Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm.

DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/- mice, respectively, and that Mlh1 promoter methylation in Mlh1+/- sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.

Multislice/multidetector-row computed tomography findings of a rare coronary anomaly: the first septal perforator branch originating from the left main coronary artery.

Multislice/multidetector-row computed tomography (MDCT) is now widely used for noninvasive assessment of coronary arteries, and it may sometimes reveal coronary anomalies. Detection of such anomalies may be relevant both during follow-up and for planning cardiac or coronary surgical/interventional procedures. These anomalies may be missed unless carefully sought. In this paper, we present the MDCT images of a first septal perforator branch originating from the left main coronary artery, which represents an extremely rare coronary anomaly. To the best of our knowledge, this is the first case in the literature where MDCT images are presented.

The management of adnexal masses in premenopausal patients: a ten-year retrospective study at a single center.

PURPOSE OF INVESTIGATION: To distinguish adnexal masses as benign and malignant, and to thereby identity the suitable surgical method for these masses, in premenopausal women, by retrospectively evaluating over a ten-year period, the diagnostic parameters, such as serum CA 125 and transvaginal ultrasonography (TVS), in combination with the presence of ascites in the abdomen. MATERIALS AND METHODS: The study was conducted with 255 premenopausal patients diagnosed with adnexal masses who had been admitted to the Gaziantep University Faculty of Medicine, Clinic of Gynecology and Obstetrics, between January 2003 and January 2013. Data collected from these patients included age, menopausal state, information regarding the presence of ascites, ultrasound findings, and serum CA 125 levels. RESULTS: The mean age of the women included in the study was 32.79 ± 8.11 (range: 18-51) years. Based on the criteria mentioned above, 152 patients were treated by laparoscopy based on a strong suspicion of benign mass, while 103 patients were treated by laparotomy, based on a strong suspicion of malignant mass. CA 125 values did not have a significant effect on malignancy risk. Based on the TVS results, three malignant masses were reported postoperatively in the patient group strongly suspected to have benign masses, while five benign masses were reported postoperatively in the patient group strongly suspected to have malignant masses.An evaluation of the present diagnostic method showed that the TVS has a positive predictive value (PPV) of 94.19% in identifying malignant masses, and a negative predictive value (NPV) of 98.22% in identifying benign masses. CONCLUSION: TVS and CA 125, along with an evaluation of menopausal status and ascites, can be an effective approach for diagnosing adnexal masses, and also for determining the proper surgical method to follow.

The efficacy of single-high dose inhaled corticosteroid versus oral prednisone treatment on exhaled leukotriene and 8-isoprostane levels in mild to moderate asthmatic children with asthma exacerbation.

BACKGROUND: The anti-inflammatory effect of high-dose inhaled corticosteroids (ICS) in children with asthma exacerbation is unknown. We aimed to investigate the efficacy of single-high dose ICS versus oral prednisone treatment followed by a course of six day high-dose ICS or oral prednisone (P) treatment on the concentrations of Cys-LTs and 8-isoprostane levels in the exhaled breath condensate (EBC) of children with asthma exacerbation. METHODS: Ninety-four children with moderate-severe asthma exacerbation were evaluated with asthma scores, peak expiratory flow rate (PEF), forced expiratory volume in first second (FEV1) and exhaled Cys-LT and 8-isoprostane levels before and after treatment. EBC was collected from 52 patients before and four hours after treatment with inhaled fluticasone propionate (FP) (4000 µg) or P and after six days of treatment with FP-1000 µg/day or P. Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit. RESULTS: Both single high-dose FP (n=59) and p (n=35) treatment resulted in a significant improvement in asthma score (p<0.0001), PEF (p<0.0001), and FEV1 (p<0.0001). Cys-LT concentration in the EBC decreased significantly both after the initial treatment (p=0.001), and at the end of the six-day period in the FP group (p<0.0001). 8-Isoprostane concentration was lower only after six days of treatment with FP-1000 µg/day in the FP group (p=0.023). There was a significant decrease in exhaled Cys-LTs after four hours (p=0.012) and six days of P treatment (p=0.018) in children with asthma exacerbation. CONCLUSIONS: High-dose ICS treatment may be useful in the treatment of children with asthma exacerbation. The effects start as early as after four hours. The suppression of Cys-LTs production contributes to the early effects. Suppression of both Cys-LTs and oxidants may favourably contribute to the effects observed later.

