Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

Endoscopic stapedotomy: classic versus reversal technique.

OBJECTIVES: To compare hearing outcome and surgical complications between endoscopic classic and reversal stapedotomies. PATIENTS AND METHODS: A prospective single blinded randomized clinical study carried out on 60 patients with otosclerosis who were randomized into two groups; each containing 30 patients. Patients in group 1 underwent endoscopic classic stapedotomy. Patients in group 2 underwent endoscopic reversal stapedotomy. Both groups were compared as regards hearing outcome and surgical complications. RESULTS: The difference in the hearing outcome between the two groups was statistically non-significant. Post-operative closure of the air bone gap (ABG) within 10 dB was attained in 76.67% and 80% of patients in groups 1 and 2, respectively. The differences in the surgical complications between the two studied groups were statistically non-significant. CONCLUSION: Endoscopic classic and reversal stapedotomies are comparable to each other as regards hearing outcome and surgical complications. The authors recommend further studies with relatively larger sample size.

e-GRASP: an integrated evolutionary and GRASP resource for exploring disease associations.

BACKGROUND: Genome-wide association studies (GWAS) have become a mainstay of biological research concerned with discovering genetic variation linked to phenotypic traits and diseases. Both discrete and continuous traits can be analyzed in GWAS to discover associations between single nucleotide polymorphisms (SNPs) and traits of interest. Associations are typically determined by estimating the significance of the statistical relationship between genetic loci and the given trait. However, the prioritization of bona fide, reproducible genetic associations from GWAS results remains a central challenge in identifying genomic loci underlying common complex diseases. Evolutionary-aware meta-analysis of the growing GWAS literature is one way to address this challenge and to advance from association to causation in the discovery of genotype-phenotype relationships. DESCRIPTION: We have created an evolutionary GWAS resource to enable in-depth query and exploration of published GWAS results. This resource uses the publically available GWAS results annotated in the GRASP2 database. The GRASP2 database includes results from 2082 studies, 177 broad phenotype categories, and ~8.87 million SNP-phenotype associations. For each SNP in e-GRASP, we present information from the GRASP2 database for convenience as well as evolutionary information (e.g., rate and timespan). Users can, therefore, identify not only SNPs with highly significant phenotype-association P-values, but also SNPs that are highly replicated and/or occur at evolutionarily conserved sites that are likely to be functionally important. Additionally, we provide an evolutionary-adjusted SNP association ranking (E-rank) that uses cross-species evolutionary conservation scores and population allele frequencies to transform P-values in an effort to enhance the discovery of SNPs with a greater probability of biologically meaningful disease associations. CONCLUSION: By adding an evolutionary dimension to the GWAS results available in the GRASP2 database, our e-GRASP resource will enable a more effective exploration of SNPs not only by the statistical significance of trait associations, but also by the number of studies in which associations have been replicated, and the evolutionary context of the associated mutations. Therefore, e-GRASP will be a valuable resource for aiding researchers in the identification of bona fide, reproducible genetic associations from GWAS results. This resource is freely available at http://www.mypeg.info/egrasp .

High expression of matrix metalloproteinases: MMP-2 and MMP-9 predicts poor survival outcome in colorectal carcinoma.

AIM: To evaluate the expression pattern of matrix metalloproteinases (MMPs); MMP-2, MMP-7 and MMP-9 in colorectal cancer (CRC) and determine its prognostic potential. PATIENTS & METHODS: CRC samples of 127 patients were studied. Protein expressions of MMP-2, -7 and -9 were analyzed by immunohistochemistry and association with clinicopathological variables was statistically analyzed. RESULTS: Overexpressions of MMP-2 and MMP-9 correlated with poor outcome as evaluated by univariate Kaplan-Meier for disease-free survival (p = 0.04, p = 0.0001) and disease-specific survival (p = 0.01, p = 0.01), respectively. Cox analysis of MMP-2 and -9 were significant independent predictors of disease-free survival (p = 0.006, p = 0.018) and disease-specific survival (p = 0.004, p = 0.049), respectively. CONCLUSION: MMPs expression patterns provide useful prognostic information in CRC, while predicting the patients at high risk for recurrent disease.

Prognostic value of bcl-2 expression among women with breast cancer in Libya.

