Decoding Complexity in Synthetic Oligonucleotides: Unraveling Coeluting Isobaric Impurity Ions by High Resolution Mass Spectrometry.

Analyzing coeluting impurities with similar masses in synthetic oligonucleotides by liquid chromatography-mass spectrometry (LC-MS) poses challenges due to inadequate separation in either dimension. Herein, we present a direct method employing fully resolved isotopic envelopes, enabled by high resolution mass spectrometry (HRMS), to identify and quantify isobaric impurity ions resulting from the deletion or addition of a uracil (U) or cytosine (C) nucleotide from or to the full-length sequence. These impurities may each encompass multiple sequence variants arising from various deletion or addition sites. The method utilizes a full or targeted MS analysis to measure accurate isotopic distributions that are chemical formula dependent but nucleotide sequence independent. This characteristic enables the quantification of isobaric impurity ions involving sequence variants, a capability typically unavailable in sequence-dependent MS/MS methods. Notably, this approach does not rely on standard curves to determine isobaric impurity compositions in test samples; instead, it utilizes the individual isotopic distributions measured for each impurity standard. Moreover, in cases where specific impurity standards are unavailable, the measured isotopic distributions can be adequately replaced with the theoretical distributions (calculated based on chemical formulas of standards) adjusted using experiment-specific correction factors. In summary, this streamlined approach overcomes the limitations of LC-MS analysis for coeluting isobaric impurity ions, offering a promising solution for the in-depth profiling of complex impurity mixtures in synthetic oligonucleotide therapeutics.

Tandem mass spectrometric sequence characterization of synthetic thymidine-rich oligonucleotides.

Tandem mass spectrometry (MS/MS) can provide direct and accurate sequence characterization of synthetic oligonucleotide drugs, including modified oligonucleotides. Multiple factors can affect oligonucleotide MS/MS sequencing, including the intrinsic properties of oligonucleotides (i.e., nucleotide composition and structural modifications) and instrument parameters associated with the ion activation for fragmentation. In this study, MS/MS sequencing of a thymidine (T)-rich and phosphorothioate (PS)-modified DNA oligonucleotide was investigated using two fragmentation techniques: trap-type collision-induced dissociation ("CID") and beam-type CID also termed as higher-energy collisional dissociation ("HCD"), preceded by a hydrophilic interaction liquid chromatography (HILIC) separation. A low to moderate charge state (-4), which predominated under the optimized HILIC-MS conditions, was selected as the precursor ion for MS/MS analysis. Comparison of the two distinctive ion activation mechanisms on the same precursor demonstrated that HCD was superior to CID in promoting higher sequence coverage and analytical sensitivity in sequence elucidation of T-rich DNA oligonucleotides. Specifically, HCD provided more sequence-defining fragments with higher fragment intensities than CID. Furthermore, the direct comparison between unmodified and PS-modified DNA oligonucleotides demonstrated a loss of MS/MS fragmentation efficiency by PS modification in both CID and HCD approaches, and a resultant reduction in sequence coverage. The deficiency in PS DNA sequence coverage observed with single collision energy HCD, however, was partially recovered by applying HCD with multiple collision energies. Collectively, this work demonstrated that HCD is advantageous to MS/MS sequencing of T-rich PS-modified DNA oligonucleotides.

