Integrated Serosurveillance for Onchocerciasis, Lymphatic Filariasis, and Schistosomiasis in North Darfur, Sudan.

Sudan is endemic for multiple neglected tropical diseases, including trachoma, onchocerciasis (OV), lymphatic filariasis (LF), and schistosomiasis (SCH). In 2019, dried blood spot samples were collected for a baseline trachoma serosurvey in three localities (El Seraif, Kotom, and Saraf Omrah) in North Darfur State. None were classified previously as OV- or LF-endemic, although low levels of SCH had been identified in all three. Approximately 30 households from 25 communities in each locality were selected by multistage cluster random sampling. Collections of DBSs were analyzed by multiplex bead assay for antibodies to multiple pathogens. This paper presents data on OV (Ov16), LF (Wb123, Bm14, Bm33), and SCH (soluble egg antigen [SEA], Sm25) antibodies among 8,322 individuals from 2,119 households. The survey-adjusted seroprevalence estimates for Ov16 were <0.3% in all localities. Lymphatic filariasis-antigen seroprevalences were discordant. Seroprevalence estimates ranged from 4.6-6.0% (Wb123), 0.99-1.4% (Bm14), and 29.2-33.3% (Bm33). Schistosomiasis seroprevalence estimates among school-aged children ranged from 2.7-8.0% (SEA) and 10.9-15.6% (Sm25). Ov16 seropositivity was low and supported the localities' classification as nonendemic. The results suggested LF exposure, but discordance between antigens, challenges defining seropositivity thresholds, and the absence of programmatic guidance based on antibody serology alone for Wuchereria bancrofti indicate a need for remapping surveys to confirm transmission. Schistosomiasis antibody levels were high enough to warrant further mapping to guide treatment decisions. The lack of gold standards limited interpretation of results, particularly for LF, but in resource-challenged areas, integrated serological surveillance offers the possibility of efficient monitoring of exposure to multiple diseases.

Entomological survey of sibling species in the Anopheles funestus group in Tanzania confirms the role of Anopheles parensis as a secondary malaria vector.

BACKGROUND: Malaria transmission in Tanzania is driven by mosquitoes of the Anopheles gambiae complex and Anopheles funestus group. The latter includes An. funestus s.s., an anthropophilic vector, which is now strongly resistant to public health insecticides, and several sibling species, which remain largely understudied despite their potential as secondary vectors. This paper provides the initial results of a cross-country study of the species composition, distribution and malaria transmission potential of members of the Anopheles funestus group in Tanzania. METHODS: Mosquitoes were collected inside homes in 12 regions across Tanzania between 2018 and 2022 using Centres for Disease Control and Prevention (CDC) light traps and Prokopack aspirators. Polymerase chain reaction (PCR) assays targeting the noncoding internal transcribed spacer 2 (ITS2) and 18S ribosomal DNA (18S rDNA) were used to identify sibling species in the An. funestus group and presence of Plasmodium infections, respectively. Where DNA fragments failed to amplify during PCR, we sequenced the ITS2 region to identify any polymorphisms. RESULTS: The following sibling species of the An. funestus group were found across Tanzania: An. funestus s.s. (50.3%), An. parensis (11.4%), An. rivulorum (1.1%), An. leesoni (0.3%). Sequencing of the ITS2 region in the nonamplified samples showed that polymorphisms at the priming sites of standard species-specific primers obstructed PCR amplification, although the ITS2 sequences closely matched those of An. funestus s.s., barring these polymorphisms. Of the 914 samples tested for Plasmodium infections, 11 An. funestus s.s. (1.2%), and 2 An. parensis (0.2%) individuals were confirmed positive for P. falciparum. The highest malaria transmission intensities [entomological inoculation rate (EIR)] contributed by the Funestus group were in the north-western region [108.3 infectious bites/person/year (ib/p/y)] and the south-eastern region (72.2 ib/p/y). CONCLUSIONS: Whereas An. funestus s.s. is the dominant malaria vector in the Funestus group in Tanzania, this survey confirms the occurrence of Plasmodium-infected An. parensis, an observation previously made in at least two other occasions in the country. The findings indicate the need to better understand the ecology and vectorial capacity of this and other secondary malaria vectors in the region to improve malaria control.