Zwolle risk score predicts contrast-induced acute kidney injury in STEMI patients undergoing PCI.

OBJECTIVE: Contrast-induced acute kidney injury (CI-AKI) is a common complication in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The Mehran risk score was defined originally in elective PCI and may be predictive of CI-AKI. The aim of the present study was to investigate whether the Zwolle score predicts CI-AKI in patients with acute STEMI undergoing primary PCI. PATIENTS AND METHODS: We analyzed the data of 314 consecutive patients (mean age 56.3 ± 11.4 years) with acute STEMI undergoing primary PCI. The study population was divided into two groups according to CI-AKI development. The Mehran score, Zwolle score, baseline characteristics, and in-hospital outcomes were recorded. RESULTS: Patients with CI-AKI had higher Mehran and Zwolle scores. In a receiver operating characteristic (ROC) curve analysis, high area under the curve (AUC) values were determined for Zwolle and Mehran scores (0.85 and 0.79, respectively) for CI-AKI development. A Zwolle score greater than 2 predicted CI-AKI with a sensitivity of 76.3 % and a specificity of 75.4 %. A Mehran score greater than 5 predicted CI-AKI with a sensitivity of 71.1 % and a specificity of 73.6 %. CONCLUSION: Zwolle score predicts CI-AKI slightly better than the Mehran score in patients with STEMI undergoing primary PCI. This simple score can be used at the catheterization laboratory for risk stratification for the development of CI-AKI.

Metabolic syndrome and long-term cardiovascular outcomes in NSTEMI with unstable angina.

BACKGROUND AND AIM: Metabolic syndrome (MS) is associated with cardiovascular mortality and morbidity in patients with acute coronary syndrome. The purpose of this study was to evaluate the impact of MS on long-term clinical outcomes in patients with pure non-ST segment myocardial infarction (NSTEMI) or unstable angina pectoris (USAP). METHODS AND RESULTS: We prospectively enrolled 310 consecutive NSTEMI/USAP patients (74 females; mean age, 59.3 ± 11.9 years). The study population was divided into two groups: MS(+) and MS(-). The clinical outcomes of the patients were followed for up to 3 years. Increased 3-year cardiovascular mortality and reinfarction were observed in the MS(+) group, as compared to the MS(-) group (15 vs. 3.4%, p = 0.001, and 22.2 vs. 8.3%, p = 0.001, respectively). Hospitalization rates for heart failure and stroke were not significantly different between the two groups on follow-up. By a Cox multivariate analysis, a significant association was noted between MS and the adjusted risk of 3-year cardiovascular mortality (odds ratio 3.4, 95% confidence interval, 1.24-9.1, p = 0.02). CONCLUSION: These results suggest that MS is associated with an increased risk of 3-year cardiovascular mortality and reinfarction in patients with NSTEMI/USAP.

A new echocardiographic parameter of arterial stiffness in end-stage renal disease.

BACKGROUND: Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Arterial stiffness is an independent predictive parameter of overall and cardiovascular mortality in these patients. However, the defined procedures for the measurement of arterial stiffness are time consuming and not practical in daily practice. METHODS: The study population included 50 patients with ESRD who were treated with hemodialysis (HD; n=23) or peritoneal dialysis (PD; n=27) and 70 age- and sex-matched control subjects. Aortofemoral pulse wave velocity (PWV), carotid intima-media thickness (CIMT), and color M-mode propagation velocity of the descending aorta (aortic propagation velocity, APV) were measured. RESULTS: Compared to the control group, the patients with ESRD had significantly lower APV (46.4 ± 12.4 vs. 58.5 ± 8.5, p < 0.01) and higher PWV (10.5 ± 2.5 vs. 9.2 ± 1.2, p < 0.01) and CIMT (0.66 ± 0.15 vs. 0.43 ± 0.06, p < 0.01) measurements. There were significant correlations between APV and CIMT (r = - 0.769, p < 0.001), APV and PWV (r = - 0.682, p < 0.001), and PWV and CIMT (r = 0.564, p < 0.001). There were no significant differences in APV and PWV between the PD and HD patients. CONCLUSION: Arterial stiffness is an important indicator of atherosclerosis and arterial aging in patients with ESRD. The measurement of APV is an easy and practical new echocardiographic method and may be used to identify arterial stiffness in these patients.

