Challenges in the management of new daily persistent headache at a tertiary headache center-A retrospective real-world evidence study.

OBJECTIVE: In this retrospective cross-sectional real-world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH). BACKGROUND: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence-based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found. METHODS: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories ("no effect," "partial effect," "full effect," "partial effect and cessation due to adverse events," and "full effect and cessation due to adverse events"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2). RESULTS: Fifty-one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation. CONCLUSION: In this study we add real-world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension-type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double-blinded placebo-controlled trials.

Structural characteristics and regenerative potential: Insights from the molly fish spinal cord.

Unlike mammals, species such as fish and amphibians can regenerate damaged spinal cords, offering insights into potential therapeutic targets. This study investigates the structural features of the molly fish spinal cord through light and electron microscopy. The most notable characteristic was the presence of Mauthner cells (M-cells), which exhibited large cell bodies and processes, as well as synaptic connections with astrocytes. These astrocytic connections contained synaptic vesicles, suggesting electrical transmission at the M-cell endings. Astrocytes, which were labeled with glial fibrillary acidic protein (GFAP), contained cytoplasmic glycogen granules, potentially serving as an emergency fuel source. Two types of oligodendrocytes were identified: a small, dark cell and a larger, lighter cell, both of which reacted strongly with oligodendrocyte transcription factor 2 (Olig2). The dark oligodendrocyte resembled human oligodendrocyte precursors, while the light oligodendrocyte was similar to mature human oligodendrocytes. Additionally, proliferative neurons in the substantia grisea centralis expressed myostatin, Nrf2, and Sox9. Collectively, these findings suggest that the molly fish spinal cord has advanced structural features conducive to spinal cord regeneration and could serve as an excellent model for studying central nervous system regeneration. Further studies on the functional aspects of the molly fish spinal cord are recommended. RESEARCH HIGHLIGHTS: Mauthner cells (M-cell), with their typical large cell body and processes, were the most characteristic feature in Molly fish spinal cord, where it presented synaptic connections with astrocytes and their ends contained synaptic vesicles indicating an electrical transmission in the M-cells endings. Two types of oligodendrocytes could be recognized; both reacted intensely with Oligodendrocyte transcription factor 2 (Olig2). The proliferative neurons of the substantia grisea centralis expressed myostatin, Nrf2, and Sox9. The findings of this study suggest that molly fish possess highly developed structural features conducive to spinal cord regeneration. Consequently, they could be deemed an exemplary model for investigating central nervous system regeneration.

GATA3 Positively Correlates with BCL2 Expression in Indolent and Aggressive Histological Types of Cutaneous Basal Cell Carcinoma.

OBJECTIVE: Some histological basal cell carcinoma (BCC) types demonstrate more aggressive behavior than others. They are known as high-risk BCC and are more challenging in therapy, contrary to indolent (low-risk) BCC types. Identifying novel protein markers to predict aggressiveness and potential therapeutic targets in challenging cases is recommended. GATA3 is a transcription factor critical for epithelial and lymphocytic differentiation. This study investigated the immunohistochemical expression of GATA3 in indolent and aggressive BCC and its association with BCL2 expression. MATERIAL AND METHODS: Retrospectively collected indolent and aggressive BCC groups (24 cases each) were immunohistochemically stained with anti-GATA3 and BCL2 antibodies. The mean expression score (by area percentage) and TIL counts were determined and compared using ImageJ analysis. Stromal tumor-infiltrating lymphocytes (TIL) were counted per high-power field (HPF) on hematoxylin and eosin (H&E) staining. RESULTS: GATA3 and BCL2 expressions were significantly higher in the indolent group than in the aggressive group. GATA3 expression significantly correlated with BCL2 score and TIL counts. Higher GATA3 expression was significantly associated with a more indolent BCC histological type, higher BCL2 expression, and higher TIL count. CONCLUSION: GATA3 is a possible target for immunomodulation experiments to improve BCC immunotherapy outcomes.

Aflatoxin B1 exposure exacerbates chemokine receptor expression in the BTBR T+ Itpr3tf/J Mouse Model, unveiling insights into autism spectrum disorder: A focus on brain and spleen.