Targeting Dectin-1 and or VISTA enhances anti-tumor immunity in melanoma but not colorectal cancer model.

PURPOSE: Acquired resistance to immune checkpoint blockers (ICBs) is a major barrier in cancer treatment, emphasizing the need for innovative strategies. Dectin-1 (gene Clec7a) is a C-type lectin receptor best known for its ability to recognize ß-glucan-rich structures in fungal cell walls. While Dectin-1 is expressed in myeloid cells and tumor cells, its significance in cancer remains the subject of controversy. METHODS: Using Celc7a-/- mice and curdlan administration to stimulate Dectin-1 signaling, we explored its impact. VISTA KO mice were employed to assess VISTA's role, and bulk RNAseq analyzed curdlan effects on neutrophils. RESULTS: Our findings reveal myeloid cells as primary Dectin-1 expressing cells in the tumor microenvironment (TME), displaying an activated phenotype. Strong Dectin-1 co-expression/co-localization with VISTA and PD-L1 in TME myeloid cells was observed. While Dectin-1 deletion lacked protective effects, curdlan stimulation significantly curtailed B16-F10 tumor progression. RNAseq and pathway analyses supported curdlan's role in triggering a cascade of events leading to increased production of pro-inflammatory mediators, potentially resulting in the recruitment and activation of immune cells. Moreover, we identified a heterogeneous subset of Dectin-1+ effector T cells in the TME. Similar to mice, human myeloid cells are the prominent cells expressing Dectin-1 in cancer patients. CONCLUSION: Our study proposes Dectin-1 as a potential adjunctive target with ICBs, orchestrating a comprehensive engagement of innate and adaptive immune responses in melanoma. This innovative approach holds promise for overcoming acquired resistance to ICBs in cancer treatment, offering avenues for further exploration and development.

The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation.

Double-strand breaks (DSBs) are DNA lesions that pose a significant threat to genomic stability. The repair of DSBs by the homologous recombination (HR) pathway is preceded by DNA end resection, the 5' to 3' nucleolytic degradation of DNA away from the DSB. We and others previously identified a role for RNF138, a really interesting new gene finger E3 ubiquitin ligase, in stimulating DNA end resection and HR. Yet, little is known about how RNF138's function is regulated in the context of DSB repair. Here, we show that RNF138 is phosphorylated at residue T27 by cyclin-dependent kinase (CDK) activity during the S and G2 phases of the cell cycle. We also observe that RNF138 is ubiquitylated constitutively, with ubiquitylation occurring in part on residue K158 and rising during the S/G2 phases. Interestingly, RNF138 ubiquitylation decreases upon genotoxic stress. By mutating RNF138 at residues T27, K158, and the previously identified S124 ataxia telangiectasia mutated phosphorylation site (Han et al., 2016, ref. 22), we find that post-translational modifications at all three positions mediate DSB repair. Cells expressing the T27A, K158R, and S124A variants of RNF138 are impaired in DNA end resection, HR activity, and are more sensitive to ionizing radiation compared to those expressing wildtype RNF138. Our findings shed more light on how RNF138 activity is controlled by the cell during HR.

Oil and gas produced waters fail to meet beneficial reuse recommendations for use as dust suppressants.