Relationship between exhaled leukotriene and 8-isoprostane levels and asthma severity, asthma control level, and asthma control test score.

OBJECTIVE: Exhaled breath condensate (EBC) is a completely non-invasive method for the collection of airway secretions to measure intense inflammation in the airways of asthmatics. It has been shown that the childhood asthma control test (c-ACT) is a good tool for use in the evaluation of asthmatics. Whether the c-ACT score and asthma control level correlate with the airway inflammation is not well known. We aimed to evaluate the relationship between exhaled cysteinyl leukotrienes (Cys-LTs) and 8-isoprostane levels and asthma severity, asthma control level and c-ACT score in asthmatic children. METHODS: Thirty asthmatic children were evaluated with c-ACT score and pulmonary function tests. Asthma severity and asthma control level were assessed according to GINA. EBC was collected and Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit. RESULTS: Exhaled 8-isoprostane level in patients with moderate persistent asthma [114 (55-146)pg/ml] was higher than in the mild persistent group [52 (21-91)pg/ml] (p=0.05, Mann-Whitney U [MWU]). EBC 8-isoprostane in children with 1-4 asthma exacerbations/year [52 (16-80)pg/ml] was significantly lower than in children with >4 asthma exacerbations/year [114 (57-129)pg/ml] (p<0.05, MWU). No significant relation was determined between exhaled 8-isoprostane and Cys-LTs levels and c-ACT score and asthma control level. Exhaled 8-isoprostane correlated negatively with bronchodilator response (p=0.015, r=-0.45). CONCLUSIONS: Exhaled 8-isoprostane, as an oxidative stress specifier, was found to be increased in relation with asthma exacerbation frequency and oxidative stress increases with the severity of asthma. In contrast to asthma severity level, c-ACT score and asthma control level may not reflect airway inflammation.

Is group C really needed as a separate group from D in COPD? A single-center cross-sectional study.

INTRODUCTION: GOLD 2017 report proposed that the combined COPD assessment should be done according only to symptom burden and exacerbation history in the previous year. OBJECTIVE: This study aims to investigate the change in the COPD groups after the GOLD 2017 revision and also to discuss the evaluation of group C and D as a single group after the GOLD 2019 report. METHOD: The study was designed as a cross-sectional. 251 stable COPD patients admitted to our out-patient clinic; aged ...40 years, at least one-year diagnosis of COPD and ...10 pack-year smoking history were consecutively recruited for the study. RESULTS: In GOLD 2017, a significant difference was found between the distribution of all groups compared to GOLD 2011 (P...=...0,001). 31 patients included in group C were reclassified into group A and 37 patients in group D were reclassified into group B. The FEV1 values of group A and B patients were significantly low and group C and D patients had had exacerbations in more frequently the previous year in GOLD 2017 compared to GOLD 2011. CONCLUSION: After the GOLD 2017 revision, the rate of group C patients decreased even more compared to GOLD 2011 and the group C and D may be considered as a single group in terms of the treatment recommendations with the GOLD 2019 revision. We think that future prospective studies are needed to support this suggestion.

Pontocerebellar hypoplasia associated with nevoid hyperpigmentation and dysmorphic findings: a new subtype?

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. Lineer nevoid hyperpigmentation is a rare skin condition characterized by whorls and streaks of hyperpigmented macules in a reticulate pattern along Blaschko's lines. Herein we present a three year-old male patient with pontocerebellar hypoplasia associated with nevoid hyperpigmentation on the upper part of the body. Besides he has some dysmorphic features including microcephaly, triangular chin, long philtrum, long hand fingers, flexion contracture in all of the distal phalanges of both hands, and strabismus.

Multiple relapses in extramedullary localization of acute lymphoblastic leukemia.

Extramedullary relapses of acute lymphoblastic leukemia in children and young adults are rare and in most cases are usually related to the central nervous system or testes. We describe a case of a 25-year-old man with an acute lymphoblastic leukemia with multiple extramedullary relapses in the testes, gallbladder, breast, parotid gland and eye at various times (Fig. 5, Ref. 21).

Ethnomedicinal landscape: distribution of used medicinal plant species in Nepal.

