospective follow-up at a tertiary hospital in Oman. CRC prevalence estimates were calculated over age, gender, governorate, and time of follow-up. RESULTS: A total of 442 CRC cases were enumerated among 3701 colonoscopies, with an overall CRC prevalence estimate of 11.9 per 100 colonoscopies (95% CI: 10.9, 13.0). Gender-specific CRC prevalence was higher among males compared with females (13.3 vs. 10.5). Age-specific CRC prevalence increased with advancing age, from 2.8 among those less than 40 years of age to 26.5 among aged 70 years or more. Regional CRC prevalence was highest among residents in Batinah Governorate. Over the 5-years of follow-up, there was a slow rise in CRC prevalence with an annual increment of 0.59%. CONCLUSION: The study provides supportive evidence for a steady increase in CRC prevalence over age categories and years of follow-up and depicted the variations of gender-specific CRC prevalence estimates over increasing age categories. The study calls for timely formulation and adoption of national CRC screening programs centered on the colonoscopy use as primary prevention and maximizing its utilization and efficiency.

A Role for the Orphan Human Cytochrome P450 2S1 in Polyunsaturated Fatty Acid ω-1 Hydroxylation Using an Untargeted Metabolomic Approach.

Cytochrome P450 (P450) 2S1 is one of the orphan P450s, known to be expressed but not having a defined function with an endogenous substrate or in drug oxidations. Although it has been clearly demonstrated to catalyze reductive reactions, its role in NADPH-dependent oxidations has been ambiguous. In our efforts to characterize orphan human P450 enzymes, we used an untargeted liquid chromatography-mass spectromterymetabolomic approach with recombinant human P450 2S1 and extracts of rat stomach and intestine, sites of P450 2S1 localization in humans and animals. The search yielded several candidates, including the product 19-hydroxyarachidonic acid. Subsequent 18O analysis and in vitro studies with commercial arachidonic acid and 19-hydroxyarachidonic acid were used to validate ω-1 hydroxylation of the former molecule as a NADPH- and O2-dependent reaction. Steady-state kinetic assays were done for ω-1 hydroxylation reactions of P450 2S1 with several other long-chain fatty acids, including arachidonic, linoleic, α-linolenic, eicosapentaenoic, and docosapentaenoic acids. Rates of hydroxylation were slow, but no detectable activity was seen with either medium-chain length or saturated fatty acids. P450 2S1 is known to be expressed, at least at the mRNA level, to the extent of some other non-3A subfamily P450s in the human gastrointestinal tract, and the activity may be relevant. We conclude that P450 2S1 is a fatty acid ω-1 hydroxylase, although the physiologic relevance of these oxidations remains to be established. The metabolomic approaches we employed in this study are feasible for orphan P450s and other enzymes, in regard to annotation of function, in mammals and other organisms. SIGNIFICANCE STATEMENT: An untargeted mass spectrometry approach was utilized to identify ω-1 hydroxylation of arachidonic acid as an oxidative reaction catalyzed by human cytochrome P450 2S1. The enzyme also catalyzes the relatively slow ω-1 hydroxylation of several other unsaturated long-chain fatty acids.

Folate/Vitamin B12 Supplementation Combats Oxidative Stress-Associated Carcinogenesis in a Rat Model of Colon Cancer.

Folate and vitamin B12 deficiency is associated with depletion of the major intracellular antioxidant glutathione, and oxidative stress is emerging as an etiological mechanism for colon cancer. Azoxymethane (AOM), a potent carcinogen, induces colon cancer in rats by causing pathophysiological changes and oxidative stress. We investigated the synergistic effect of folate and vitamin B12 supplementation against AOM-induced carcinogenesis and oxidative stress in rat colon. Adult male rats were distributed into four groups: 1) Basal diet only; 2) AOM injection (15 mg/kg once per week in weeks 5 and 6); 3) Folate and vitamin B12 supplemented diet; 4) Folate and B12 diet with AOM injection. After 16 weeks, rats were sacrificed, colon tissue dissected, indicators of oxidative stress were measured, and immunohistochemical and ultrastructural changes were evaluated. AOM-injected rats showed oxidative stress, evident by glutathione depletion, oxidation of cellular proteins, and DNA oxidative damage. AOM increased mucosal levels of antiapoptotic and proapoptotic proteins Bcl2 and Bax and caused ultrastructure changes in colonic cell organelles. Folate and vitamin B12 supplementation decreased the level of oxidative stress and ameliorated the cytotoxic effects of AOM. In this in vivo experimental model of colon cancer, folate and vitamin B12 supplementation combats carcinogen-induced oxidative stress.