The effect of tamoxifen on the lipid profile in women: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: The effect of tamoxifen administration on serum lipids in females remains unclear. The studies which have explored this topic have produced conflicting results, probably due to discrepancies in the length of the intervention, differences in baseline variables or other factors. To answer this research question, we decided to conduct this systematic review and meta-analysis to assess the effects of tamoxifen on the lipid profile in women. METHODS: A comprehensive search was conducted in Web of Science, Scopus, PubMed/Medline and Embase, from the inception of these databases up to June 2021. We used a random effects meta-analysis to generate the combined results. RESULTS: The overall findings were generated from 18 eligible trials. As compared to placebo, tamoxifen led to a notable reduction of the total cholesterol (TC) (WMD: -23.03 mg/dL, 95% CI: -25.94 to -20.12, P˂0.001), and the low-density lipoprotein-cholesterol (LDL-C) (WMD: -18.68 mg/dL, 95% CI: -24.31 to -13.04, P˂0.001). However, tamoxifen did not alter triglycerides (TG) concentrations (WMD: +1.06 mg/dL, 95% CI: -11.08 to 13.20, P = 0.864) significantly. A pronounced reduction of the high-density lipoprotein-cholesterol (HDLC) was noted in the RCTs with a duration of ≤52 weeks (WMD: -2.06 mg/dL) and when tamoxifen was administered in participants with a BMI ≥25 kg/m2 (WMD: -1.42 mg/dL). Notable reductions in TC (WMD: -23.57 mg/dL) and LDL-C (WMD: -19.21 mg/dL) was detected when the dose of tamoxifen was ≥20 mg/day. Moreover, a significant reduction of TC (WMD: -20.23 mg/dL) and LDL-C (WMD: -24.13 mg/dL) was observed in the RCTs with a duration of ≤52 weeks. CONCLUSION: Tamoxifen can alter the lipid profile in females, particularly by decreasing TC, LDL-C and HDLC. Tamoxifen can further reduce TC and LDL-C if the dose of administration is ≥20 mg/day, the treatment duration is ≤52 weeks and if it prescribed in subjects with dyslipidemia.

Evaluation of Marjoram Leaves (Oregano vulgar) as Feed Supplement on Quality of Semen in Awasian Pollination Rams.

This study aimed to evaluate the effect of Marjoram leaves (Oregano vulgar) as a feed supplement on sexual efficiency and semen quality in Awasian pollination rams. The study was conducted on ten rams in one of the private fields in the Babylon governorate. The rams were divided randomly into two groups. First group rams are regarded as a control group (group A) that feeds on exceptional concentric food for pollination rams. The second group consists of 5 rams (group B) provided with the same concentric food plus a supplement of 3 mg/kg of body weight of Oregano vulgar leaves (fresh) 3 times daily for 49 days before the pollination season (April and May). Semen samples were collected at the end of 49 days by artificial vagina to evaluate the volume of ejaculate, sperm number, concentration, motility, viability, and deformities, and to measure the sperm pleomorphic parameters of the head, nucleus, and acrosome. The antioxidant status of seminal plasma was evaluated by measuring superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant capacity (TAC). ELISA tests were used on blood serum samples to measure the hormone levels of luteinizing hormone (LH), testosterone, and estrogen. The study demonstrated a significant increase in motility, the viability of sperm, and decreasing deformities. There was no significant variation in perimorphic parameters of the head, nucleus, and acrosome sperm after using the fresh leaves of Oregano vulgar as supplementation to Awasion sheep. However, there was an increase in the antioxidant enzymes (SOD, GPX, and TAC) in seminal plasma and an increase in LH, testosterone, and estrogen in the blood serum of experimental group B. These findings show that using fresh leaves of Oregano vulgar improved the sexual efficiency of pollinated rams and maintained the physiology and perimorphic parameters of semen and sperm.

UV and Visible Light-Driven Production of Hydroxyl Radicals by Reduced Forms of N, F, and P Codoped Titanium Dioxide.

The photocatalytic activities of reduced titanium dioxide (TiO2) materials have been investigated by measuring their ability to produce hydroxyl radicals under UV and visible light irradiation. Degussa P25 TiO2 was doped with nitrogen (N), fluorine (F), and/or phosphorus (P) and then subjected to surface modification employing a thermo-physicochemical process in the presence of reducing agent sodium borohydride (NaBH4). The reduced TiO2 materials were characterized by a number of X-ray, spectroscopic and imaging methods. Surface doping of TiO2 was employed to modulate the band gap energies into the visible wavelength region for better overlap with the solar spectrum. Hydroxyl radical generation, central to TiO2 photocatalytic water purification applications, was quantitated using coumarin as a trap under UV and visible light irradiation of the reduced TiO2 materials. At 350 nm irradiation, the yield of hydroxyl radicals generated by the reduced forms of TiO2 was nearly 90% of hydroxyl radicals generated by the Degussa P25 TiO2. Hydroxyl radical generation by these reduced forms of TiO2 was also observed under visible light irradiation (419 and 450 nm). These results demonstrated that simple surface modification of doped TiO2 can lead to visible light activity, which is important for more economical solar-driven applications of TiO2 photocatalysis.