OBJECTIVE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant difficulties in social interaction, communication, and repeated stereotypic behaviour. Aflatoxin B1 (AFB1) is the most potent and well-known mycotoxin in various food sources. Despite its propensity to generate significant biochemical and structural changes in human and animal tissues, the influence of AFB1 on ASD has yet to be thoroughly studied. Mounting evidence indicates that chemokine receptors play a crucial function in the central nervous system and are implicated in developing several neuroinflammatory disorders. Chemokine receptors in individuals with ASD were elevated in the anterior cingulate gyrus astrocytes, cerebellum, and brain. METHODS: The BTBR T+Itpr3tf/J (BTBR) mice are inbred strains that exhibit strong and consistently observed deficits in social interactions, characterized by excessive self-grooming and limited vocalization in social contexts. We examined the impact of AFB1 on CCR3-, CCR7-, CCR9-, CXCR3-, CXCR4-, and CXCR6-expressing I-A/I-E+ cells in the spleen of the BTBR mouse model of autism. We evaluated the mRNA levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 chemokine receptors in the brain. RESULTS: The exposure to AFB1 in BTBR mice resulted in a significant rise in the number of I-A/I-E+CCR3+, I-A/I-E+CCR7+, I-A/I-E+CCR9+, I-A/I-E+CXCR3+, I-A/I-E+CXCR4+, and I-A/I-E+CXCR6+ cells. Furthermore, exposure to AFB1 increased mRNA expression levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 in the brain. CONCLUSIONS: These findings highlight that AFB1 exposure increases the expression of chemokine receptors in BTBR mice, indicating the necessity for further research into AFB1's role in the development of ASD.

Semaglutide ameliorated autism-like behaviors and DNA repair efficiency in male BTBR mice by recovering DNA repair gene expression.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.

Gastrointestinal stromal tumor in North Africa and the middle east: updates in presentation and management from an 11-year retrospective cohort.

OBJECTIVES: This study described the epidemiological, clinical, and survival profiles of patients with gastrointestinal stromal tumor (GIST) in North Africa and the Middle East (AfME). METHODS: This regional, multicenter, observational, retrospective study collected 11-year data on demographics, medical history, disease characteristics, current treatment approaches of GIST, the safety of the most common tyrosine kinase inhibitors (TKIs), second cancers, and survival status. RESULTS: Data of 201 eligible patients were analyzed: mean age was 56.9 ± 12.6 years; 111 (55.2%) patients were men, 21 (10.4%) patients had previous personal malignancy. The most common clinical presentation of GIST was dysphagia [92 (45.8%) patients]. The stomach was the most common primary site in 120 (60.7%) patients, 171 (85.1%) patients had localized disease at diagnosis. 198 (98.5%) GIST cases were CD117/CD34-positive. Imatinib was used in the neoadjuvant (18/21 patients), adjuvant (85/89 patients), and first-line metastatic treatment (28/33 patients) settings. The most common non-hematological toxicity associated with TKIs was vomiting in 32/85 (37.6%) patients. Overall, 100 (49.8%) patients (95%CI: 42.8-56.7%) were alive and disease-free while 30 (14.9%) patients were alive with active disease. CONCLUSION: Presentation of GIST in our AfME population is consistent with global reports, being more frequent in patients >50 years old and having the stomach as the most common primary site. Unlike what is usually reported, though, we did have more patients with lymphatic spread of the disease. Despite the global trend and advances in the treatment of GIST according to molecular profile, this is still far to happen in our population given the lack of access to molecular profiles and the high associated cost.

Aberrant expression of miRNAs predicts recurrence and survival in stage-II colorectal cancer patients from Egypt

Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify prognostic biomarkers that can define more aggressive forms of the disease. We assessed the expression levels of five miRNAs that have been previously addressed in relation to the development and progression of solid and hematological tumors. Methods: We measured the expression levels of miR-21, miR-137, miR-145, miR-320 and miR-498in stage II CRC patients from Egypt (124 tissues and 41 blood samples) by quantitative real time PCR (qPCR). The results were correlated with relevant clinicopathological factors, response to treatment and survival rates of the patients. Results: miR-137, miR-145 and miR-320 were significantly reduced in 39.5%, 48.4% and 52.4%; respectively whereas miR-21 and miR-498 were significantly overexpressed in 48.4% and 40.3% of the CRC tissues compared to the control group. In patients' blood, miR-137, miR-145 and miR-320 were significantly reduced in 46.3%, 46.3% and 51. 2%; respectively whereas mir-21 and miR-498 were significantly overexpressed in 46.3% and 43.9% of the cases, respectively. The concordance between tissue and blood was weak for miR-320 and miR-145 (kappa 40-65%), intermediate for miR-498 and miR-137 (kappa 65-75%) and strong for miR-21 (kappa 75-85%). In univariate analysis performance status, over-expression of miR-21 and miR-498 and reduced miR-137, miR-145, and miR-320 associated significantly with reduced DFS and OS. However, in multivariate analysis, miR-498 and miR-320 were independent prognostic factors for DFS whereas miR-21 was independent prognostic factors for OS. Conclusions: miRNAs play an important role in the development and progression of stage II CRC. A five markers panel (miR-21, miR-498, miR-137, miR-145 and miR-320) can predict recurrence and survival in stage II CRC patients from Egypt (AU)