Immunomodulatory effect of mesenchymal stem cells: Cell origin and cell quality variations.

The immunomodulatory property of mesenchymal stem cells (MSCs) has been previously reported. Still it is unclear if this property can be affected by the cell origin and cell quality. Using primary MSCs expanded from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) of mice, we investigated whether the immunomodulatory property of MSCs varied with cell origin and cell quality (early- vs. late-passaged BM-MSCs). BM-MSCs (p1) and AD-MSCs (p1) had a typical spindle shape, but morphological changes were observed in late-passaged BM-MSCs (p6). A pathway-focused array showed that the expression of chemokine/cytokine genes varied with different cell origins and qualities. By co-culturing with spleen mononuclear cells (MNC) for 3 days, the expression of CD4 was suppressed by all types of MSCs. By contrast, the expression of CD8 was suppressed by BM-MSCs and increased by AD-MSCs. The expression ratio of CD206 to CD86 was at a comparable level after co-culture with AD-MSCs and BM-MSCs, but was lower with late-passaged BM-MSCs. AD-MSCs highly induced the release of IL6, IL-10 and TGF-ß in culture medium. Compared with early-passaged BM-MSCs (p1), late-passaged BM-MSCs (p6) released less TGF-ß. Our data suggests that the immunomodulatory properties of MSCs vary with cell origin and cell quality and that BM-MSCs of good quality are likely the optimal source of immunomodulation.

Deleterious Variants in WNT10A, EDAR, and EDA Causing Isolated and Syndromic Tooth Agenesis: A Structural Perspective from Molecular Dynamics Simulations.

The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.

Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type-2.

We report two unrelated boys with frontonasal dysplasias type-2 (FND-2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele-like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed.

A Modified Technique of Temporary Suspension of the Ovary to the Anterior Abdominal Wall.

STUDY OBJECTIVE: To demonstrate a modified technique of temporary suspension of the ovary to the fascia of the anterior abdominal wall after operative laparoscopy for advanced stage-endometriosis to reduce postoperative adhesion formation. DESIGN: Video illustrating this modified technique of ovarian suspension (Canadian Task Force classification III). SETTING: A previous study described a technique of temporary suspension of the ovary to the abdominal wall using nylon suture [1]. Here we demonstrate a modification of this technique involving underwent temporary suspension of the right ovary, using dissolvable 3-0 plain catgut suture, after operative laparoscopy for advanced-stage endometriosis (American Society for Reproductive Medicine stage III classification). INTERVENTIONS: This patient underwent right ovariolysis for stage III endometriosis. A CO2 laser was used to evaporate spots of endometriosis on the surface of the ovary, ovarian fossa, and the wall of a small endometrioma. A 3-0 plain catgut suture was placed in the right ovarian ligament, and the needle was cut and removed from the peritoneal cavity. The ends of the sutures were brought out of the peritoneal cavity through a 3-mm skin incision using an Endo Close device (Medtronic, Minneapolis, Minnesota). The suture was tied over the fascia while allowing CO2 gas out of the peritoneal cavity, to ensure that the suture remained under tension and the ovary was well suspended without touching the abdominal wall. The suture was used to elevate the ovary away from the ovarian fossa, to avoid recurrence of adhesions between it and the ovary. Postoperatively the patient did well and was discharged home on oral pain medication on the same day of surgery. No postoperative complications related to the suspension procedure were reported. The patient had an uneventful recovery. CONCLUSION: This modified approach of temporary ovarian suspension to the fascia of the anterior abdominal wall appears to be simple, safe, and easy to learn.