Produced water from conventional oil and gas wells (O&G PW) is beneficially reused as an inexpensive alternative to commercial dust suppressants which minimize inhalable particulate matter (PM10) from unpaved roads. The efficacy and environmental impacts of using O&G PW instead of commercial products have not been extensively investigated, although O&G PW has been used for dust suppression for decades and often has elevated concentrations of environmental pollutants. In this study, the effectiveness of O&G PW is compared to commercial products under variable humidity conditions by measuring total generated PM10 emissions from treated road aggregate discs. To measure environmental impacts, model roadbeds were treated with six O&G PW and commercial products then subjected to a simulated two-year, 24-h storm event. Generated runoff water was collected and characterized. In efficacy studies, O&G PW offered variable dust reduction (10-85 %) compared to rainwater controls under high humidity (50 %) conditions but performed similarly or worse than controls when humidity was low (20 %). Conversely, all but two commercial products reduced dust emissions by over 90 % regardless of humidity. In rainfall-runoff experiments, roads treated with O&G PWs and CaCl2 Brine generated runoff that was hypersaline, indicating that mobilization of soluble salts could contribute to freshwater salinization. Though most runoff concentrations were highest from roadbeds treated with CaCl2 Brine, runoff from roadbeds treated with O&G PW had the highest concentrations of combined radium (83.6 pCi/L), sodium (3560 mg/L), and suspended solids (5330 mg/L). High sodium concentrations likely dispersed clay particles, which increased road mass loss by 47.2 kg solids/km/storm event compared to rainwater controls. Roadbeds treated with CaCl2 Brine, which had low sodium concentrations, reduced solid road mass loss by 98.1 kg solids/km/storm event. Based on this study, O&G PW do not perform as well as commercial products and pose unique risks to environmental health.

Management and outcomes of pregnant ICU patients with severe COVID-19 pneumonia in Qatar: A retrospective cohort study.

INTRODUCTION: Pregnant women are considered a high-risk group for COVID-19 due to their increased vulnerability to viral infections. The impact of COVID-19 on pregnant women is not well understood, and there is a need for data on managing severe COVID-19 in pregnant patients. This retrospective descriptive cohort study described the characteristics, hospital stay, interventions, and outcomes of pregnant patients admitted to the intensive care units (ICUs) with severe COVID-19 pneumonia in Qatar. METHODS: Data were collected from medical records and chart reviews of pregnant women admitted to Hamad Medical Corporation (HMC) with COVID-19 pneumonia from March 01, 2020, to July 31, 2021. The inclusion criteria encompassed pregnant women with a positive polymerase chain reaction (PCR) antigen test or radiological changes at admission, requiring respiratory support, and hospitalized for more than 24 hours. RESULTS: A total of 43 pregnant women were included in this study. Most patients were admitted during the first wave of the pandemic, with a median gestational age of 212 days [interquartile range 178-242 days] at presentation. The most common respiratory support methods were high-flow nasal cannula, non-invasive positive pressure ventilation, and invasive positive pressure ventilation. Convalescent plasma therapy was administered to 58% of patients, and tocilizumab was used in 28%. Renal replacement therapy was required by 4.6% of patients and 7% required extracorporeal membrane oxygenation. CONCLUSION: This study provides valuable insights into the impact of COVID-19 on pregnant patients admitted to the ICUs in Qatar. The results suggest that pregnant patients with COVID-19 pneumonia require close monitoring and appropriate interventions to minimize adverse outcomes for both mother and fetus. The data may contribute to future guidelines and management strategies for severe COVID-19 in pregnant patients.

The outcome of ultrasound-guided insertion of central hemodialysis catheter.

OBJECTIVE: To point out our experience and assess the efficacy and safety of real-time ultrasound-guided central internal jugular vein (IJV) catheterization in the treatment of hemodialysis patients. METHODS: This retrospective study comprised 150 patients with end-stage renal disease (ESRD) who had real-time ultrasonography (US)-guided IJV HD catheters placed in our hospital between March 2019 and March 2021. Patients were examined for their demographic data, etiology, site of catheter insertion, type (acute or chronic) of renal failure, technical success, operative time, number of needle punctures, and procedure-related complications. Patients who have had multiple catheter insertions, prior catheterization challenges, poor compliance, obesity, bony deformity, and coagulation disorders were considered at high-operative risk. RESULTS: All patients experienced technical success. In terms of patient clinical features, an insignificant difference was observed between the normal and high-risk groups (p-value > 0.05). Of the 150 catheters, 62 (41.3%) were placed in high-risk patients. The first-attempt success rate was 89.8% for the normal group and 72.5% for the high-risk group (p = 0.006). IJV cannulation took less time in the normal-risk group compared to the highrisk group (21.2 ± 0.09) minutes vs (35.4 ± 0.11) minutes, (p < 0.001). There were no serious complications. During the placing of the catheter in the internal jugular vein, four patients (6.4%) experienced arterial puncture in the high-risk group. Two participants in each group got a small neck hematoma. One patient developed a pneumothorax in the high-risk group, which was managed with an intercostal chest tube insertion. CONCLUSIONS: Even in the high-risk group, the real-time US-guided placement of a central catheter into the IJV is associated with a low complication rate and a high success rate. Even under US guidance, experience lowers complication rates. Real-time USguided is recommended to be used routinely during central venous catheter insertion.