BACKGROUND: The risk of losing traditional knowledge of medicinal plants and their use and conservation is very high. Documenting knowledge on distribution and use of medicinal plants by different ethnic groups and at spatial scale on a single platform is important from a conservation planning and management perspective. The sustainable use, continuous practice, and safeguarding of traditional knowledge are essential. Communication of such knowledge among scientists and policy makers at local and global level is equally important, as the available information at present is limited and scattered in Nepal. METHODS: In this paper, we aimed to address these shortcomings by cataloguing medicinal plants used by indigenous ethnic groups in Nepal through a systematic review of over 275 pertinent publications published between 1975 and July 2021. The review was complemented by field visits made in 21 districts. We determined the ethnomedicinal plants hotspots across the country and depicted them in heatmaps. RESULTS: The heatmaps show spatial hotspots and sites of poor ethnomedicinal plant use documentation, which is useful for evaluating the interaction of geographical and ethnobotanical variables. Mid-hills and mountainous areas of Nepal hold the highest number of medicinal plant species in use, which could be possibly associated with the presence of higher human population and diverse ethnic groups in these areas. CONCLUSION: Given the increasing concern about losing medicinal plants due to changing ecological, social, and climatic conditions, the results of this paper may be important for better understanding of how medicinal plants in use are distributed across the country and often linked to specific ethnic groups.

Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia?

Schizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia.

Cardiac echinococcosis associated with cerebrovascular occlusive disease and subcutaneous bullous eruptions and ulcers.

Cardiac involvement is an uncommon complication of echinococcosis. It is usually asymptomatic and may only be diagnosed incidentally. A 7-year-old boy was admitted with acute stroke and bullous and ulcerated skin lesions. He was diagnosed with cardiac echinococcosis complicated by systemic emboli to the central nervous system and superficial cutaneous arteries. In endemic areas, echinococcosis should be considered in the differential diagnosis of cardiac disease and unexplained cerebral embolism.

Ring chromosome 18 in a child with febrile seizures.

Ring chromosomes are uncommon cytogenetic findings but have meanwhile been reported for nearly all human chromosomes. Among the rare observations of ring chromosomes in man, the diagnosis of ring chromosome 18 represents a prominent group. We here describe on the cytogenetic analysis results obtained for a 9 years old male patient of non-consanguineous parents. He had growth and developmental delay, mental and motor retardation, microcephaly, microphtalmia, triangle face, small dysplastic ears, strabismus, epicanthal folds on the left, short stature, cryptorchidism, spasticity, pes equinovarus, pes planus, hypothroidism, stereotypic movements and febrile seizures. Also he had hypomyelinization and multiple hyperintense focuses within the white matter on the MRI. The generalized epileptiform abnormality originated from bilateral Centroparietal region. The metabolic investigations including blood and urine amino acids and lysosomal screening tests were normal. The chromosome analysis identified [46,XY,r(18)/46,XY] in 35% of cells a ring 18 and in 65% of cells normal karyotype in peripheral blood cells examined by standard G-bands by Trypsin using Giemsa (GTG) analysis. The dysmorphic features of the presented patient are discussed to the identification of the genotype-phenotype correlation related to his karyotype.

Tissue-specific reduction in MLH1 expression induces microsatellite instability in intestine of Mlh1+/- mice.

Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson's two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect age- and tissue-specific microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth. To assess putative tissue-specific MMR haploinsufficiency, we determined relevant molecular phenotypes (MSI, Mlh1 promoter methylation status, MLH1 protein and RNA levels) in jejuna of Mlh1+/- mice and compared them to those in spleen, as well as to MMR-proficient and -deficient controls (Mlh1+/+ and Mlh1-/- mice). While spleen MLH1 levels of Mlh1+/- mice were, as expected, approximately 50 % compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/- mice and moreover, decreased with age. Mlh1+/- mice with soma-wide Mlh1 promoter methylation often displayed severe MLH1 depletion in jejunum. Reduced (but still detectable) MLH1 levels correlated with elevated MSI in Mlh1+/- jejunum. MSI in jejunum increased with age, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, MLH1 expression levels are particularly labile in intestine of Mlh1+/- mice, giving rise to tissue-specific MSI long before neoplasia. A similar mechanism likely also operates also in the human GI epithelium and could explain the wide range in age-of-onset of LS-associated tumorigenesis.

Relationship between polymorphism in the manganese superoxide dismutase gene and breast cancer.

