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Stress has become an integral part of modern humans’ busy lives. One of the professions in which stress is highly prevalent is that of a preschool teacher. Therefore, action research was conducted in a higher education context aimed at reducing preschool teacher stress. After one month of introducing changes that met teachers’ interests and needs and realizing their baseline values, teacher stress was reduced. Moreover, the research produced multiple benefits on both the personal and professional levels. The paper points to the need to organize a motivating pedagogical environment in higher education, which will make positive changes in students’ lives and in their professional development.

This paper aims to scope the nature-human relationship in the Anthropocene, the era which is marked by man’s presence as a factor of climate and environmental changes. It is viewed from an educational perspective, considering environmentalist and Marxist viewpoints regarding the question of man and nature. The research of The Epic of Gilgamesh and the ancient Indian epic Bhagavad-Gita underlines the substantial difference between these two perspectives, considering the appearance of man in the historical field as a distinctive aspect. In that sense, literature’s transformative strength, articulated through artistic representations, reshapes human existence, erasing cultural separation between nature and man.

Purpose: To monitor the presence of legionella bacteria in the water supply system of medical institutions in order to optimize the recommendations for the quality of water used for treatment. Materials and methods: Two cross-sectional epidemiological studies were performed to prove representatives of Legionella spp. in water samples from medical and dental equipment and water from the water supply network in medical institutions (MI) in Plovdiv. During the first period of time (March 2013 - March 2015), a total of 97 samples were taken and 24 samples during the second period (July-August 2019) in two consecutive visits. The following were examined: Faculty of Dental Medicine (FDM), Surgical Complex (SC) of the University Hospital "St. Georgi" and individual dental practices (IDP). Water samples were tested at NCIPD-Sofia. Results: In the period 2013-2015, the presence of legionella bacteria was found in 33 (34.02%) of the SC samples, in 1 out of 10 samples in IDP, and there were none detected in FDM. Non-compliances with requirements of hot water temperature, type of water used when working with devices generating a fine water aerosol have been found. Five years later, only 1 positive sample of SC was proved, in which the water supply network was rehabilitated in the interval between the two surveys. Conclusion: For the purposes of good medical and dental practice, it is necessary to conduct periodic monitoring of the "legional landscape" and the microbiological status of the water used for treatment.

Background: Brucellosis is a widespread zoonotic infection with significant health and socio-economic impacts. This determines the need of a reliable laboratory diagnosis both in endemic areas around the world and in countries where it is rare and under diagnosed. Due to prolongedand hazardous cultivation procedures, the diagnosis is mostly serologically confirmed. Aim: Serological study of Bulgarian citizens with clinical and/or epidemiological data compatible to brucellosis for the period 2005-2015. Materials and methods: Based on clinical and epidemiological data obtained via standard questionnaire 3394 persons suspected for brucellosis along with 106 controls were serologically studied with Rose Bengal slide test, Standard agglutination test, Coombs’ test, Brucellacapt and ELISA. Results: Brucellosis was confirmed in 174 patients. In outbreak related cases the tests listed above were positive in 127 (78.88%), 115 (71.43%), 34 (91.98%), 143 (95.33%) and 104 (96.30%), respectively. A statistically significant positive correlation was found between Coombs’ and Brucellacapt in the studied 55 sera samples (rs = 0,72; p < 0,0000). The profile of anti-Brucella antibodies was investigated in 46 patients with different duration of the disease. In 29 (63.0%) of them the initial serum sample was positive for the three classes of antibodies and in 17 (36.9%) the primary testing didn’t detect IgM, but IgG and IgA. Conclusion: None of the serological tests alone could ensure an accurate diagnosis of brucellosis. It is necessary to use a diagnostic algorithm with appropriately selected serological tests in which Brucellacapt could successfully replace Coombs' test´ for detection of incomplete antibodies in brucellosis with long duration.

Background. Legionella pneumophila is the most common cause of the potentially fatal Legionnaires’ disease with worldwide increasing incidence reports. The bacterium is fastidious and slow growing and most laboratories do not perform culture. Aim. To present results from the first culture proven cases of Legionnaires’ disease in Bulgaria. Materials and methods. Ten lower respiratory tract materials from 10 patients were cultured for legionellae with GVPC supplement. Identification was based on growth characteristics, latex agglutination and monoclonal typing. Results. Seven L.pneumophila strains (serogroup1 and serogroup6) were isolated. Five belong to monoclonal sub-types Allentown/France, Knoxville and Philadelphia. One culture positive sputum was received at the lab 5 days after sampling. Other materials were plated on the day of sampling, but three of them were obtained long after specific therapy was started and remain negative on culture. Five from the ten patients were with fatal outcome. Three were reported to ELDSNet in real-time as travel-associated. Conclusions. Isolation of legionellae from patients remains the diagnostic ‘gold standard’. The use of selective supplement designed for water samples had no obvious impact on our results in contrast with late sampling. Isolates were from the most frequent reported L. pneumophila serogroups and five of them – from the virulence-associated Pontiac sub-groups. Legionnaires’ disease is still underdiagnosed in Bulgaria. Clinicians must be encouraged to send appropriate and timely obtained respiratory materials. This should happen even in cases with other positive microbiological results, since co-infection with viral, fungal or other bacterial pulmonary pathogens might be of importance for patients’ treatment and health.