An efficient eco advanced oxidation process for phenol mineralization using a 2D/3D nanocomposite photocatalyst and visible light irradiations.

Nanocomposites (CNTi) with different mass ratios of carbon nitride (C3N4) and TiO2 nanoparticles were prepared hydrothermally. Different characterization techniques were used including X-ray diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS), transmission electron spectroscopy (TEM) and Brunauer-Emmett-Teller (BET). UV-Vis DRS demonstrated that the CNTi nanocomposites exhibited absorption in the visible light range. A sun light - simulated photoexcitation source was used to study the kinetics of phenol degradation and its intermediates in presence of the as-prepared nanocomposite photocatalysts. These results were compared with studies when TiO2 nanoparticles were used in the presence and absence of H2O2 and/or O3. The photodegradation of phenol was evaluated spectrophotometrically and using the total organic carbon (TOC) measurements. It was observed that the photocatalytic activity of the CNTi nanocomposites was significantly higher than that of TiO2 nanoparticles. Additionally, spectrophotometry and TOC analyses confirmed that degraded phenol was completely mineralized to CO2 and H2O with the use of CNTi nanocomposites, which was not the case for TiO2 where several intermediates were formed. Furthermore, when H2O2 and O3 were simultaneously present, the 0.1% g-C3N4/TiO2 nanocomposite showed the highest phenol degradation rate and the degradation percentage was greater than 91.4% within 30 min.

Cutaneous metastatic adenocarcinoma - a case report.

Cutaneous metastases from carcinoma are relatively uncommon in clinical practice but they are very important to recognize. Cutaneous metastases may herald the diagnoses, can lead to accurate diagnoses and timely treatment. A high index of suspicion is required because the clinical finding may be subtle. The patient of cutaneous metastases may present with rapidly developing nodules or tumors. Although asymptomatic in most instances, Pain and tenderness may be noted. Here we described a 38 year old male who presented with fever, anorexia, weight loss and multiple painful nodules, plaques and tumors on his scalp, face, upper trunk and proximal portion of the upper limbs. This case present with cutaneous metastatic adenocarcinoma with atypical presentation and detection of cutaneous metastasis before primary tumor detection.

Acute pancreatitis associated with acute viral hepatitis A (HAV) - a case report.

In this case report, a young woman had acute viral hepatitis (HAV) and acute pancreatitis together. She was admitted to our hospital with fever, jaundice and abdominal pain. Hepatic and pancreatic enzymes were elevated. Her serum alanine aminotransferase (ALT) level was high. An initial abdominal ultrasound was per-formed at hospital and revealed features of acute viral hepatitis. Spiral computed imaging revealed imaging features of an acute stage of pancreatitis and gallbladder wall thickness. HAV infection was diagnosed by the detection of immunoglobulin M (IgM) against HAV in the serum. She was closely monitored and treated conservatively. On 10th day of hospital admission she was discharge after an uneventful recovery. In the current literature HAV infections have rarely been reported as a cause of acute pancreatitis.

Budd-Chiari syndrome.

A 16 years old boy hailing from Comilla presented with sudden onset of upper abdominal pain, ascites and generalized muscle wasting for 3 months. Ultrasonogram (USG), Color Doppler and Venography was done and diagnosed him a case of Budd-Chiari syndrome. The patient was treated with salt and water restriction, diuretics, repeated palliative ascetic fluid aspiration with re-accumulation within 1-2 days. He was also given Low molecular weight Heparin for 7 days, overlapped and followed by warfarin 10mg/day with target INR 2.5-3.5. Consultation with hepatobiliary surgeon was done for shunt operation, but operation was not possible due to poor general condition. This patient improved satisfactorily with low molecular weight heparin, warfarin and supportive measures. Budd-Chiari syndrome is a rare veno-occlusive disorder involving hepatic vasculature.