Safety and efficacy of percutaneous nephrolithotripsy in comorbid patients: A 3 years prospective observational study.

PURPOSE: To report the result of percutaneous nephrolithotripsy (PCNL) via standard nephrostomy tract in a single training institution. The perioperative complications in relation to the comorbid state are particularly assessed. PATIENTS AND METHODS: A prospective interventional study between January 2019 to November 2022, included 210 patients scheduled for PCNL. The average age was 40.3 ± 11.8 years (range 18- 67 years). Patients were categorized into two groups. The first group comprised 146 cases (69 .5%) with no associated co-morbidities while the second group 64 (30.5%) had co-morbidities such as obesity in 4 cases (1.9%), hypertension (HTN) in 24 cases (11.4%) cases, diabetes mellitus (DM) in 17 (8.1%) cases, history of recurrent stone surgery in 11 (5.2%) cases and more than one in 8 cases (3.8%). Co-morbidities, stone burden, location of stone, time of surgery, stay in the hospital, further operations, and negative events were among the reported data. Complications and the stone-free rate were the main outcome indicators. RESULTS: Intraoperative complications were reported in 40 (18.8%) patients (18 group 1 and 22 group 2) during PCNL. Bleeding occurred in 22 (10.5%) patients (9 group 1 and 13 group 2), blood transfusions were needed in 4 (1.9%) (2 group 1 and 2 group 2), extravasation was observed in 11 patients (5.2%) (6 group 1 and 5 group 2) and cardiac arrhythmia in 3 (1.4%) (1 group 1 and 2 group 2) patients. Postoperative complications occurred in 61 patients (29%) (24 group 1 and 37 group 2) in the form of fever in 10 patients (4.8 %) (3 group 1 and 7 group 2) and prolonged leakage in 50 patients (23.8%) (21 group 1 and 29 group 2). One patient of group 2 died from postoperative sepsis. Extravasation and postoperative leakage were higher in diabetic patients than in non-diabetics. Stonefree rate was 60.5% (127 of 210). Clinically significant residual fragments (CSRFs) found in 70 cases (33.3%) (33 group 1 and 37 group 2). In 13 cases (6.2%) (5 group 1 and 8 group 2), clinically insignificant residual fragments (CIRFs) were found. In 8 (3 group 1 and 5 group 2) of the 13 cases, spontaneous stone passage was observed within 4-6 weeks of surgery. Residual stones in three cases (1 group 1 and 2 group 2) were asymptomatic and 4 mm or less, whereas stones increased in two cases of group 2. Among all factors studied, stone burden was significantly correlated to both intraoperative and postoperative complications. The occurrence of postoperative fever increased with large stone burden. CONCLUSIONS: PCNL is a therapeutic modality that is effective, feasible, and safe for a wide range of patients with concurrent medical issues. A steep curve is required to reduce intraoperative and postoperative complications.

Use of Basilic vein in arteriovenous fistulas construction for hemodialysis access. Is it a good option alternative to prosthetic arteriovenous grafts?