Aim. The aim of this report is to present the case of a 44-year-old male tourist from Belgium with type 1 diabetes who developed necrotizing fasciitis and sepsis caused by Vibrio vulnificus during his stay at the Bulgarian Black Sea Coast. Material and methods. Data was collected from the patient's examination records. V. vulnificus was isolated by culture on blood agar and identified with biochemical tests. Results. During the initial hospitalisation the patient left the clinic without leave and returned 24 hours later. He was surgically treated and supported with intensive care. However, the patient developed severe sepsis which resulted in fatal outcome. Conclusion. It is important to highlight the need for sufficient awareness among patients with diabetes and other serious chronic diseases of the potential threat posed by V. vulnificus infections.

Gamma irradiation is efficiently applied to many foods, but nevertheless there is a distinct lack of information about the changes of macro- and micronutrients (e.g., carbohydrates, lipids, organic acids, and phenolics) in dried rose hip (RH) fruits. Therefore, in this study, for the first time, the effect of gamma irradiation (10 and 25 kGy) on RH constituents is investigated. Different analytical techniques (GC-FID, HPLC-UV, HPSEC-RID, IR-FT, and SEM) are employed to examine this effect. The irradiation treatment (10 kGy) increased the glucose content by 30% and released cellobiose from RH fruits, thus revealing cellulose destruction. The extractability of total uronic acids increased from 51% (control) to 70.5% (25 kGy-irradiated), resulting in a higher pectin yield (10.8% < 12.8% < 13.4%) and molecular heterogeneity. Moreover, de-esterification was not a major effect of the irradiation-induced degradation of pectin. The sample exposure to the highest dose did not change the content of total carotenoids, β-carotene, and (un)saturated fatty acids, but it affected the tocopherols levels. Gamma rays had a negligible effect on the phenolic constituents and did not affect ORAC and HORAC antioxidant activity. In conclusion, it can be compromised that the exposition of dried RH is safe and can be successfully applied to decontaminate fruits without affecting their nutritional value and biological activity.

Brucellosis is still the most common zoonosis worldwide. Despite this, it is unknown and underdiagnosed infection in non-endemic areas. For some parts of the world it became a re-emerging infection. After several decades brucellosis re-emerged in Bulgaria. In 2005 an outbreak of imported human cases was detected and soon after, two autochthonous outbreaks occurred (2006 and 2015) with a total of 161 persons diagnosed.

An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials.

The antioxidative activities and mechanism of action were studied of eight synthesised cinnamoyl- and hydroxycinnamoyl amides of biogenic amines (caffeoyldopamine, cinnamoyldopamine, p-coumaroyldopamine, feruloyldopamine, sinapoyldopamine, caffeoylphenylethylamine, caffeoyltyramine, and caffeoyltryptamine) in a wide concentration range (2.5-20 × 10-4M) during autoxidation of triacylglycerols of sunflower oil. It was established that all amides exhibited excellent antioxidant activity, higher than or comparable with that of caffeic acid. The best activity was shown by caffeoyldopamine followed by cinnamoyldopamine and caffeoyltyramine. The analysis of the kinetic data obtained showed that the presence of hydroxyl groups in the amino part (derivatives of dopamine and tyramine) led to direct oxidation of the molecules during the process and stabilisation of the resulting radicals. In contrast, the amides without hydroxyl groups in the amino part participated in the side reaction with peroxides and the resulting radicals took part in one side reaction of the chain propagation as did caffeic acid.

