Multiple skull base defects in the setting of spontaneous cerebrospinal fluid rhinorrhea; a dual institution view.

PURPOSE: Idiopathic intracranial hypertension (IIH) is a condition of high cerebrospinal fluid (CSF) pressure that presents with CSF leak. The implications of multiple skull base defects (SBD) and associated synchronous CSF leaks have not been previously explored. MATERIALS AND METHODS: A dual institutional case-control study examined multiple SBD's and encephaloceles on the risk of CSF leak and postoperative failures post-repair. IIH patients with CSF leaks and IIH controls without leaks were selected retrospectively. Chi square analysis evaluated for statistically significant alterations in probability with CSF leak development. RESULTS: 192 patients were selected with 108 IIH controls and 84 spontaneous CSF leak cases. Signs and symptoms for IIH controls and CSF leak cases respectively were pulsatile tinnitus (60.2 % and 29.8 %), headaches (96.3 % and 63.1 %), papilledema (74.1 % and 12.5 %), visual field defects (60.8 % and 13 %) (p < 0.001). Encephalocele formation in controls was 3.7 % compared to cases at 91.6 % (p < 0.001). Multiple SBD's in controls compared cases was 0.9 % and 46.4 % respectively (p < 0.001). Subgroup analysis of CSF leak cases showed 15 patients with two CSF leak repairs due to a recurrence. 27 (39.1 %) single leak cases had multiple SDB's while 12 (80 %) recurrent leaks had multiple SDB's (p = 0.004). CONCLUSIONS: Patients with radiographic evidence of multiple SBD's and encephaloceles represent a high-risk population with a propensity for CSF leaks. Secondary SBD's are common in patients with spontaneous CSF rhinorrhea and higher in patients with a recurrence.

Linezolid toxic optic neuropathy: A case report and review of visual prognosis.

Purpose: To describe a case of linezolid toxic optic neuropathy in a 71-year-old female and review the relevant literature. Observations: An adult female with progressive, symmetric vision loss was hypothesized to have linezolid toxic optic neuropathy. Following cessation of linezolid, the patient experienced improvement in visual function over two months. Conclusions and importance: Patients diagnosed with linezolid toxic optic neuropathy can expect some return of visual function after cessation. The degree of return does not correlate to the cumulative dose of the drug. The goal of this study was to summarize and add to the current body of literature on the topic.

Fabrication of a Simple and Efficient HPLC Reduction Column for Online Conversion of Aristolochic Acids to Aristolactams Prior to Sensitive Fluorescence Detection.

Aristolochic acids (AAs) are nephrotoxic and carcinogenic nitrophenanthrene carboxylic acids produced naturally by plants from the Aristolochia and Asarum genera, which have been used extensively as herbal medicines. In addition to consuming AA-containing herbal medicinal products, there is emerging evidence that humans are also exposed to AA through the environment. In 2022, the World Health Organization (WHO) called for global action to remove AA exposure sources and to implement preventative measures against the development of AA-associated cancers. Herein, we report the development of a simple and efficient iron powder-packed reduction column that allows online post-column conversion of the nonfluorescing AA to its corresponding strongly fluorescing aristolactam (AL), facilitating the sensitive and selective detection of AA in herbal medicinal products, food grain, arable soil, or groundwater samples by high-performance liquid chromatography with fluorescence detection. Moreover, AL, a group of naturally occurring derivatives of AA that have demonstrated toxicity to cultured bacteria, human cells, and rats, is monitored and quantified simultaneously with AA in one single run without sacrificing sensitivity. In comparison with existing analytical methods for AA measurement, the newly developed method is not only inexpensive and less laborious, but it also offers improved sensitivity. We believe this novel method will find wide application in identifying the presence of AA in food, herbal medicines, and environmental samples, thus assisting in the identification and removal of AA exposure sources.

Cadmium dietary exposure assessment in the adult population and pre-school children in the Republic of Serbia.