PURPOSE: For patients with a failed forearm autogenous fistula (AF) and an exhausted cephalic vein, there is controversy about whether a brachial basilic AF with transposition or an arteriovenous prosthetic bridging graft (BG) must be the second vascular access option. This work measured and compared these two modalities according to patency rates, complications, and revisions. PATIENTS AND METHODS: A retrospective study of 104 cases that had either a brachial basilic AF (72) or an Arteriovenous BG (32). Technical success, operative complications, procedurerelated mortality, maturation time, functional primary, secondary, and overall patency rates were all assessed. RESULTS: Technical success was obtained in all participants. No procedure-linked mortality. Maturation time for BGs was significantly shorter than AFs. The complication rate was significantly higher in BGs than in AFs. The most prevalent complication was access thrombosis. The functional primary patency rate was significantly higher in AF than in BG at 12-month followup: 77.7% vs 53.1% (p < 0.012). secondary patency rate was higher in AF than in BG at 1-year follow-up 62.5% vs 42.8% (p = 0.063), respectively. In addition, BGs required more interventions to preserve patency. CONCLUSIONS: AF had higher primary, secondary and overall functional patency rates and needed fewer procedures to keep patency than BGs. Cases that need early vascular access as a result of central venous catheter complications or who have a reduced life expectancy may benefit from BGs.

Unravelling the Role of PARP1 in Homeostasis and Tumorigenesis: Implications for Anti-Cancer Therapies and Overcoming Resistance.

Detailing the connection between homeostatic functions of enzymatic families and eventual progression into tumorigenesis is crucial to our understanding of anti-cancer therapies. One key enzyme group involved in this process is the Poly (ADP-ribose) polymerase (PARP) family, responsible for an expansive number of cellular functions, featuring members well established as regulators of DNA repair, genomic stability and beyond. Several PARP inhibitors (PARPi) have been approved for clinical use in a range of cancers, with many more still in trials. Unfortunately, the occurrence of resistance to PARPi therapy is growing in prevalence and requires the introduction of novel counter-resistance mechanisms to maintain efficacy. In this review, we summarize the updated understanding of the vast homeostatic functions the PARP family mediates and pin the importance of PARPi therapies as anti-cancer agents while discussing resistance mechanisms and current up-and-coming counter-strategies for countering such resistance.

Implications for selecting persistent hot spots of schistosomiasis from community- and school-based surveys in Blue Nile, North Kordofan, and Sennar States, Sudan.

In several schistosomiasis-endemic countries, the prevalence has remained high in some areas owing to reinfection despite repeated mass drug administration (MDA) interventions; these areas are referred to as persistent hot spots. Identifying hotspots is critical for interrupting transmission. This study aimed to determine an effective means of identifying persistent hot spots. First, we investigated the differences between Schistosoma haematobium and Schistosoma mansoni prevalence among school-aged children (SAC) estimated by a community-based survey, for which local key informants purposively selected communities, and a randomly sampled school-based survey. A total of 6,225 individuals residing in 60 villages in 8 districts of North Kordofan, Blue Nile, or Sennar States, Sudan participated in a community-based survey in March 2018. Additionally, the data of 3,959 students attending 71 schools in the same 8 districts were extracted from a nationwide school-based survey conducted in January 2017. The community-based survey identified 3 districts wherein the prevalence of S. haematobium or S. mansoni infection among SAC was significantly higher than that determined by the randomly sampled school survey (e.g., S. haematobium in the Sennar district: 10.8% vs. 1.1%, P<0.001). At the state level, the prevalence of schistosomiasis among SAC, as determined by the community-based survey, was consistently significantly higher than that determined by the school-based survey. Purposeful selection of villages or schools based on a history of MDA, latrine coverage, open defecation, and the prevalence of bloody urine improved the ability for identifying persistent hot spots.

Programmatic Implications for Schistosomiasis Elimination Based on Community-Based Survey in the Blue Nile, North Kordofan, and Sennar States, Sudan.

Schistosomiasis prevalence has remained high in some areas due to reinfection despite repeated mass drug administration interventions. We aimed to explore its risk factors in order to help to design adequate interventions in such high-transmission areas. A total of 6225 individuals residing in 60 villages in 8 districts of North Kordofan, Blue Nile, or Sennar States, Sudan participated in the community-based survey in March 2018. First, we investigated Schistosoma haematobium and Schistosoma mansoni prevalences among school-aged children and adults. Second, the associations between risk factors and schistosomiasis were explored. Those without any type of latrine in their households had higher odds of being infected with schistosomiasis than those with a latrine (odds ratio (OR) = 1.53; 95% confidence interval (CI) 1.20-1.94; p = 0.001), and the odds of being positive for schistosomiasis among people living in a household without an improved latrine were higher than for their counterparts with an improved latrine (OR = 1.63; CI 1.05-2.55; p = 0.03). Furthermore, people with households or outside compounds found to contain human faeces had higher odds of being infected with schistosomiasis than their counterparts (OR = 1.36, 95% CI 1.01-1.83, p = 0.04). Installing an improved latrine and eliminating open defecation should be highlighted in schistosomiasis elimination projects in high-transmission areas.