Manganese superoxide dismutase (MnSOD) acts as an antioxidant and protects cells from the harmful effects of reactive oxygen species. We investigated the relationship between the MnSOD Ala-9Val polymorphism and breast cancer. Genotypes of 250 cases and 330 controls were determined by use of PCR-RFLP. Compared with the MnSOD Val/Val genotype, the MnSOD Val/Ala or MnSOD Ala/Ala genotype was not significantly associated with the overall risk for breast cancer. The risk increased in women with MnSOD Ala allele-containing genotypes as well as higher level of education (Ala/Ala: OR, 6.00; 95% CI, 1.02-35.33), BMI >or= 25 kg/m(2) (Val/Ala: OR, 1.74; 95% CI, 1.10-2.76), late age at first pregnancy (Val/Ala: OR, 1.52; 95% CI, 1.01-2.42), and premenopausal status (Val/Ala: OR, 1.78; 95% CI, 1.03-3.10). In conclusion, the MnSOD Ala-9Val polymorphism may contribute to an increased risk for breast cancer development, particularly in the presence of a higher level of education, high BMI, late age at first pregnancy, and premenopausal status.

Intracranial and subcutaneous lipoma associated with sagittal sinus fenestration and falcine sinus.

Intracranial lipomas are rare lesions. Intracranial lipoma associated with a subcutaneous lipoma is extremely rare. Various vascular abnormalities have been described in association with intracranial lipoma, including distension, kinking, or narrowing of arteries and veins; arteriovenous malformation; and aneurysm. To our knowledge, association of sagittal sinus fenestration, falcine sinus, and absent straight sinus with intraextracranial lipoma has not been reported before. We report the imaging findings of an infant with interhemispheric and subcutaneous lipoma associated with falcine sinus and sagittal sinus fenestration.

Somatic SNPs of the BRCA2 gene at the fragments encoding RAD51 binding sites of canine mammary tumors.

Mammary tumors are the most common tumor type both in women and in female dogs. In women, heritable breast cancers have been linked mutations in the breast cancer susceptibility gene BRCA2 and it contains eight BRC repeats in exon 11 that bind to RAD51. In this study, we investigated the sequence variations of BRC1-BRC8 and C-terminus of canine BRCA2 gene. From a total of 64 canine patients with mammary tumors, 31 mammary tumors with benign and malign carcinomas and the 3 normal mammary glands were used for the study. In this study, 19 SNPs of exon 11 of BRCA2 in canine mammary tumors were detected for the first time. The c.2383A>C (T1425P) SNP was found to be the most probable disease-associated nsSNP. Our findings suggest that T1425P variation in BRC3 to be the most probable disease-associated nsSNP and may affect RAD51 binding strength.

Association between the plasma levels of IMA and coronary atherosclerotic plaque burden and ischemic burden in early phase of non-ST-segment-elevation acute coronary syndromes.

OBJECTIVE: Ischemia-modified albumin (IMA), a novel biochemical marker, is known to reflect ischemia in early phases of acute coronary syndrome (ACS). In the present study, we evaluated the role of IMA on the prediction of coronary atherosclerotic plaque burden and ischemic burden in patients with non-ST-segment-elevation acute coronary syndromes (NSTEACS). PATIENTS AND METHODS: Ninety-six consecutive NSTEACS patients presented within the first three hours of symptom onset were prospectively enrolled in this study. Blood samples were collected in the first 30 min of admission for IMA measurement. Serum levels of IMA were analyzed using the rapid and colorimetric method and reported in absorbance units (ABSU). Coronary plaque burden was assessed by using angiographic Gensini score (GS). In addition, patients were divided into large (LIBG) and small ischemic burden (SIBG) groups based on angiography findings. RESULTS: Patients were dichotomized into two groups according to median GS as follows; with GS ≤ 44 and GS > 44, respectively. Mean IMA was significantly higher in GS > 44 group as compared to GS ≤ 44 group (0.746 ± 0.15 vs. 0.550 ± 0.12 ABSU, p < 0.001). The GS was positively correlated with the levels of IMA (r = 0.673, p < 0.001). IMA was significantly higher in LIBG as compared to SIBG (0.745 ± 0.16 vs. 0.570 ± 0.13 ABSU, p < 0.001). CONCLUSIONS: IMA measurement in early phases of NSTEACS may give predictive information about ischemic burden and coronary atherosclerotic plaque burden; thus, may be useful in decision-making about treatment options in these patients.