We studied the association of the immunohistochemical bcl-2 expression in Libyan breast cancer with clinicopathological variables and patient outcome. Histological samples from 170 previously untreated primary Libyan breast carcinoma patients were examined. In immunohistochemistry, the NCL-L-bcl-2-486 monoclonal antibody was used. Positive expression of bcl-2 was found in 106 patients (62.4 %). The bcl-2 expression was significantly associated with estrogen receptor (p<0.0001) and progesterone receptor positive tumors (p=0.002), small tumor size (p<0.0001), low tumor grade (p<0.0001), negative axillary lymph nodes (p<0.0001), early stages (p=0.001), and low risk of metastasis (p<0.0001). Positive expression was also associated with older patients (>50 years; p=0.04). Histological subtypes and family history of breast cancer did not have significant relationship with bcl-2. Patients with positive expression of bcl-2 had lower recurrence rate than bcl-2-negative patients and better survival after median follow-up of 47 months. Patients with high bcl-2 staining were associated with the best survival. The role of bcl-2 as an independent predictor of disease-specific survival was assessed in a multivariate survival (Cox) analysis, including age, hormonal status, recurrence, histological grade, and clinical stage variables. Bcl-2 (p<0.0001) and clinical stage (p=0.016) were independent predicators of disease-specific survival. For analysis of disease-free survival, the same variables were entered to the model and only bcl-2 proved to be an independent predictor (p=0.002). Patients with positive expression of bcl-2 were associated with low grade of malignancy, with lower recurrence rate, with lower rate of death, and with longer survival time. Bcl-2 is an independent predictor of breast cancer outcome, and it provides useful prognostic information in Libyan breast cancer. Thus, it could be used with classical clinicopathological factors to improve patient selection for therapy.

Canal Transportation and Centring Ratio of Paediatric vs Regular Files in Primary Teeth.

BACKGROUND: During mechanical preparation of the primary root canal, the original anatomy of the tooth should be preserved and the instrument should be perfectly balanced centrally into the canal space for reducing the probability of canal transportation. The aim of this research was to compare canal transportation and canal centring ability in primary root canals using ProTaper Next (Dentsply Mailfair,), AF baby (Fanta), and Kidzo Elephant (Endostar, Poldent Sp.) files. MATERIALS AND METHODS: Eighteen root canals were randomly divided into 3 experimental groups (n = 6 in each group). Instrumentation was performed using ProTaper Next, Fanta AF baby, and Kidzo Elephant files in groups 1, 2, and 3, respectively. During the instrumentation procedure, the irrigation of 2 mL of 1.5% sodium hypochlorite between each file was done, followed by 5 mL of 17% ethylenediaminetetraacetic acid as a final irrigating solution. Cone-beam computed tomography images were obtained before and after instrumentation. Each group was evaluated for transportation and centring ratios. RESULTS: On comparing all the tested groups within each root canal level canal transportation, the results revealed a statistically nonsignificant difference in the buccolingual direction (P > 0.05). Meanwhile, in the mesiodistal direction, group 1 showed a statistically highly significant difference compared to groups 2 and 3 at the cervical level (P < .01). However, in both middle and apical root canal levels, there was a statistically nonsignificant difference amongst all groups (P > 0.05). Regarding the centring ability comparison of the 3 groups within each root canal level, there was a statistically nonsignificant difference amongst all groups (P > 0.05) in both buccolingual and mesiodistal directions. CONCLUSIONS: The ProTaper Next regular rotary file and the paediatric rotary files showed no difference in canal transportation and centring ability in the buccolingual direction, while in the mesiodistal direction at the cervical root canal level, the ProTaper Next showed high transportation liability.

Prognostic significance of DNA image cytometry in Libyan breast cancer.

BACKGROUND: We evaluated the relation of nuclear DNA content and clinicopathological features and prognosis in primary breast cancer of female Libyan patients with variable stage and grade and different treatment regimes. PATIENTS AND METHODS: Histological samples from 104 patients of breast carcinoma were retrospectively studied by computerized nuclear DNA cytometry. Isolated nuclei from paraffin sections were stained with Feulgen stain and DNA was measured using a computer-assisted image analysis cytometry system. In each case, 200 nuclei were measured and the DNA histograms, S phase fraction (SPF) and number of cells above 5c and 9c were determined. We applied different approaches in the analysis of DNA to compare the DNA histograms with different clinicopathological features and survival. RESULTS: The mean of DNA ploidy mode for all tumors was 3.43; 82.7% of tumors were aneuploid and 17.3% were diploid. The median SPF was 3.5% for DNA diploid and 13.5% for DNA aneuploid tumors. DNA aneuploid tumors and high SPF were associated with advanced stage, distant metastasis, high histological grade and lymph node involvement. The SPF was also associated with large tumor size and with younger patients (<50 years). In the overall population (median follow-up 51 months), patients with aneuploid DNA histograms and high SPF values had shorter survival times than those with diploid DNA histograms and low SPF values (p = 0.001, p < 0.0001, respectively). Also, short survival was associated with a multiploid DNA histogram and with DNA aneuploid cells ≥5 cells (p < 0.0001, p = 0.001, respectively). In a Cox multivariate analysis, DNA ploidy (p = 0.010), age (p = 0.038) and clinical stage (p = 0.001) were independent predictors of overall survival, and DNA ploidy (p = 0.018) and clinical stage (p = 0.001) also proved to be independent predictors of disease-specific survival. The SPF cutoff point of 11% might be applied to separate patients into good and poor prognosis groups. CONCLUSIONS: DNA image cytometry with careful analysis of the histograms may provide valuable prognostic information in Libyan breast cancer, with potential clinical implications in patient management, particularly in predicting the patients at high risk for metastasis and recurrence who should be considered as candidates for combined adjuvant therapy.