Juvenile onset ankylosing spondylitis with ankylosing tarsitis: a rare combination.

Ankylosing spondylitis is the most common whereas ankylosing tarsitis is the least common subgroup of juvenile onset spondyloarthritides. In our recent study a male presented with ankle joint pain and swelling with limited movements and characteristic radiological changes including; periarticular swelling, thickened heel pad, hyperostosis and reduced ankle, calcaneo-cuboid and talo-navicular joint space for ankylosing tarsitis. He also had persistent inflammatory low back pain with radiological sacroilitis satisfying the clinical features for ankylosing spondylitis. The patient was treated with different anti-inflammatory agents including intra-articular methyl-prednisolone with short-term relief. Associated back pain was improved with spine mobilizing exercise.

Performances of toluene removal by activated carbon derived from durian shell.

In the effort to find alternative low cost adsorbent for volatile organic vapors has prompted this research in assessing the effectiveness of activated carbon produced from durian shell in removing toluene vapors. Durian shells were impregnated with different concentrations of H3PO4 followed by carbonization at 500 °C for 20 min under nitrogen atmosphere. The prepared durian shell activated carbon (DSAC) was characterized for its physical and chemical properties. The removal efficiency of toluene by DSAC was performed using different toluene concentrations. Results showed that the highest BET surface area of the produced DSAC was 1404 m2/g. Highest removal efficiency of toluene vapors was achieved by using DSAC impregnated with 30% of acid concentration heated at 500 °C for 20 min heating duration. However, there is insignificant difference between removal efficiency of toluene by DSAC and different toluene concentrations. The toluene adsorption by DSAC was better fitted into Freundlich model.

Qualitative assessment of esophageal pH recordings.

Quantitative analysis of reflux episodes (the pH score) was used to diagnose pathologic reflux. The aim of the present study was to determine the pattern and significance of variables that may affect the pH scores. The quality of the first esophageal pH recordings were analysed and its effects on the pH scores as calculated by computer were determined. The most common abnormality 13/123 (10.6 per cent) was related to disconnection of the probe or the reference electrode from the pH meter resulting in falsely high pH scores. Abnormalities suggesting incorrect location of the probe occurred in 12/123 (9.7 per cent) resulting in falsely high or low pH scores. Finally, pH curve drift was found in 6 (4.9 per cent) of the recordings. It is concluded that the calculated pH score by computer may be misleading. Therefore, the quality of the pH recording should be determined before interpretation of pH measurement.

Pattern of gastroesophageal reflux in children.

OBJECTIVE: Gastroesophageal reflux disease is a common health problem in children worldwide. There are no published data on this disease in children from Saudi Arabia. The objective of this study is, therefore, to report on the pattern of gastroesophageal reflux disease in Saudi children. METHODS: Retrospective review of all children referred to the Pediatric Gastroenterology Division at King Khaled University Hospital in Riyadh. RESULTS: The diagnosis was confirmed in 85 children, all but 2 were Saudi nationals, and the male to female ratio was 1.6. The median age of onset of symptoms was 10 months, whereas the median age at referral was 20 months. The pattern of clinical presentation indicates that vomiting is the most common presentation occurring in 82% of the children, followed by respiratory disease in 38%. An underlying condition was found in 41% of the children, (35/85) the most common of which was neurological impairment. Peptic esophagitis was present in 51.5% of the children who underwent endoscopy. The median duration of follow up was 6 months. Good response to medical therapy was documented in 72% of normal children and 27% of those with underlying disease. All of the 23 children who had fundoplication in our institution had one or more of the underlying disorders. CONCLUSION: Gastroesophageal reflux disease is a common problem in Saudi children. The overall pattern in this report is similar to descriptions in the literature. Prospective multicenter studies are needed to confirm this pattern and to provide more focused descriptions of other aspects of the disease.