Cadmium (Cd) is a toxic metal, present in all matrices of the environment and a common food contaminant. Human exposure to it may elicit many diverse health impairments. The aim of this study was to assess the dietary exposure to Cd for the adult population and preschool children in Serbia using probabilistic methodology. We measured Cd in 11,227 food samples belonging to 50 food items on the Serbian market. Cd was detected in 90% of the tested food items, and in 30.8% of the overall tested samples. The food item that contributed the most to total dietary Cd intake was potatoes (median Cd concentration of 7 ng/g) in adults, and fruit and vegetable juices in children (median Cd concentration of 19 ng/g). Weekly Cd intake shown as 50th and 95th percentiles were 2.54 and 4.74 µg/kg bw in the adult population, and 3.29 and 4.93 µg/kg bw in children. The results of this study are rather preliminary and should be considered as an indication of the need for further, more refined research, which would contribute to a more realistic risk assessment as a high-priority approach, especially in the case of vulnerable subpopulations such as children. Abbreviations: AT SDR: Agency for Toxic Substances and Disease Registry; EEA: European Environment Agency; EFSA: European Food Safety Authority; FAO/WHO: Food and Agriculture Organization/World Health Organization; HI: hazard index; IARC: International Agency for Research on Cancer; JECFA: Joint FAO/WHO Expert Committee on Food Additives; LOD: limit of detection; Cd: cadmium; TWI: tolerable weekly intake; UNEP: United Nations Environment Program; WI: weekly intake.

Acrylamide and Potential Risk of Diabetes Mellitus: Effects on Human Population, Glucose Metabolism and Beta-Cell Toxicity.

Diabetes mellitus is a frequent endocrine disorder characterized by hyperglycemia. Acrylamide (AA) is food contaminant formed during the high-temperature processing of food rich in carbohydrates and low in proteins. Recent human epidemiological studies have shown a potential association between AA exposure and the prevalence of diabetes in the general population. In male rats, AA treatment promoted pancreatic islet remodeling, which was determined by alpha-cell expansion and beta-cell reduction, while in female rats AA caused hyperglycemia and histopathological changes in pancreatic islets. In vitro and in vivo rodent model systems have revealed that AA induces oxidative stress in beta cells and that AA impairs glucose metabolism and the insulin signaling pathway. Animal studies have shown that diabetic rodents are more sensitive to acrylamide and that AA aggravates the diabetic state. In this review, we provide an overview of human epidemiological studies that examined the relation between AA exposure and glucose disorders. In addition, the effects of AA treatment on pancreatic islet structure, beta-cell function and glucose metabolism in animal models are comprehensively analyzed with an emphasis on sex-related responses. Furthermore, oxidative stress as a putative mechanism of AA-induced toxicity in beta cells is explored. Finally, we discuss the effects of AA on diabetics in a rodent model system.

New neryl esters from Helichrysum italicum (Roth) G. Don (Asteraceae) essential oil.

Helichrysum italicum (immortelle) is a dwarf aromatic shrub native to the Mediterranean region. The typical subspecies (italicum) produces an essential oil rich in neryl acetate and characteristic ß-diketones, italidiones, highly valued in the perfume industry. As esters are an important group of aroma-active volatiles, herein the composition of the ester fraction of this immortelle chemotype essential oil was studied in detail. Chromatographic separation of Corsican immortelle essential oil enabled the discovery of numerous potentially olfactory-interesting esters of nerol and/or angelic acid, undetectable by direct GC-MS analyses of the unfractioned oil. Four esters of nerol and medium-chain branched fatty acids represent new natural products, while several other esters have a rather restricted occurrence in the Plant Kingdom.

Linking the antimicrobial and anti-inflammatory effects of immortelle essential oil with its chemical composition - The interplay between the major and minor constituents.