Quantification of protein enrichment at site-specific DNA double-strand breaks by chromatin immunoprecipitation in cultured human cells.

Here, we present a chromatin-immunoprecipitation-based protocol to quantify the recruitment of proteins adjacent to site-specific DNA double-strand breaks (DSBs), such as proteins involved in DSB repair. We describe steps to induce DSBs in U2OS osteosarcoma cells stably expressing the restriction endonucleases FokI or AsiSI. We then detail the procedures of chromatin isolation and immunoprecipitation, followed by protein elution and quantitative-PCR-based quantification of DNA. This protocol cannot be used on DSBs generated at random loci by DNA damaging agents. For complete details on the use and execution of this protocol, please refer to Fitieh et al. (2022).1.

Spatiotemporal mapping of malaria incidence in Sudan using routine surveillance data.

Malaria is a serious threat to global health, with over [Formula: see text] of the cases reported in 2020 by the World Health Organization in African countries, including Sudan. Sudan is a low-income country with a limited healthcare system and a substantial burden of malaria. The epidemiology of malaria in Sudan is rapidly changing due to factors including the rapidly developing resistance to drugs and insecticides among the parasites and vectors, respectively; the growing population living in humanitarian settings due to political instability; and the recent emergence of Anopheles stephensi in the country. These factors contribute to changes in the distribution of the parasites species as well as malaria vectors in Sudan, and the shifting patterns of malaria epidemiology underscore the need for investment in improved situational awareness, early preparedness, and a national prevention and control strategy that is updated, evidence based, and proactive. A key component of this strategy is accurate, high-resolution endemicity maps of species-specific malaria. Here, we present a spatiotemporal Bayesian model, developed in collaboration with the Sudanese Ministry of Health, that predicts a fine-scale (1 km [Formula: see text] 1 km) clinical incidence and seasonality profiles for Plasmodium falciparum and Plasmodium vivax across the country. We use monthly malaria case counts for both species collected via routine surveillance between January 2017 and December 2019, as well as a suite of high-resolution environmental covariates to inform our predictions. These epidemiological maps provide a useful resource for strategic planning and cost-effective implementation of malaria interventions, thus informing policymakers in Sudan to achieve success in malaria control and elimination.

Bioassay-Guided extraction of andrographis paniculata for intervention of in-vitro prostate cancer progression in metabolic syndrome environment.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for prostate cancer (PCa) progression. Thus, this life-threatening disease demands a proactive treatment strategy. Andrographis paniculata (AP) is a promising candidate with various medicinal properties. However, the bioactivity of AP is influenced by its processing conditions especially the extraction solvent. OBJECTIVE: In the present study, bioassay-guided screening technique was employed to identify the best AP extract in the management of MetS, PCa, and MetS-PCa co-disease in vitro. METHODS: Five AP extracts by different solvent systems; APE1 (aqueous), APE2 (absolute methanol), APE3 (absolute ethanol), APE4 (40% methanol), and APE5 (60% ethanol) were screened through their phytochemical profile, in-vitro anti-cancer, anti-obese, and anti-hyperglycemic properties. The best extract was further tested for its potential in MetS-induced PCa progression. RESULTS: APE2 contained the highest andrographolide (1.34 ± 0.05 mg/mL) and total phenolic content (8.85 ± 0.63 GAE/gDW). However, APE3 has the highest flavonoid content (11.52 ± 0.80 RE/gDW). APE2 was also a good scavenger of DPPH radicals (EC50 = 397.0 µg/mL). In cell-based assays, among all extracts, APE2 exhibited the highest antiproliferative activity (IC50 = 57.5 ± 11.8 µg/mL) on DU145 cancer cell line as well as on its migration activity. In in-vitro anti-obese study, all extracts significantly reduced lipid formation in 3T3-L1 cells. The highest insulin-sensitizing and -mimicking actions were exerted by both APE2 and APE3. Taken together, APE2 showed collectively good activity in the inhibition of PCa progression and MetS manifestation in vitro, compared to other extracts. Therefore, APE2 was further investigated for its potential to intervene DU145 progression induced with leptin (10-100 ng/mL) and adipocyte conditioned media (CM) (10% v/v). Interestingly, APE2 significantly diminished the progression of the cancer cell that has been pre-treated with leptin and CM through cell cycle arrest at S phase and induction of cell death. CONCLUSION: In conclusion, AP extracts rich with andrographolide has the potential to be used as an alternative to ameliorate PCa progression induced by factors highly expressed in MetS.