Type 5 human adenoviruses (Ad5) deleted of genes encoding the early region 1B 55-kDa (E1B55K) protein including Onyx-015 (dl1520) and H101 are best known for their oncolytic potential. As a vaccine vector the E1B55K deletion may allow for the insertion of a transgene nearly 1,000 base pairs larger than now possible. This has the potential of extending the application for which the vectors are clinically known. However, the immune priming ability of E1B55K-deleted vectors is unknown, undermining our ability to gauge their usefulness in vaccine applications. For this reason, we created an E1B55K-deleted Ad5 vector expressing full-length single chain HIVBaLgp120 attached to a flexible linker and the first two domains of rhesus CD4 (rhFLSC) in exchange for the E3 region. In cell-based experiments the E1B55K-deleted vector promoted higher levels of innate immune signals including chemokines, cytokines, and the NKG2D ligands MIC A/B compared to an E1B55K wild-type vector expressing the same immunogen. Based on these results we evaluated the immune priming ability of the E1B55K-deleted vector in mice. The E1B55K-deleted vector promoted similar levels of Ad5-, HIVgp120, and rhFLSC-specific cellular and humoral immune responses as the E1B55K wild-type vector. In pre-clinical HIV-vaccine studies the wild-type vector has been employed as part of a very effective prime-boost strategy. This study demonstrates that E1B55K-deleted adenoviruses may serve as effective vaccine delivery vectors.

BackgroundThe ability of Taenia solium to modulate the immune system likely contributes to their longevity in the human host. We tested the hypothesis that the nature of the immune response is related to the location of parasite and clinical manifestations of infection.MethodologyPeripheral blood mononuclear cells (PBMC) were obtained from untreated patients with neurocysticercosis (NCC), categorized as having parenchymal or subarachnoid infection by the presence of cysts exclusively within the parenchyma or in subarachnoid spaces of the brain, and from uninfected (control) individuals matched by age and gender to each patient. Using multiplex detection technology, sera from NCC patients and controls and cytokine production by PBMC after T. solium antigen (TsAg) stimulation were assayed for levels of inflammatory and regulatory cytokines. PBMC were phenotyped by flow cytometry ex vivo and following in vitro stimulation with TsAg.Principal findingsSera from patients with parenchymal NCC demonstrated significantly higher Th1 (IFN-γ/IL-12) and Th2 (IL-4/IL-13) cytokine responses and trends towards higher levels of IL-1β/IL-8/IL-5 than those obtained from patients with subarachnoid NCC. Also higher in vitro antigen-driven TNF-β secretion was detected in PBMC supernatants from parenchymal than in subarachnoid NCC. In contrast, there was a significantly higher IL-10 response to TsAg stimulation in patients with subarachnoid NCC compared to parenchymal NCC. Although no differences in regulatory T cells (Tregs) frequencies were found ex vivo, there was a trend towards greater expansion of Tregs upon TsAg stimulation in subarachnoid than in parenchymal NCC when data were normalized for the corresponding controls.Conclusions/significanceT. solium infection of the subarachnoid space is associated with an enhanced regulatory immune response compared to infection in the parenchyma. The resulting anti-inflammatory milieu may represent a parasite strategy to maintain a permissive environment in the host or diminish inflammatory damage from the host immune response in the central nervous system.

Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP activities were similar. The complex challenge outcomes may reflect differences in IgG subtypes, Fc glycosylation, Fc-R polymorphisms, and/or the microbiome, key areas for future studies. This first demonstration of a sex-difference in SIV vaccine-induced protection emphasizes the need for sex-balancing in vaccine trials. Our results highlight the importance of mucosal immunity and memory B cells at the SIV exposure site for protection.

Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown.41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points.Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression.

Brucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5-40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis.Blood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM.This work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may allow for better follow-up care of brucellosis patients through improved identification of patients at risk for relapse.

Purpose: This primary aim of the study was to establish the normative values of brain ventricles and indices in the adult North Indian population. Secondary aims were to evaluate sex and age-related differences, assess the applicability of widely cited normal ventricle size ranges in the study population, and explore the correlation between ventricular dimensions and anthropometric parameters., Methods: Magnetic resonance imaging (MRI) of 142 healthy individuals, aged between 18 to 72 years, was conducted and sagittal and axial images were utilized for brain ventricles measurements., Results: The study revealed following mean values for brain ventricles and indices in males: frontal horn width (FHW), third ventricle width (TVW), fourth ventricle anteroposterior width (FVWAP), fourth ventricle transverse width (FVWT) and the transverse inner diameter of the skull (TIDS) were 33.07 mm, 4.20 mm, 8.62 mm, 13.12 mm, and 117.6 mm respectively. In females, the corresponding dimensions were 30.20 mm, 3.65 mm, 8.20 mm, 12.62 mm, and 116.05 mm, respectively. Statistically significant differences between the sexes were observed only in TVW. The mean values of Evans' index were 0.25 ± 0.020 in females and 0.26 ± 0.024 in males., Conclusion: The findings contribute valuable insights into the normal values of brain ventricles and indices among healthy adult individuals of North Indian origin, as determined by MRI. The exploration of sex and age-related differences holds significance for facilitating the diagnosis and management of hydrocephalic patients. The calculated mean values of Evans' index provide a reliable metric for aiding the diagnosis of various neurological disorders, including the early detection of hydrocephalus and cerebral atrophy, and offer crucial follow-up information for affected patients.