Immortelle (Helichrysum italicum, Asteraceae) essential oil has been widely used in alternative medicine to accelerate wound healing, as well as in cosmetic products to stimulate skin regeneration and to reduce the appearance of wrinkles. It is also considered a natural and safe culinary spice that could also be applied in the food industry as a preservative in the future. The therapeutic efficacy of this oil changes with the natural variability of the composition. Herein we tested and mutually compared the antimicrobial and anti-inflammatory activities of four commercial immortelle oils differing in the relative amounts of marker compounds, i.e. neryl esters, α-pinene, γ- and ar-curcumenes, and ß-diketones. The anti-inflammatory effect of selected chromatographic fractions, enriched in the aforementioned constituents, was evaluated by studying toxicity toward rat peritoneal macrophages, their nitric oxide production, myeloperoxidase, and arginase activities. Subsequently, the compositional and activity data were subjected to a multivariate statistical treatment to reveal the possible correlation(s) between the percentage of essential-oil constituents and the observed activities. The obtained results imply that immortelle oil efficiency as an antimicrobial and/or anti-inflammatory agent is most plausibly a result of a synergistic action between its constituents, and/or, rather unexpectedly, the presence of some minor constituents.

Occupational Exposure to Formaldehyde and Cancer Risk Assessment in an Anatomy Laboratory.

Dissecting a human cadaver is an irreplaceable practice in general training of medical students. Cadavers in anatomy laboratories are usually preserved in formalin, an embalming fluid whose basic component is formaldehyde (FA). The aim of this study is to assess the cancer risk of employees and students that are exposed to FA based on the results of three monitoring campaigns, as well as to suggest permanent solutions to the problem of FA exposure based on the results obtained. Three sampling campaigns of formaldehyde concentration in indoor environments were conducted at five different locations at the Anatomy Department of the Faculty of Medicine with the purpose of assessing permanent employees' and medical faculty first year students' exposure to FA. Indoor air was continuously sampled during 8 h of laboratory work and analyzed in accordance with the NIOSH Method 3500. Exceeding of the 8 h time-weighted average (8 h TWA) values recommended by Occupational Safety and Health Administration (OSHA) of 0.75 ppm was recorded in 37% of the samples during the three-month monitoring campaign. Cancer risk assessment levels for permanent employees were in the range from 6.43 × 10-3 to 8.77 × 10-4, while the cancer risk assessment levels for students ranged from 8.94 × 10-7 to 1.83 × 10-6. The results of the research show that cancer risk assessment for employees is several thousand times higher than the limit recommended by the EPA (10-6) and point to the importance of reducing exposure to formaldehyde through the reconstruction of the existing ventilation system, continual monitoring, the use of formaldehyde-free products, and plastination of anatomical specimens.

Very-Long-Chain Wax Constituents from Primula veris and P. acaulis: Does the Paradigm of Non-Branched vs. Branched Chain Dominance Universally Hold in all Plant Taxa?

Herein n-, iso- and anteiso-series of very-long-chained (VLC) alkanes (C21 -C35 ), fatty acid benzyl esters (FABEs; C20 -C32 ), and 2-alkanones (C23 -C35 ) were identified in the wax of Primula veris L. and P. acaulis (L.) L. (Primulaceae). For the very first time in a sample of natural origin, the presence of iso- and anteiso-VLC FABEs and 2-alkanones was unequivocally confirmed by synthetic work, derivatization, and NMR. It should be noted that the studied species produced unusually high amounts of branched wax constituents (e. g., >50 % of 2-alkanones were branched isomers). The domination of iso-isomers, probably biosynthesized from leucine-derived starters, is a unique feature in the Plant Kingdom. The plant organ distribution of these VLC compounds in P. acaulis samples (different habitats and phenological phases) pointed to their possible ecological value. This was supported by a eutectic behavior of binary blends of FABEs and alkanes, as well as by high UV-C absorption by FABEs.

Long-chain syn-1-phenylalkane-1,3-diyl diacetates, related phenylalkane derivatives, and sec-alcohols, all possessing dominantly iso-branched chain termini, and 2/3-methyl-branched fatty acids from Primula veris L. (Primulaceae) wax.