The Role of DNA Repair in Genomic Instability of Multiple Myeloma.

Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug resistance in MM. The dysregulation of DNA repair function may provide an alternative explanation for genomic instability observed in MM cells and in cells derived from MM patients. This review provides an overview of DNA repair pathways with a special focus on their involvement in MM and discusses the role they play in MM progression and drug resistance. This review highlights how unrepaired DNA damage due to aberrant DNA repair response in MM exacerbates genomic instability and chromosomal abnormalities, enabling MM progression and drug resistance.

Mutagenicity and safety pharmacology of a standardized antidiabetic polyherbal formulation.

Synacinn is a standardized polyherbal extract formulated for the treatment of diabetes mellitus and its complications. This study aims to assess the mutagenicity potential of Synacinn by Ames assay and in vivo bone marrow micronucleus (MN) test on Sprague Dawley rat. Human ether-a-go-go-related gene (hERG) assay and Functional Observation Battery (FOB) were done for the safety pharmacology tests. In the Ames assay, Dose Range Finding (DRF) study and mutagenicity assays (+/- S9) were carried out. For the MN test, a preliminary and definitive study were conducted. In-life observations and number of immature and mature erythrocytes in the bone marrow cells were recorded. The hERG assay was conducted to determine the inhibitory effect on hERG potassium channel current expressed in human embryonic kidney cells (HEK293). FOB tests were performed orally (250, 750, and 2000 mg/kg) on Sprague Dawley rats. Synacinn is non-mutagenic against all tested strains of Salmonella typhimurium and did not induce any clastogenicity in the rat bone marrow. Synacinn also did not produce any significant inhibition (p ≤ 0.05) on hERG potassium current. Synacinn did not cause any neurobehavioural changes in rats up to 2000 mg/kg. Thus, no mutagenicity, cardiotoxicity and neurotoxicity effects of Synacinn were observed in this study.

Bardet-Biedl syndrome: a case series.

BACKGROUND: Bardet-Biedl syndrome is a rare multisystem autosomal recessive disorder that falls under the spectrum of ciliopathy disorders. It is characterized by rod-cone dystrophy, renal malformations, polydactyly, learning difficulties, central obesity, and hypogonadism. Many minor features that are related with Bardet-Biedl syndrome might aid in diagnosis and are crucial in clinical management. Bardet-Biedl syndrome is diagnosed on the basis of clinical signs and symptoms, which can be confirmed by genetic testing. Here we present four cases of Bardet-Biedl syndrome. To our knowledge, these are the first cases of Bardet-Biedl syndrome reported from Sudan. CASE PRESENTATION: Here, we report four Sudanese patients who presented with a variety of clinical manifestations of Bardet-Biedl syndrome (two males, 50 and 16 years old; two females, 38 and 18 years old). The first two patients presented with features of chronic kidney disease. The third patient had recently been diagnosed with type 1 diabetes and diabetic ketoacidosis. The fourth patient showed signs of retinal dystrophy early on. Case 1: a 38-year-old female presented with vomiting and irritability; the patient was diagnosed with Bardet-Biedl syndrome as she fulfilled six items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, renal abnormalities, learning disabilities, and genitourinary malformations), as well as one secondary feature (cardiovascular involvement, that is, left ventricular hypertrophy). Case 2: a 50-year-old male presented with fatigability; the patient was diagnosed with Bardet-Biedl syndrome as he fulfilled four items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, and renal abnormalities) in addition to two secondary features (diabetes mellitus and cardiovascular involvement, that is, left ventricular hypertrophy). Case 3: an 18-year-old female presented with polyuria, polydipsia, weight loss, and epigastric pain for 2 days; the patient was diagnosed with Bardet-Biedl syndrome because he had four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) in addition to three secondary features (developmental delay, diabetes mellitus, and strabismus). Case 4: a 16-year-old male presented with a blurring of vision; the patient was diagnosed with Bardet-Biedl syndrome as he exhibited four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) plus two secondary features (developmental delay and cataract). CONCLUSION: The scarcity of Bardet-Biedl syndrome necessitates a high index of suspicion to diagnose this syndrome. Increased awareness among physicians is required for the early diagnosis and treatment of Bardet-Biedl syndrome and to avoid complications and mortality.