Pediatric Foley Catheter Placement After Operative Hysteroscopy Does Not Cause Ascending Infection.

STUDY OBJECTIVE: To determine the incidence of postoperative ascending infection without antibiotics with the use of a pediatric Foley catheter (PFC) after operative hysteroscopy for intrauterine pathology. DESIGN: Retrospective case series (Canadian Task Force classification III). SETTING: University-affiliated outpatient medical center. PATIENTS: Patients who underwent operative hysteroscopy for uterine septum, arcuate uterine anomaly, or multiple submucosal myomas between 1992 and 2015. INTERVENTIONS: In all patients, a PFC was placed in the endometrial cavity at the conclusion of operative hysteroscopy and left in place for 7 days to reduce intrauterine adhesion formation. MEASUREMENTS AND MAIN RESULTS: A total of 1010 patients who underwent operative hysteroscopy for uterine septum (n = 479), arcuate uterine anomaly (n = 483), or multiple submucosal myomas (n = 48) were studied. All patients presented with infertility, recurrent pregnancy loss, or excessive uterine bleeding (in patients with submucous myomas). In all patients, a PFC was placed at the conclusion of the procedure and left in place for 7 days. An 8Fr PFC was used after hysteroscopic division of uterine septum or arcuate uterine anomaly, and a 10Fr PFC was used after hysteroscopic myomectomy. Patients with a history of pelvic inflammatory disease were excluded. Following PFC placement, patients were prescribed estrogen for 6 weeks and progestogen for the last 10 days of the estrogen course. No prophylactic antibiotic therapy was provided. All patients were discharged to home on the same day. Postoperative pain was well controlled with oral pain medication in 98.5% of the patients. There were no reported postoperative infections, and all patients had an uneventful recovery. CONCLUSION: In 1010 consecutive operative hysteroscopies followed by temporary (7-day) PFC placement, no clinically significant uterine infection was observed.

Cytotoxic Effects of Sarcophyton sp. Soft Corals-Is There a Correlation to Their NMR Fingerprints?

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17-100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC50 values ranging from 10-60 µg/mL. No obvious correlation between the extracts' IC50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels.

PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly.

Deafblindness is part of several genetic disorders. We investigated a consanguineous Egyptian family with two siblings affected by congenital hearing loss and retinal degeneration, initially diagnosed as Usher syndrome type 1. At teenage, severe enamel dysplasia, developmental delay, and microcephaly became apparent. Genome-wide homozygosity mapping and whole-exome sequencing detected a homozygous missense mutation, c.1238G>T (p.Gly413Val), affecting a highly conserved residue of peroxisomal biogenesis factor 6, PEX6. Biochemical profiling of the siblings revealed abnormal and borderline plasma phytanic acid concentration, and cerebral imaging revealed white matter disease in both. We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells. We propose PEX6, and possibly other peroxisomal genes, as candidate for the rare cooccurrence of deafblindness and enamel dysplasia. Our study for the first time links peroxisome biogenesis disorders to retinal ciliopathies.

Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity.

Chemical mutagens with an aromatic ring system may be enzymatically transformed to afford aryl radical species that preferentially react at the C8-site of 2'-deoxyguanosine (dG). The resulting carbon-linked C8-aryl-dG adduct possesses altered biophysical and genetic coding properties compared to the precursor nucleoside. Described herein are structural and in vitro mutagenicity studies of a series of fluorescent C8-aryl-dG analogues that differ in aryl ring size and are representative of authentic DNA adducts. These structural mimics have been inserted into a hotspot sequence for frameshift mutations, namely, the reiterated G3-position of the NarI sequence within 12mer (NarI(12)) and 22mer (NarI(22)) oligonucleotides. In the NarI(12) duplexes, the C8-aryl-dG adducts display a preference for adopting an anti-conformation opposite C, despite the strong syn preference of the free nucleoside. Using the NarI(22) sequence as a template for DNA synthesis in vitro, mutagenicity of the C8-aryl-dG adducts was assayed with representative high-fidelity replicative versus lesion bypass Y-family DNA polymerases, namely, Escherichia coli pol I Klenow fragment exo(-) (Kf(-)) and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Our experiments provide a basis for a model involving a two-base slippage and subsequent realignment process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical structures.