Herein, the results of the first study of non-flavonoid constituents of aboveground surface-wax washings of Primula veris L. (Primulaceae) are presented. Chromatography of the washings yielded a minor fraction composed of n-, iso-, and anteiso-series of long-chained syn-1-phenylalkane-1,3-diyl diacetates, 3-oxo-1-phenylalkan-1-yl acetates, 1-phenylalkane-1,3-diones, 1-hydroxy-1-phenylalkan-3-ones, sec-alcohols (2- to 10-alkanols), and n-, iso-, anteiso-, 2-methylalkanoic and 3-methylalkanoic acids; 118 of these constituents represent up to now unreported natural compounds. The structural/stereochemical elucidation was accomplished by the synthesis of authentic standards, derivatization reactions, the use of gas chromatographic retention data and detailed 1D and 2D-NMR analyses of the obtained complex chromatographic fraction. Primula veris produces unusually high amounts of branched long-chained metabolites (>60%) except for the fatty acids where the percentage of branched isomers is comparable to the ones with n-chains. Noteworthy is the fact that long-chained α- and ß-methyl substituted fatty acids were detected herein for the first time in the kingdom Plantae.

Subchronic exposure to acrylamide leads to pancreatic islet remodeling determined by alpha cell expansion and beta cell mass reduction in adult rats.

Acrylamide (AA) is a toxic substance, used to synthesize polymers for industrial and laboratory processes. Also, AA is a food contaminant formed during the high temperature preparation of carbohydrate-rich food. The main subject of this study was to examine effects of subchronic AA treatment on the islets of Langerhans of adult rats. Adult male Wistar rats were orally treated with 25 or 50 mg/kg bw of AA for 3 weeks. Qualitative and quantitative immunohistochemical evaluation of glucagon and insulin expression and stereological analyses of pancreatic alpha and beta cells were performed. Serum insulin and glucose levels were measured. Analysis of glucagon-immunostained sections revealed a dose-dependent increase of intensity of glucagon immunopositive signal, alpha cell surface and numerical densities, volume density of alpha cell nuclei and nucleocytoplasmic ratio in AA-treated groups compared to the control. In insulin-immunolabeled pancreatic sections in AA-treated animals was observed decrease of intensity of insulin immunopositive signal, beta cell surface, numerical and volume densities and volume density of beta cell cytoplasm. Serum insulin and glucose concentrations remained unchanged after both AA treatments. The number of islets of Langerhans was not affected by AA treatment. Our results suggest that AA subchronic treatment of adult rats leads to remodeling of islet of Langerhans characterized by alpha cell expansion and beta cell mass reduction.

Effects of acrylamide on oxidant/antioxidant parameters and CYP2E1 expression in rat pancreatic endocrine cells.

Oxidative stress is one of the principle mechanism of acrylamide-induced toxicity. Acrylamide is metabolized by cytochrome P450 2E1 (CYP2E1) to glycidamide or by direct conjugation with glutathione. Bearing in mind that up to now the effects of acrylamide on oxidative stress status and CYP2E1 level in endocrine pancreas have not been studied we performed qualitative and quantitative immunohistochemical evaluation of inducible nitric oxide synthase (iNOS), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), catalase (CAT) and CYP2E1 expression in islets of Langerhans of rats subchronically treated with 25 or 50mg/kg bw of acrylamide. Since the majority of cells (>80%) in rodent islets are beta cells, in parallel studies, we employed the Rin-5F beta cell line to examine effects of acrylamide on redox status and the activity of CAT, SOD and glutathione-S-transferase (GST), their gene expression, and CYP2E1, NF-E2 p45-related factor 2 (Nrf2) and iNOS expression. Immunohistochemically stained pancreatic sections revealed that acrylamide induced increase of iNOS and decrease of CYP2E1 protein expression, while expression of antioxidant enzymes was not significantly affected by acrylamide in islets of Langerhans. Analysis of Mallory-Azan stained pancreatic sections revealed increased diameter of blood vessels lumen in pancreatic islets of acrylamide-treated rats. Increase in the GST activity, lipid peroxidation and nitrite level, and decrease in GSH content, CAT and SOD activities was observed in acrylamide-exposed Rin-5F cells. Level of mRNA was increased for iNOS, SOD1 and SOD2, and decreased for GSTP1, Nrf2 and CYP2E1 in acrylamide-treated Rin-5F cells. This is the first report of the effects of acrylamide on oxidant/antioxidant parameters and CYP2E1 expression in pancreatic endocrine cells.