Purpose: In the present study, we want to systematize the previous studies on the scapular foramina (SF) and nutrient foramina (NF) with emphasis on the clinical relevance of this topic. Although seemingly not important, radiologists, clinicians and surgeons should be aware of the presence and characteristics of the SF and NF and look out for possible mistakes that may cause harm to the patients during either the diagnostic process or surgery., Methods: A comprehensive search was conducted in multiple databases, including PubMed, Scopus, Web of Science, Embase, Cochrane Library and Google Scholar. The whole process was divided into three stages. In the first stage, the following search terms were used: ((scapular foramina) or (scapular foramen) or (scapular nutrient foramina) or (scapular nutrient foramen) or (scapula foramen) or (scapula foramina) or (scapula nutrient foramina))., Results: The results of the present meta-analysis were based on a total of 3316 studied scapulae. A pooled prevalence of scapulae in which at least one SF was found was set to be 11.29%. The most common localization of the SF was found to be the infraspinous fossa, in which the SF occurred with the prevalence of 52.31%. Subsequently, a pooled prevalence of scapulae in which at least one NF occurs was established at 74.23%., Conclusion: The presented data contribute to a comprehensive understanding of the prevalence, distribution, and characteristics of suprascapular and nutrient foramina in scapulae, considering different topographical areas, genders, and sides., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

There is an association between sleep quality and glioma-specific outcomes, including survival. The critical role of sleep in survival among subjects with glioma may be due to sleep-induced activation of brain drainage (BD), that is dramatically suppressed in subjects with glioma. Emerging evidence demonstrates that photobiomodulation (PBM) is an effective technology for both the stimulation of BD and as an add-on therapy for glioma. Emerging evidence suggests that PBM during sleep stimulates BD more strongly than when awake. In this study on male Wistar rats, we clearly demonstrate that the PBM course during sleep vs. when awake more effectively suppresses glioma growth and increases survival compared with the control. The study of the mechanisms of this phenomenon revealed stronger effects of the PBM course in sleeping vs. awake rats on the stimulation of BD and an immune response against glioma, including an increase in the number of CD8+ in glioma cells, activation of apoptosis, and blockage of the proliferation of glioma cells. Our new technology for sleep-phototherapy opens a new strategy to improve the quality of medical care for patients with brain cancer, using promising smart-sleep and non-invasive approaches of glioma treatment.

Background: The inferior gluteal artery (IGA) is a large terminal branch of the anterior division of the internal iliac artery (ADIIA). There is a significant lack of data regarding the variable anatomy of the IGA., Materials and Methods: A retrospective study was conducted to establish anatomical variations, their prevalence and morphometrical data on IGA and its branches. The results of 75 consecutive patients who underwent pelvic computed tomography angiography were analysed., Results: The origin variation of each IGA was deeply analysed. Four origin variations have been observed. The most common type O1 occurred in 86 of the studied cases (62.3%). The median IGA length was set to be 68.50 mm (lower quartile [LQ]: 54.29; higher quartile [HQ]: 86.06). The median distance from the origin of the ADIIA to the origin of the IGA was set to be 38.22 mm (LQ: 20.22; HQ: 55.97). The median origin diameter of the IGA was established at 4.69 mm (LQ: 4.13; HQ: 5.45)., Conclusions: The present study thoroughly analysed the complete anatomy of the IGA and the branches of the ADIIA. A novel classification system for the origin of the IGA was created, where the most prevalent origin was from the ADIIA (type 1; 62.3%). Furthermore, the morphometric properties (such as the diameter and length) of the branches of the ADIIA were analysed. This data may be incredibly useful for physicians performing operations in the pelvis, such as interventional intraarterial procedures or various gynaecological surgeries.