Reproductive toxicity to male mice of nose only exposure to water- pipe smoke.

BACKGROUND/AIMS: Water-pipe smoking (WPS) is popular in the Middle East and is starting to gain popularity in several Western countries as well. It is widely and erroneously perceived to be less harmful than other forms of tobacco use. The reproductive adverse effects of cigarette smoking have been studied before with conflicting results, but data on the possible adverse reproductive effects of WPS are lacking. Here, we assessed the effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored "moasel" tobacco in mice. METHODS: The duration of the session was 30 min/day for one month. Control mice were exposed to air. Twenty-four h after the last exposure, mice were killed and the testes and plasma removed for analysis. In testicular homogenates total protein, alkaline phosphatase activity, several indices of oxidative damage and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) were quantified. The plasma concentrations of leptin, testosterone, estrogen and luteinizing hormone (LH) were also measured. Histological analysis of testes and lungs was also conducted. RESULTS: WPS caused statistically significant decreases in the plasma concentrations of leptin, testosterone, and LH, and in the concentrations of total protein and the antioxidant indices measured. A statistically non-significant decrease in VEGFR2 protein in the WPS--exposed mice compared to the control mice was also found. The body and testicular weights of mice exposed to WPS, as well as their testicular alkaline phosphatase activity and light microscopic histology, and plasma estrogen concentration were all not significantly affected by WPS. CONCLUSION: Further studies on the functional implications of these findings in mice exposed to WPS for longer durations are warranted.

Risk genes and autoantibodies in Egyptian children with type 1 diabetes - low frequency of autoantibodies in carriers of the HLA-DRB1*04:05-DQA1*03-DQB1*02 risk haplotype.

BACKGROUND: The study aimed to define the frequencies of type 1 diabetes-associated gene polymorphisms and their associations with various diabetes-associated autoantibodies in Egyptian children. METHODS: One hundred and one children with type 1 diabetes and 160 healthy controls from the same region were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles; for INS and protein tyrosine phosphatase, non-receptor type 22 gene polymorphisms (rs689 and rs2476601); and for diabetes-associated autoantibodies. RESULTS: Most children with diabetes (77.2%) were positive for the HLA-(DR3)-DQA1*05-DQB1*02 (DR3-DQ2) haplotype compared with 26.2% of the controls (OR = 9.5; p < 0.001). HLA-DRB1*04:02-DQA1*03-DQB1*03:02 (DR4-DQ8) (26.7%, OR = 3.3; p < 0.001), DRB1*04:05-DQA1*03-DQB1*02 (DR4-DQ2) (23.8%, OR 5.2; p < 0.001), and DRB1*04:05-DQA1*03-DQB1*03:02 (DR4-DQ8) (8.9%, OR = 7.7; p = 0.007) were also significantly increased. HLA-(DR15)-DQB1*06:01, (DR13)-DQB1*06:03, and DRB1*04:03-DQA1*03-DQB1*03:02 were the most protective haplotypes with OR values from 0.04 to 0.06. Patients positive for DR3-DQ2 but negative for DR4 haplotypes had a high frequency of glutamic acid decarboxylase antibodies (78%; p < 0.001 versus other genotypes), but only 26.6% of those with DR3-DQ2/DR4-DQ2 tested positive for glutamic acid decarboxylase antibodies (p = 0.006 versus other genotypes). Subjects with the DR4-DQ8 haplotype without DR3-DQ2 or DR4-DQ2 were more often positive for islet antigen-2 and zinc transporter 8 antibodies (55.5%, p = 0.007 and 55.5%, p = 0.01 respectively). The AA genotype of the INS gene was more common in patients than in controls (75.2 versus 59.5%, OR = 2.07; p = 0.018). CONCLUSIONS: Besides a strong HLA-DR3-DQ2 association, a relatively high frequency of the DR4-DQ2 haplotype characterized the diabetic population. The low frequency of autoantibodies in children with HLA-DR4-DQ2 may indicate specific pathogenetic pathways associated with this haplotype.