Meat industry wastewater: microbiological quality and antimicrobial susceptibility of E. coli and Salmonella sp. isolates, case study in Vojvodina, Serbia.

Wastewater from meat processing industries is a fusion of compounds with a high load of organic matter, and pathogen microorganisms like Escherichia coli, and Salmonella sp. The aim of this research was to determine microbiological characteristics of the wastewater discharged from the meat processing industry in order to get a more detailed insight into meat industry wastewater pollution, and to evaluate the resistance of bacterial strains E. coli and Salmonella sp. to antibiotics. The evaluation of the antimicrobial susceptibility was performed on 37 strains of E. coli and eight strains of Salmonella sp. to nine different antibiotics. The number of faecal pollution indicators was very high in all samples. From a total of 37 strains of E. coli, a moderate degree of resistance was shown to tetracycline (37.83%); a low degree of resistance to ampicillin (21.62%), streptomycin (24.32%), trimethoprim-sulfamethoxazol (18.92%) and nalidixic acid (16.22%); and very low to: chloramphenicol (13.51%), ciprofloxacin (2.7%), gentamicin and cefotaxime (0.0%). The results for eight strains of Salmonella sp. show that all eight isolates had some degree of susceptibility to nine tested antimicrobial agents and six strains were fully susceptible to all tested antibiotics.

The rs2030324 SNP of brain-derived neurotrophic factor (BDNF) is associated with visual cognitive processing in multiple sclerosis.

PURPOSE: To investigate the associations between the rs2030324 SNP of brain-derived neurotrophic factor (BDNF) and neuropsychological (NP) test measures in multiple sclerosis (MS) patients. BACKGROUND: BDNF regulates the survival of neuronal and non-neuronal cells and plays a critical role in neurochemical processes underlying learning and memory. METHODS: A total of 209 MS patients (161 females; 48 males) underwent brain MRI and genotyping for BDNF rs2030324. The NP testing (n=108) assessed processing speed, working memory, new learning and executive control. The MRI measurements included T1 and T2 lesion volume, whole brain, white and gray matter volumes, magnetization transfer imaging and regional subcortical brain volumes. RESULTS: The T/T rs2030324 genotype group performed poorly on the Brief Visuospatial Memory Test-Revised (p=0.031) and the Symbol Digit Modalities Test (p=0.045) compared to the C/C genotype group. Because these NP tests both involve visual processing, the relationship with the volume of the thalamus was assessed. The BDNF rs2030324 genotype was associated with the volume of the left thalamus (p=0.036). There were no significant associations with whole brain lesional and atrophy MRI measures. CONCLUSIONS: The C allele of BDNF rs2030324 is associated with protection against visual cognitive processing deficits via mechanisms that appear associated with the volume of the thalamus.

Glatiramer acetate recovers microscopic tissue damage in patients with multiple sclerosis. A case-control diffusion imaging study.