Background: The main goal of the present meta-analysis was to provide physicians, especially surgeons, with crucial data on the complete anatomy of the inferior alveolar nerve (IAN). It is hoped that our results will help reduce the complication rates in procedures associated with this anatomical entity., Materials and Methods: Major online medical databases such as PubMed, Embase, Scopus, Web of Science, Google Scholar, and Cochrane Library were searched to gather all studies on IAN anatomy, including topography, morphology, and variations., Results: The mean thickness of the IAN in the mandibular angle area was found to be 2.32 mm (LL: 1.82 ; HL: 2.78). The mean thickness of the IAN in the mandibular body region was found to be 2.49 mm (LL: 2.02 ; HL: 2.98). The mean thickness of the IAN in the mental region was established at 1.70 mm (LL: 1.54; HL: 1.86). The mean distance from the IAN to the external (buccal) surface of the first molar was found to be 4.99 mm (LL: 3.84; HL: 6.13)., Conclusions: In conclusion, this is currently the most up-to-date and thorough analysis of the complete anatomy of the IAN. We have provided morphometric data that present the spatial relationship of the IAN with numerous anatomical landmarks in the mandibular region. These include the ramus of the mandible, the first, second, and third molars, and the body of the mandible, among others. It is hoped that the results of the present meta-analysis will be a helpful tool for physicians, especially surgeons, performing various oral and maxillofacial procedures, such as third molar removal or IAN block anaesthesia.

Anatomical nomenclature commonly does not follow changes in the clinical language and demands. Therefore we tried to explain the pelvic relationships based on the changes that occur in the pelvis as well as to compare different nomenclatural strategies used in every day language. Courses of fasciae in the male and female pelvis are also considered.

The main objective of the present study was to clarify the anatomical characteristics of the GDA. In order to fulfill this objective, novel classification systems of both the origin and branching pattern of the said vessel were created. Being aware of the variable anatomy of the GDA is of great importance when performing hepatopancreaticobilliary procedures. The results of 75 consecutive patients who underwent abdomen computed tomography angiography (CTA) were analyzed. A total of 74 GDA were analyzed. Of these, 42 were from women (56.8%) and 32 were from men (43.2%). The most common direction of origin of the GDA was inferior (n = 38; 51.4%). The origin variation of each GDA was deeply analyzed. Initially, eight types of origin variations were evaluated, of which types 1-3 constituted 83.8%. Furthermore, analogously, branching pattern types were also established. Initially, 11 branching variations were evaluated, of which types 1-3 constituted 87.8%. The GDA is subject to numerous variations, both in the origin and in the branching pattern of the vessel. In order to clarify the anatomical characteristics of this vessel, novel classifications of the origin and branching patterns were made, presenting the most frequent patterns. Our results may be of great use for surgeons performing hepatopancreaticobilliary surgeries, such as the Whipple procedure or vascular reconstructions after cholangiocarcinoma resections. Being aware of the anatomical variations of relevant structures associated with a surgical procedure may help reduce potential intraoperative and/or postoperative complications., (© 2023 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Lingual nerve (LN) injury during surgical procedures in the third molar region warrants a detailed study of its common pathway and important variations. Therefore, the objective of this study was to analyze and compile the multiple anatomical variations of the LN for use in oral and maxillofacial surgery. It is anticipated that the results of the present meta-analysis may help to minimize the possible complications when performing procedures associated with this anatomical entity. Major online databases such as PubMed, Web of Science, Scopus, Embase were used to gather all relevant studies regarding the LN anatomy. The results were established based on a total of 1665 LNs. The pooled prevalence of the LN being located below the lingual/ alveolar crest was found to be 77.87% (95% CI: 0.00%-100.00%). The LN was located above the lingual/ alveolar crest in 8.21% (95% CI: 4.63%-12.89%) of examined nerves. The most common shape of the LN was established to be round with a prevalence of 40.96% (95% CI: 23.96%-59.06%), followed by oval at 37.98% (95% CI: 23.98%-53.02%) and flat at 25.16% (95% CI: 12.85%-39.77%). In conclusion, we believe that this is the most accurate and up-to-date study regarding the anatomy of the LN. The LN was found to be located below the lingual/alveolar crest in 77.87% of the cases. Furthermore, the LN was found to enter the tongue under the submandibular duct in 68.39% of the cases. Knowledge about the anatomy of the LN is crucial for numerous oral and maxillofacial procedures such as during the extraction of the third molar., (© 2023 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Background: This meta-analysis aimed to present data on the sella turcica (ST) morphology and variations. Furthermore, a detailed morphometric analysis of the ST was conducted., Methods: Major online databases such as PubMed, Scopus, Embase, Web of Science, and the Cochrane Library were searched through. The overall search process was conducted in three stages., Results: This meta-analysis was based on the results of 18,364 patients and demonstrates the most up-to-date and relevant data regarding the morphology of the ST in the available literature. Four classification methods of the ST shape can be distinguished, in which the most commonly occurring variants are the normal ST (55.56%), the U-shaped ST (73.58%), the circular type of ST (42.29%), and non-bridging ST (55.64%). The overall midpoint height of the ST was 6.59 mm (SE = 0.13). The overall length of the ST was 9.06 mm (SE = 0.15). The overall volume of the ST was 845.80 mm 3 (SE = 288.92). Four main classification methods of ST morphology can be distinguished in the available literature. Various morphometric characteristics of the ST may be applied in clinical practice to evaluate its shape, dimensions, and normal or pathological variants.