Interstrand DNA-DNA cross-link formation between adenine residues and abasic sites in duplex DNA.

The loss of a coding nucleobase from the structure of DNA is a common event that generates an abasic (Ap) site (1). Ap sites exist as an equilibrating mixture of a cyclic hemiacetal and a ring-opened aldehyde. Aldehydes are electrophilic functional groups that can form covalent adducts with nucleophilic sites in DNA. Thus, Ap sites present a potentially reactive aldehyde as part of the internal structure of DNA. Here we report evidence that the aldehyde group of Ap sites in duplex DNA can form a covalent adduct with the N(6)-amino group of adenine residues on the opposing strand. The resulting interstrand DNA-DNA cross-link occurs at 5'-ApT/5'-AA sequences in remarkably high yields (15-70%) under physiologically relevant conditions. This naturally occurring DNA-templated reaction has the potential to generate cross-links in the genetic material of living cells.

Amelioration of azoxymethane induced-carcinogenesis by reducing oxidative stress in rat colon by natural extracts.

BACKGROUND: Azoxymethane (AOM) is a potent carcinogenic agent commonly used to induce colon cancer in rats; the cytotoxicity of AOM is considered to mediate oxidative stress. This study investigated the chemopreventive effect of three natural extracts [pomegranate peel extract (PomPE), papaya peel extract (PapPE) and seaweed extract (SE)] against AOM-induced oxidative stress and carcinogenesis in rat colon. METHODS: Eighty Sprague-Dawley rats (aged 4 weeks) were randomly divided into 8 groups (10 rats/group). Control group was fed a basal diet; AOM-treated group was fed a basal diet and received AOM intraperitonial injections for two weeks at a dose of 15 mg/kg bodyweight, whereas the other six groups were received oral supplementation of PomPE, PapPE or SE, in the presence or absence of AOM injection. All animals were continuously fed ad-libitum until aged 16 weeks, then all rats were sacrificed and the colon tissues were examined microscopically for pathological changes and aberrant crypt foci (ACF) development, genotoxicity (induced micronuclei (MN) cells enumeration), and glutathione and lipid peroxidation. RESULTS: Our results showed that AOM-induced ACF development and pathological changes in the colonic mucosal tissues, increased bone marrow MN cells and oxidative stress (glutathione depletion, lipid peroxidation) in rat colonic cells. The concomitant treatment of AOM with PomPE, PapPE or SE significantly ameliorated the cytotoxic effects of AOM. CONCLUSIONS: The results of this study provide in-vivo evidence that PomPE, PapPE and SE reduced the AOM-induced colon cancer in rats, through their potent anti-oxidant activities.

A Literature Review of Vertical Dimension in Prosthodontics Theory and Practice - Part 1: Theoretical Foundations.

Vertical dimension (VD) is a critical factor in prosthodontics, playing a pivotal role in the functional and aesthetic outcomes of dental treatments. This literature review explores theoretical foundations and the various aspects of VD, including its definition, measurement, and clinical significance in prosthodontics. The relationship between VD and temporomandibular disorders (TMDs) is examined. Additionally, the impact of VD on facial proportions and aesthetics is significant, as it affects the lower third of the face and influences the patient's overall appearance and self-esteem. In conclusion, understanding the intricate relationship between VD, TMDs, facial aesthetics, and psychological well-being is essential for effective prosthodontic treatment. This comprehensive review provides valuable insights into the multifaceted role of VD in enhancing both functional and aesthetic outcomes, ultimately improving patient satisfaction and quality of life.