Traditional magnetic resonance imaging (MRI) techniques have contributed to the management of multiple sclerosis (MS) but are limited in their ability to detect neuronal damage. Advanced MRI metrics provide assessment of microscopic neuronal changes; however, few studies have examined the effects of MS therapies on these measures. This prospective, open-label, observational study evaluated the effect of subcutaneous glatiramer acetate (GA) 20mg/day on the 1- and 2-year changes in diffusion-weighted imaging (DWI) measures in patients with relapsing-remitting (RR) MS and in age- and sex-matched healthy controls (HC). Inclusion criteria were age 18-65, RR disease course, expanded disability status scale (EDSS) score ≤5.5 and disease duration<20 years. MS patients and HC underwent 1.5T MRI scans and clinical examinations at baseline and at 1- and 2-year follow-up. Nineteen RRMS patients and 16 HC completed the 1-year follow-up and 16 MS patients and 13 HC the 2-year follow-up of the study. In MS patients, treatment with GA promoted recovery of DWI mean parenchymal diffusivity (MPD) at year 1 (-7.1%, p=0.007) and at year 2 (-10.1%, p=0.028). The recovery of DWI MPD was significantly higher in MS patients compared to HC at year 1 (p=0.01) and year 2 (p<0.001). GA promoted recovery of DWI entropy at 2 years (-1.2%, p=0.018). No significant DWI MPD and entropy changes were observed in HC over the follow-up. No significant deterioration in magnetization transfer ratio occurred over the follow-up in MS patients and HC. Patients on GA and HC did not develop significant global or regional atrophy over 2 years. GA significantly improved microscopic tissue damage in the brain, as measured by DWI over the 1- and 2-year follow-up.

The role of postpartum intravenous corticosteroids in the prevention of relapses in multiple sclerosis.

Multiple sclerosis (MS) is most prevalent in women of childbearing age. It is well established that the relapse rate decreases during pregnancy but increases significantly during the first postpartum trimester. The objective of this retrospective study was to evaluate the effectiveness of the administration of 1 g of intravenous methylprednisolone (IVMP) after delivery in the prevention of MS relapses. The study involved 47 women with one or more documented pregnancies; each pregnancy was treated as a separate case. There were 50 cases with relapsing-remitting MS and 2 with secondary progressive MS. The cases were divided into two groups: the IVMP group (those who received 1 g of IVMP after delivery) and the no-IVMP group (those who did not receive IVMP after delivery). There were 39 cases in the IVMP group and 13 in the no-IVMP group. During the first postpartum trimester, relapses occurred in 17.9% of the IVMP group, compared with 46.2% of the no-IVMP group (P = .0448). The difference in relapse percentage between the two groups during the second and third postpartum trimesters was not statistically significant. Our study shows a statistically significant benefit of postpartum IVMP administration in reducing MS relapses.

Functional brain network changes associated with maintenance of cognitive function in multiple sclerosis.

In multiple sclerosis (MS) functional changes in connectivity due to cortical reorganization could lead to cognitive impairment (CI), or reflect a re-adjustment to reduce the clinical effects of widespread tissue damage. Such alterations in connectivity could result in changes in neural activation as assayed by executive function tasks. We examined cognitive function in MS patients with mild to moderate CI and age-matched controls. We evaluated brain activity using functional magnetic resonance imaging (fMRI) during the successful performance of the Wisconsin card sorting (WCS) task by MS patients, showing compensatory maintenance of normal function, as measured by response latency and error rate. To assess changes in functional connectivity throughout the brain, we performed a global functional brain network analysis by computing voxel-by-voxel correlations on the fMRI time series data and carrying out a hierarchical cluster analysis. We found that during the WCS task there is a significant reduction in the number of smaller size brain functional networks, and a change in the brain areas representing the nodes of these networks in MS patients compared to age-matched controls. There is also a concomitant increase in the strength of functional connections between brain loci separated at intermediate-scale distances in these patients. These functional alterations might reflect compensatory neuroplastic reorganization underlying maintenance of relatively normal cognitive function in the face of white matter lesions and cortical atrophy produced by MS.

MRI characteristics of patients with antiphospholipid syndrome and multiple sclerosis.

MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (-) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA- MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA- patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.