Air quality in Malaysia: impacts, management issues and future challenges.

OBJECTIVE: Observations have been made on the long-term trends of major air pollutants in Malaysia including nitrogen dioxide, carbon monoxide, the ozone and total suspended particulate matter (particularly PM10), and sulfur dioxide, emitted from industrial and urban areas from early 1970s until late 1998. METHODOLOGY: The data show that the status of atmospheric environment in Malaysia, in particular in highly industrialized areas such as Klang Valley, was determined both by local and transboundary emissions and could be described as haze and non-haze periods. RESULTS: During the non-haze periods, vehicular emissions accounted for more than 70% of the total emissions in the urban areas and have demonstrated two peaks in the diurnal variations of the aforementioned air pollutants, except ozone. The morning 'rush-hour' peak was mainly due to vehicle emissions, while the late evening peak was mainly attributed to meteorological conditions, particularly atmospheric stability and wind speed. Total suspended particulate matter was the main pollutant with its concentrations at few sites often exceeding the Recommended Malaysia Air Quality Guidelines. The levels of other pollutants were generally within the guidelines. Since 1980, six major haze episodes were officially reported in Malaysia: April 1983, August 1990, June 1991, October 1991, August to October 1994, and July to October 1997. The 1997 haze episode was the worst ever experienced by the country. Short-term observations using continuous monitoring systems during the haze episodes during these periods clearly showed that suspended particulate matter (PM10) was the main cause of haze and was transboundary in nature. Large forest fires in parts of Sumatra and Kalimantan during the haze period, clearly evident in satellite images, were identified as the probable key sources of the widespread heavy haze that extended across Southeast Asia from Indonesia to Singapore, Malaysia and Brunei. The results of several studies have also provided strong evidence that biomass burning is the dominating source of particulate matter. The severity and extent of 1997's haze pollution was unprecedented, affecting some 300 million people across the region. The amount of economic costs suffered by Southeast Asian countries during this environmental disaster was enormous and is yet to be fully determined. Among the important sectors severely affected were air and land transport, shipping, construction, tourism and agro-based industries. The economic cost of the haze-related damage to Malaysia presented in this study include short-term health costs, production losses, tourism-related losses and the cost of avertive action. Although the cost reported here is likely to be underestimated, they are nevertheless significant (roughly RM1 billion). CONCLUSIONS: The general air quality of Malaysia since 1970 has deteriorated. Studies have shown that should no effective countermeasures be introduced, the emissions of sulfur dioxide, nitrogen oxides, particulate matter, hydrocarbons and carbon monoxide in the year 2005 would increase by 1.4, 2.12, 1.47 and 2.27 times, respectively, from the 1992 levels.

Childhood obesity: referred cases to a tertiary health center in Riyadh, Saudi Arabia.

OBJECTIVE: To show the pattern of etiology of childhood obesity referred to our endocrinology clinic between December 1989 and December 1994. SUBJECT AND METHODS: All the children referred to our clinic at the above stipulated dates were studied. This is a retrospective medical records review of these patients. The patients' height and weight were measured by trained staff of the clinic. The Quetelet index also known as Body Mass Index (BMI) was calculated as weight (kg)/height (m)2 for each patient. Laboratory data as well as results of clinical investigations were also obtained from the records of the patients. RESULTS: 52 patients with ages ranging between 2 years and 16 years (median 8 years) were studied. Male:female ratio was 1:1.35 (67.3%) of the patients were Saudis while 17 (32.7%) were non-Saudis. The etiology of obesity among the series were nutritional 46 (88.5%), Prader-Willi Syndrome 3 (5.8%), Laurence-Moon-Biedl Syndrome 1 (1.9%), pseudohypoparathyroidism 1 (1.9%) and hypothyroidism 1 (1.9%). The study showed that the majority of the patients had simple nutritional obesity.

Infantile cholestasis in the Central-Eastern Province Saudi Arabia.

