Nevin Manimala

Am J Hematol. 2026 Mar 15. doi: 10.1002/ajh.70283. Online ahead of print.

ABSTRACT

Concerns about the efficacy of high-dose methotrexate (HD-MTX) in preventing CNS recurrence in large B-cell lymphomas (LBCL) are based on studies with interpretation biases and incomplete information about HD-MTX dosing schedule and CNS events. We evaluated a pharmacokinetic-informed, CNS-directed HD-MTX protocol (3 g/m² over 3 h, preceded by a bolus) in 336 LBCL patients achieving CMR after RCHOP or derivatives. HD-MTX use was based on institutional risk scores. In this study, CNS risk was reassessed using updated criteria: CNS-IPI ≥ 4, ≥ 3 extranodal sites, or involvement of testis, kidney, adrenal gland, uterus, or breast. According to these criteria, risk was low in 228 (68%) patients and high in 108 (32%); HD-MTX was given to 20 (9%) and 49 (45%), respectively. HD-MTX was well tolerated: 96% completed therapy. After a median follow-up of 77 months, 13 (4%) patients experienced CNS relapse, always as isolated events. Among high-risk patients, CNS relapse occurred in 19% (11/59) without HD-MTX versus 0% (0/49) with HD-MTX (p = 0.0009); significant reductions were seen in patients with high-risk organ involvement (32% to 0%, p = 0.002) or ≥ 3 extranodal sites (18% to 0%, p = 0.04). HD-MTX was independently associated with improved PFS and OS in high-risk patients, likely due to reduced CNS relapses (0% vs. 19%; p = 0.0009), whereas rates of unrelated deaths (8% vs. 15%; p = 0.26) and systemic relapses (18% vs. 22%; p = 0.81) were similar. In conclusion, HD-MTX, administered via a pharmacokinetic-informed, CNS-directed schedule, with or without intrathecal chemotherapy, significantly reduces CNS relapses and improves outcomes in high-risk LBCL patients in CMR. Trial Registration: ClinicalTrials.gov Identifier: NCT07181785.

PMID:41832699 | DOI:10.1002/ajh.70283

Curr Pharm Des. 2026 Mar 12. doi: 10.2174/0113816128397599251204081009. Online ahead of print.

ABSTRACT

INTRODUCTION: Obesity and hypertension synergistically increase cardiovascular risk, with Monocyte Chemoattractant Protein-1 (MCP-1), Endothelin-1 (ET-1), and Pro-B-Type Natriuretic Peptide (Pro- BNP) implicated in vascular dysfunction and cardiac stress. However, their combined role in obesity-driven hypertension remains poorly understood. This study aimed to investigate the associations between MCP-1, ET-1, and Pro-BNP levels in obese hypertensive patients and evaluate their collective contribution to disease pathogenesis.

METHODS: This prospective, non-randomized clinical study enrolled 97 adult male participants, stratified into four groups: healthy controls (n = 22), overweight normotensive individuals (n = 25), class I obese hypertensive patients (n = 25), and class II obese hypertensive patients (n = 25). Blood samples were collected and analyzed for metabolic parameters (fasting glucose, insulin, lipid profile), oxidative stress markers (MDA, GSH, SOD), and inflammatory cytokines (VEGF, IL-1β, IL-9). Gene expression levels of MCP-1, ET-1, and Pro-BNP were quantified using real-time PCR, while protein expression was assessed via Western blotting. Statistical analyses included one-way ANOVA with Bonferroni correction, Pearson correlation coefficients, and multivariable linear regression models adjusted for age, BMI, metabolic, and oxidative stress parameters.

RESULTS: Class II obese hypertensive patients exhibited the highest systolic and diastolic blood pressure, body mass index, and the most severe metabolic dysregulation, including elevated fasting glucose, insulin resistance, and dyslipidemia. Oxidative stress was significantly increased, as indicated by elevated MDA levels and reduced GSH and SOD activity. Inflammatory cytokines, including VEGF, IL-1β, and IL-9, were markedly elevated in this group. Gene and protein expression levels of Pro-BNP, ET-1, and MCP-1 were significantly upregulated in a stepwise manner across the groups, with class II patients showing the highest expression. Specifically, protein levels of Pro-BNP, ET-1, and MCP-1 were increased by 204.8%, 222.2%, and 180.6%, respectively, compared with healthy controls (all p < 0.05). Strong positive correlations were observed between Pro-BNP and both ET-1 and MCP-1 (r = 0.991, p < 0.001 for both). Receiver operating characteristic (ROC) analysis demonstrated high predictive accuracy for Pro-BNP (AUC = 0.94), ET-1 (AUC = 0.89), and MCP-1 (AUC = 0.92), with a combined biomarker panel achieving an AUC of 0.97.