The objective of this meta-analysis was to present transparent data on the morphology of the pituitary gland (PG) using the available data in the literature. The main online medical databases, such as PubMed, Embase, Scopus, and Web of Science, were searched to gather all relevant studies regarding PG morphology. The mean overall volume of the PG was found to be 597.23 mm 3 (SE = 28.81). The mean overall height of the PG was established to be 5.64 mm (SE = 0.11). The mean overall length of the PG was found to be 9.98 mm (SE = 0.26). In the present study, the PG's overall morphology and morphometric features were analyzed. Our results showed that, on average, females from Asia have the highest volume of PG (706.69 mm 3 ), and males from Europe have the lowest (456.42 mm 3 ). These values are crucial to be aware of because they represent the normal average properties of the PG, which may be used as reference points when trying to diagnose potential pathologies of this gland. Furthermore, the present study's results prove how the PG's size decreases with age. The results of the present study may be helpful for physicians, especially surgeons, performing procedures on the PG.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

A new application of the photodynamic treatment (PDT) is presented for the opening of blood-brain barrier (BBB) and the brain clearing activation that is associated with it, including the use of gold nanoparticles as emerging photosensitizer carriers in PDT. The obtained results clearly demonstrate 2 pathways for the brain clearing: (1) using PDT-opening of BBB and intravenous injection of FITC-dextran we showed a clearance of this tracer via the meningeal lymphatic system in the subdural space; (2) using optical coherence tomography and intraparenchymal injection of gold nanorods, we observed their clearance through the exit gate of cerebral spinal fluid from the brain into the deep cervical lymph node, where the gold nanorods were accumulated. These data contribute to a better understanding of the cerebrovascular effects of PDT and shed light on mechanisms, underlying brain clearing after PDT-related opening of BBB, including clearance from nanoparticles as drug carriers., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of stable cell lines for expression of large-molecule therapeutics represents a significant portion of the time and effort required to advance a molecule to enabling regulatory toxicology studies and clinical evaluation. Our development strategy employs two different approaches for cell line development based on the needs of a particular project: a random integration approach for projects where high-level expression is critical, and a site-specific integration approach for projects in which speed and reduced employee time spend is a necessity. Here we describe both our random integration and site-specific integration platforms and their applications in support of monoclonal antibody development and production. We also compare product quality attributes of monoclonal antibodies produced with a nonclonal cell pool or clonal cell lines derived from the two platforms. Our data suggests that material source (pools vs. clones) does not significantly alter the examined product quality attributes. Our current practice is to leverage this observation with our site-specific integration platform, where material generated from cell pools is used for an early molecular assessment of a given candidate to make informed decisions around development strategy. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1463-1467, 2017., (© 2017 American Institute of Chemical Engineers.)

Weak partitioning chromatography (WPC) has been proposed for the purification of monoclonal antibodies using an anion exchange (AEX) resin to simultaneously remove both acidic and basic protein impurities. Despite potential advantages, the relationship between resin structure and WPC performance has not been evaluated systematically. In this work, we determine the structure of representative AEX resins (Fractogel® EMD TMAE HiCap, Q Sepharose FF, and POROS 50 HQ) using transmission electron microscopy and inverse size exclusion chromatography and characterize protein interactions while operating these resins under WPC conditions using two mAb monomers, a mAb dimer, mAb multimers, and BSA as model products and impurities. We determine the isocratic elution behavior of the weakly bound monomer and dimer species and the adsorptive and mass transfer properties of the strongly bound multimers and BSA by confocal laser scanning microscopy. The results show that for each resin, using the product K p value as guidance, salt, and pH conditions can be found where mAb multimers and BSA are simultaneously removed. Isocratic elution and adsorption mechanisms are, however, different for each resin and for the different components. Under WPC conditions, the Fractogel resin exhibited very slow diffusion of both mAb monomer and dimer species but fast adsorption for both mAb multimers and BSA with high capacity for BSA, while the Sepharose resin, because of its small pore size, was unable to effectively remove mAb multimers. The POROS resin was instead able to bind both multimers and BSA effectively, while exhibiting a greater resolution of mAb monomer and dimer species. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:425-434, 2017., (© 2017 American Institute of Chemical Engineers.)