Barriers to Kidney Transplantation among Adults on Maintenance Dialysis in Western Region Saudi Arabia: A Cross-Sectional Study.

Kidney transplantation (KT) is the treatment of choice for patients with end-stage renal disease. However, in Saudi Arabia, KT accounts for only 4.5% of the total existing renal replacement therapies in 2016. This cross-sectional study was conducted from September 2017 to January 2018. The aim was to assess the main barriers to the low KT rate in the Saudi community. Data were obtained by direct interviewing using a specifically pre-coded and pre-tested online questionnaire. A total of 321 adult hemodialysis and peritoneal dialysis (PD) (hemodialysis and PD, respectively) patients eligible for KT were selected from several dialysis units in Jeddah, accounting for 11% of the total dialysis population in Jeddah. The mean age was 49.9 ± 14.9 years, and 62.1% were male. Twenty-six percent were employed, and 88.2% were Saudis. Of those interviewed, 90.7% had been counseled for KT mostly by the nephrologist (86.5%) and 178 (55.5%) were referred for pre-transplant evaluation and 92 (28.6 %) were on the active transplant list. The most common barriers were lack of donor availability for 107 patients (40.5%), 58 patients (22%) worried about long-term complications, and 24 (9.1%) worried about surgical complications. Only 17 patients (6.4 %) reported financial constraints as the main reason for not having a KT, especially in non-Saudi patients. Additional initiatives to promote and improve the education and knowledge about kidney donation and the current outcome of KT is needed to improve the transplant rate in the country.

Sonic Hedgehog Expression is Associated with Lymph Node Invasion in Urothelial Bladder Cancer.

Bladder cancer (BC) is a deadly disease characterized by high recurrence rates and frequent progression to an aggressive phenotype. Dysregulation of various signaling pathways have been implicated in BC tumorigenesis, however, the clinical relevance of sonic hedgehog pathway (Shh) remains under investigated. The aim of the current study was to analyze the prognostic value of Shh expression in patients with bladder carcinoma. Immunohistochemical expression of Shh was performed using tissue microarray with 128 specimens from bladder cancer patients. Kaplan-meier survival was analysed and correlation between Shh protein expression and patients' clinicopathological parameters wasexamined using Fisher's exact test. The immuno-staining results revealed that Shh protein exhibits cytoplasmic localization and is expressed in 49% of the analyzed bladder cancer cohort. Our data indicated that high Shh expression significantly correlated with increased lymph node metastasis (p = 0.02), however no association was reported between Shh expression and other clinicopatholigical parameters. High expression of sonic hedgehog was associated with lymph node invasion which may indicate that Shh might play an important role in progression and metastasis of bladder cancer.

Prognostic value of proliferation markers: immunohistochemical ki-67 expression and cytometric s-phase fraction of women with breast cancer in libya.

BACKGROUND: We evaluated the association of the immunohistochemical Ki-67 expression, and S-phase fraction with clinicopathological variables and patient outcome. PATIENTS AND METHODS: Histological samples from 100 primary Libyan breast carcinoma patients were retrospectively studied with monoclonal antibody to Ki-67. S-phase fraction was determined by DNA image cytometry. RESULTS: The median Ki-67 percentage for all tumors was 27.5%, ranging from 1 to 80% and the median S-phase fraction (SPF) was 11%, ranging from 0 to 62 %. Tumors with high Ki-67 expression were found in 76% of patients and with high SPF values in 56%. Ki-67 expression was more frequent in tumors with high SPF than low SPF. High Ki-67 and high SPF were associated with advanced stages, poor differentiation of tumors, positive lymph nodes, and distant metastasis. The Ki-67 was associated with hormone receptor negative tumors. The SPF was higher in young patients (<50 years) than in older patients. In the overall population (median follow-up 49 months), patients with high Ki-67 and high SPF had shorter survival time and predicted recurrence than patients with low Ki-67 and low SPF. In a Cox multivariate analysis, high SPF (p= 0.007), hormonal status (p= 0.001) and clinical stage (p=0.005) were independent predictors of disease-specific survival. The Ki-67 (p=0.065) in borderline significance proved to be independent predictor of disease-free survival. The SPF showed more statistically significance with a high grade of malignancy and survival time than Ki-67. CONCLUSIONS: The SPF value is useful cell proliferation marker to assess tumor prognosis. These markers may reflect the aggressive behavior of Libyan breast cancer and predict of the recurrence. It is therefore important to take these markers into consideration to select a high risk subgroup of the patients for intensive treatment.