Investigation of a foodborne outbreak at a mass gathering in Petaling District, Selangor, Malaysia.

Objective: On 6 October 2019, Petaling District Health Office received notification of a possible foodborne outbreak involving a mass gathering event. This report presents the processes of diagnosis verification, case identification, determination of associated risk factors and commencement of control measures in managing the outbreak. Methods: Cases were defined as those who attended the mass gathering event on 6 October 2019, consumed the pre-packaged food and subsequently developed vomiting, abdominal pain, diarrhoea or other symptoms (e.g. fever, nausea and dizziness). Epidemiological, environmental and laboratory investigations were performed. Data were analysed using SPSS software (version 24.0). Results: A total of 169 cases were identified. The attack rate was 7.2%, and cases ranged in age from 7 to 50 years, with a median of 20 years. A total of 156 (92.3%) cases had vomiting, 137 (81.1%) had abdominal pain and 83 (49.1%) had diarrhoea. Consuming nasi lemak at the mass gathering was found to be significantly associated with developing illness (odds ratio: 9.90, 95% confidence interval: 6.46-15.16). The samples from suspected food, food handlers and the environment were positive for Bacillus cereus, Staphylococcus aureus or coliforms. Discussion: The outbreak at this mass gathering was probably caused by food contaminated with B. cereus and S. aureus. To prevent future outbreaks, we recommend mass gathering events use certified catering services that have adequate food safety training.

Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents.

Solid tumours are often poorly oxygenated, which confers resistance to standard treatment modalities. Targeting hypoxic tumours requires compounds, such as nitroimidazoles (NIs), equipped with the ability to reach and become activated within diffusion limited tumour niches. NIs become selectively entrapped in hypoxic cells through bioreductive activation, and have shown promise as hypoxia directed therapeutics. However, little is known about their mechanism of action, hindering the broader clinical usage of NIs. Iodoazomycin arabinofuranoside (IAZA) and fluoroazomycin arabinofuranoside (FAZA) are clinically validated 2-NI hypoxic radiotracers with excellent tumour uptake properties. Hypoxic cancer cells have also shown preferential susceptibility to IAZA and FAZA treatment, making them ideal candidates for an in-depth study in a therapeutic setting. Using a head and neck cancer model, we show that hypoxic cells display higher sensitivity to IAZA and FAZA, where the drugs alter cell morphology, compromise DNA replication, slow down cell cycle progression and induce replication stress, ultimately leading to cytostasis. Effects of IAZA and FAZA on target cellular macromolecules (DNA, proteins and glutathione) were characterized to uncover potential mechanism(s) of action. Covalent binding of these NIs was only observed to cellular proteins, but not to DNA, under hypoxia. While protein levels remained unaffected, catalytic activities of NI target proteins, such as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the detoxification enzyme glutathione S-transferase (GST) were significantly curtailed in response to drug treatment under hypoxia. Intraperitoneal administration of IAZA was well-tolerated in mice and produced early (but transient) growth inhibition of subcutaneous mouse tumours.