Effective cleaning of chromatography resin is required to prevent fouling and maximize the number of processing cycles which can be achieved. Optimization of resin cleaning procedures, however, can lead to prohibitive material, labor, and time requirements, even when using milliliter scale chromatography columns. In this work, high throughput (HT) techniques were used to evaluate cleaning agents for a monoclonal antibody (mAb) polishing step utilizing Fractogel(®) EMD TMAE HiCap (M) anion exchange (AEX) resin. For this particular mAb feed stream, the AEX resin could not be fully restored with traditional NaCl and NaOH cleaning solutions, resulting in a loss of impurity capacity with resin cycling. Miniaturized microliter scale chromatography columns and an automated liquid handling system (LHS) were employed to evaluate various experimental cleaning conditions. Cleaning agents were monitored for their ability to maintain resin impurity capacity over multiple processing cycles by analyzing the flowthrough material for turbidity and high molecular weight (HMW) content. HT experiments indicated that a 167 mM acetic acid strip solution followed by a 0.5 M NaOH, 2 M NaCl sanitization provided approximately 90% cleaning improvement over solutions containing solely NaCl and/or NaOH. Results from the microliter scale HT experiments were confirmed in subsequent evaluations at the milliliter scale. These results identify cleaning agents which may restore resin performance for applications involving fouling species in ion exchange systems. In addition, this work demonstrates the use of miniaturized columns operated with an automated LHS for HT evaluation of chromatographic cleaning procedures, effectively decreasing material requirements while simultaneously increasing throughput. Biotechnol. Bioeng. 2016;113: 1251-1259. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Anion exchange chromatography (AEX) operated under weak partitioning mode has been proven to be a powerful polishing step as well as a robust viral clearance step in Pfizer's monoclonal antibody (mAb) platform purification process. A multivariate design of experiment (DoE) study was conducted to understand the impact of operating parameters and feedstream impurity levels on viral clearance by weak partitioning mode AEX. Bacteriophage was used initially as a surrogate for neutral and acidic isoelectric point mammalian viruses (e.g., retrovirus and parvovirus). Five different mAbs were used in the evaluation of process parameters such as load challenge (both product and impurities), load pH, load conductivity, and contact time (bed height and flow-rate). The operating ranges obtained from phage clearance studies and Pfizer's historical data were used to define an appropriate operating range for a subsequent clearance study with model retrovirus and parvovirus. Both phage and virus clearance evaluations included feedstreams containing different levels of impurities such as high molecular mass species (HMMS), host cell proteins (HCPs), and host cell DNA. For all the conditions tested, over 5 log10 of clearance for both retrovirus and parvovirus was achieved. The results demonstrated that weak partitioning mode AEX chromatography is a robust step for viral clearance and has the potential to be included as part of the modular viral clearance approach., (© 2015 American Institute of Chemical Engineers.)

A significant consequence of scaling up production of high titer monoclonal antibody (mAb) processes in existing facilities is the generation of in-process pools that exceed the capacity of storage vessels. A semi-continuous downstream process where columns and filters are linked and operated in tandem would eliminate the need for intermediate holding tanks. This study is a bench-scale demonstration of the feasibility of a tandem process for the purification of mAbs employing an affinity Protein A capture step, followed by a flow-through anion-exchange (AEX) step with the possibility of adding an in-line virus filtration step (VF). All three steps were linked sequentially and operated as one continuous process using an ÄKTA FPLC equipped with two pumps and a system of valves and bypasses that allowed the components to be engaged at different stages of the process. The AEX column was operated in a weak partitioning (WP) mode enabled by a precise in-line titration of Protein A effluent. In order to avoid complex control schemes and facilitate validation, quality and robustness were built into the system through selection of buffers based on thermodynamic and empirical models. The tandem system utilized the simplest possible combination of valves, pumps, controls, and automation, so that it could easily be implemented in a clinical or commercial production facility. Linking the purification steps in a tandem process is expected to generate savings in time and production costs and also reduce the size of quality systems due to reduced documentation requirements, microbial sampling, and elimination of hold time validation., (Copyright © 2013 Wiley Periodicals, Inc.)

Fouling of chromatographic resins over their operational lifetimes can be a significant problem for commercial bioseparations. In this article, scanning electron microscopy (SEM), batch uptake experiments, confocal laser scanning microscopy (CLSM) and small-scale column studies were applied to characterize a case study where fouling had been observed during process development. The fouling was found to occur on an anion exchange (AEX) polishing step following a protein A affinity capture step in a process for the purification of a monoclonal antibody. Fouled resin samples analyzed by SEM and batch uptake experiments indicated that after successive batch cycles, significant blockage of the pores at the resin surface occurred, thereby decreasing the protein uptake rate. Further studies were performed using CLSM to allow temporal and spatial measurements of protein adsorption within the resin, for clean, partially fouled and extensively fouled resin samples. These samples were packed within a miniaturized flowcell and challenged with fluorescently labeled albumin that enabled in situ measurements. The results indicated that the foulant has a significant impact on the kinetics of adsorption, severely decreasing the protein uptake rate, but only results in a minimal decrease in saturation capacity. The impact of the foulant on the kinetics of adsorption was further investigated by loading BSA onto fouled resin over an extended range of flow rates. By decreasing the flow rate during BSA loading, the capacity of the resin was recovered. These data support the hypothesis that the foulant is located on the particle surface, only penetrating the particle to a limited degree. The increased understanding into the nature of the fouling can help in the continued process development of this industrial example., (Copyright © 2013 Wiley Periodicals, Inc.)