In the King Khalid University Hospital (Central Province) and King Fahad Hospital of the University (Eastern Province) Saudi Arabia, we identified 64 infants with cholestasis. The causes of cholestasis were idiopathic neonatal hepatitis in 29; extrahepatic biliary atresia in 17; neonatal hepatitis secondary to Rubella and Cytomegalovirus in six and four infants, respectively; paucity of intrahepatic bile ducts in six and galactosaemia in two. The diagnosis was confirmed by liver biopsy and or operative cholangiography, in all infants.

Helicobacter pylori infection in children in Saudi Arabia.

20 children with suspected Helicobacter pylori (H. pylori) infection are presented. The mean age of the children was 9.4 years (range 4-13 years). The mean H. pylori IgG and IgA antibodies were 677 units and 760.7 units respectively. Antral biopsy cultures were positive in five children. Histopathology of the gastric antral and duodenal biopsies showed H. pylori gastritis in 11 children, duodenitis and gastritis in five, normal histology in three and one child had normal histology with H. pylori like organism on the surface of the antral mucosa. From this study, we conclude that serology is a good diagnostic test for H. pylori infection in Saudi Arabia.

Comparison of Helicobacter pylori antibody levels in children in Riyadh.

Helicobacter pylori (H. pylori) antibodies were determined in 229 asymptomatic children and 43 symptomatic children in Saudi Arabia. There is a significant difference in IgG and IgA antibodies for both asymptomatic and symptomatic children (p = 0.00001). We conclude that Helicobacter pylori antibody determination by ELISA is a good screening test for diagnosis of Helicobacter pylori infection in children in Saudi Arabia.

Spectrum of Haemophilus influenzae type b disease in children at a university hospital in Riyadh, Saudi Arabia.

During a period of 5 years, 42 cases of invasive Haemophilus influenzae type b (Hib) disease were studied. An outstanding finding in our patients was occult bacteraemia, which was detected in 13 (31 per cent) patients. Other clinical conditions encountered were nine (21 per cent) patients with pneumonia, nine (21 per cent) with meningitis, six (14 per cent) with cellulitis, three (7 per cent) with arthritis, one (2 per cent) with epiglottitis, and one (2 per cent) with urinary tract infection. The mean age of children was 21 months (range 1-156 months); the majority (62 per cent) belonged to the age group 7-18 months. There were 24 females and 18 males. Eighty-one per cent of these patients were Saudi nationals. Five isolates (12 per cent) of Hib were resistant to ampicillin and similar numbers were resistant to chlorampenicol. Twenty-five children (60 per cent) were treated with ampicillin, nine (21 per cent) with chlorampenicol and eight (19 per cent) with ceftriaxone. All patients made complete recovery.

Childhood pneumococcal bacteraemia in Riyadh, Saudi Arabia.

Forty-nine children with pneumococcal bacteraemia seen during a 5-year period (1 January 1991 to 31 December 1995) at King Khalid University Hospital were studied. The majority (61.2%) were under 2 years of age. The focus of infection was pneumonia, pharyngitis or undetermined in 28.6%, 18.4% and 20.4%, respectively. Diseases that had probably predisposed them to pneumococcal bacteraemia (mainly nephrotic syndrome) were encountered in 24.5% of cases. Forty-five per cent of the cases occurred during the summer season and in 29% the disease was nosocomially acquired. No death was recorded in this series and the reasons for this are discussed. Detection of pneumococcal antigens from blood taken for culture was successful in 96% of cases; this test is important in the diagnosis of pneumococcal bacteraemia in partially treated patients. Antimicrobial susceptibility testing showed 20.4% of the isolates to be relatively penicillin-resistant. Resistance to other antimicrobial agents was also recorded and multiple resistance was noted in 22% of isolates. There was a significant difference between the ceftriaxone MIC of the relatively penicillin-resistant strains compared with penicillin-sensitive strains. The emergence and the steady increase in the numbers of relatively penicillin-resistant pneumococcal strains in Saudi Arabia during the last 10 years are discussed.