The purpose of this study has been to describe the microanatomy of the recurrent artery of Heubner (RAH) in detail, to deepen anatomical knowledge and aid neurosurgeons in their work. The material was obtained from cadavers (ages 31-75 years) at routine autopsy. A total of 70 human brains (39 male and 31 female) were examined. People who died due to neurological disorders were not included in the study. Right after dissection, the arteries were perfused with acrylic paint emulsion, through the Circle of Willis or electively through the RAH. Brains were fixed in a 10% solution of formaldehyde, sectioned and placed in methyl salicylate for tissue transparency. To obtain corrosion-casts, the vessels were perfused with polyvinyl chloride or Mercox CL-2R resin and corroded using concentrated potassium chloride. The obtained material was analyzed using a stereoscopic light microscope. The RAH was present in 138 hemispheres with a mean of 1.99 RAH per hemisphere (275 RAH in total). The mean RAH length was 25.2 mm and the mean RAH diameter, in its place of origin, was 1 mm. Two to 30 branches (mean=9.4) originated from the stem of the RAH. The number of RAHs showed a negative correlation to the number of arteries from the medial group of lenticulo-striate arteries (LSA) (R=-0.62; p < 0.0001) which branch off the middle cerebral artery (MCA). This study further supports the RAH embryologic theory by Abbie. The RAH, in its extra- and intracerebral course, may join with the middle group of the LSA or directly with the MCA., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Most mAb platform purification processes consist of an affinity capture step followed by one or two polishing steps. An understanding of the performance linkages between the unit operations can lead to robust manufacturing processes. In this study, a weak-partitioning anion-exchange chromatography polishing step used in a mAb purification process was characterized through high-throughput screening (HTS) experiments, small-scale experiments including a cycling study performed on qualified scale-down models, and large-scale manufacturing runs. When material from a Protein A column that had been cycled <10× was loaded on the AEX resin, early breakthrough of impurities and premature loss of capacity was observed. As the cycle number on the Protein A resin increased, the capacity of the subsequent AEX step increased. Different control strategies were considered for preventing impurity breakthrough and improving AEX resin lifetimes. Depth filtration of the Protein A peak pool significantly improved the AEX resin capacity, robustness, and lifetime. Further, the turbidity of the Protein A pool has the potential for use as an in-process control parameter for monitoring the performance of the AEX step., (Copyright © 2012 Wiley Periodicals, Inc.)

The properties of Fractogel(®) EMD TMAE HiCap (M), a tentacle-type anion exchange resin used for a polishing step in a monoclonal antibody (mAb) purification process, were investigated for both virgin and used samples to determine the influence of process related fouling. Inverse size exclusion chromatography indicated a bimodal distribution of pore sizes consisting mostly of small pores, 4-5 nm in radius and likely associated with the grafted tentacles. Similar results were obtained for resin samples fouled by process use, indicating that the core structure of these particles is unchanged. Transmission electron micrographs showed that the resin backbone matrix has a microgranular structure. However, a dense skin layer, 0.2-0.5 μm thick, was also seen at the exterior surface of the fouled particles. The binding capacity attained for BSA after 90 min of contact was 165 ± 4 mg/mL for both virgin and fouled samples, close to the equilibrium capacity of 178 ± 2 mg/mL attained after 24h. On the other hand, the capacities attained at 90 min for the much larger thyroglobulin were only 90 ± 4 and 25 ± 2 mg/mL, respectively, for virgin and fouled samples. The BSA adsorption kinetics was also slower for the fouled resin, but much larger kinetic differences between virgin and fouled resin were seen for thyroglobulin. Based on the shape of intraparticle protein concentration profiles determined by confocal laser scanning microscopy (CLSM), the protein transport mechanism is consistent with solid diffusion for both virgin and fouled resin samples and proteins. However, transport is hindered by the foulant layer to a much greater extent for thyroglobulin as a result of its larger size. Additional measurements indicated that the foulant layer is consistent with mAb aggregates irreversibly bound at the particle exterior surface., (Copyright © 2013 Elsevier B.V. All rights reserved.)