DISCUSSION: The robust interrelationships among MCP-1, ET-1, and Pro-BNP suggest their synergistic involvement in promoting vascular inflammation, endothelial dysfunction, and cardiac stress in obesity-related hypertension. These biomarkers may serve as diagnostic indicators and therapeutic targets. Limitations include the male-only cohort and cross-sectional design.

CONCLUSION: The robust interrelationships among MCP-1, ET-1, and Pro-BNP suggest their synergistic involvement in promoting vascular inflammation, endothelial dysfunction, and cardiac stress in obesity-related hypertension. These biomarkers may serve as valuable diagnostic indicators and potential therapeutic targets. Further interventional studies are warranted to validate their clinical utility and explore targeted treatment strategies.

PMID:41832687 | DOI:10.2174/0113816128397599251204081009

Curr Pharm Des. 2026 Mar 12. doi: 10.2174/0113816128423981251208075251. Online ahead of print.

ABSTRACT

INTRODUCTION: Skin hyperpigmentation is a common concern that can significantly impact aesthetic perception and self-esteem. Consequently, there is growing interest in identifying natural inhibitors of melanin synthesis to develop cosmetic formulations that are effective, safe, and sustainable. This study aimed to develop, characterize, and evaluate the in vitro anti-melanogenic potential of emulsions containing jaboticaba (Plynia peruviana (Poir.) Govaerts) peel extract in combination with azelaic acid (AA).

METHODS: Four distinct formulations were prepared: TAAJ (AA + jaboticaba extract, with turbo-shear mixing), AAJ (AA + jaboticaba extract, without high-shear mixing), TAAAE (AA + ellagic acid (EA), with turbo- shear mixing), and TAA (AA, with turbo-shear mixing). All formulations underwent physicochemical characterization and statistical analysis.

RESULTS: Particle sizes ranged from 295.20 to 630.50 nm, with polydispersity index (PDI) values between 0.1 and 1.0, and zeta potential from -6.82 to +2.02 mV. Jaboticaba peel extract demonstrated excellent performance in both antioxidant assays and mushroom tyrosinase inhibition, surpassing conventional agents. TAAJ exhibited the highest anti-melanogenic activity, achieving the greatest tyrosinase inhibition and the lowest IC50. TAAJ and AAJ showed the strongest copper-ion chelating activity, while jaboticaba peel extract and TAAAE also displayed chelating capacity; TAA showed none. TAA induced the most significant reduction in melanin synthesis in B16F10 melanoma cells.

DISCUSSION: Among the tested formulations, the most promising was selected based on macroscopic characteristics, presenting a homogeneous, milky appearance without phase separation. This suggests that all tested formulations exhibited some degree of anti-melanogenic activity, likely through distinct mechanisms influenced by the complex interactions among their active components.

CONCLUSION: To the best of our knowledge, no previous studies have investigated jaboticaba peel extract for skin hyperpigmentation. These findings highlight jaboticaba peel extract-an agro-industrial byproduct-as a promising and eco-friendly ingredient for hyperpigmentation treatment, supporting the development of innovative cosmetic formulations leveraging sustainable, plant-based resources.

PMID:41832683 | DOI:10.2174/0113816128423981251208075251

Curr Pharm Des. 2026 Mar 11. doi: 10.2174/0113816128431488251204105511. Online ahead of print.

ABSTRACT

BACKGROUND: Environmental exposure to volatile organic compounds (VOCs) may adversely affect liver function, particularly in adolescents; however, the evidence remains scarce.

OBJECTIVE: This study aimed to evaluate the individual and combined effects of VOCs exposure on liver function in adolescents, as well as the potential mediating role of lactate dehydrogenase (LDH) and possible intervention strategies.

METHODS: In total, 1,280 adolescents aged 12-19 years from the National Health and Nutrition Examination Survey were studied to examine the associations between 15 VOC metabolites and 4 liver function indicators. Four statistical models were employed to assess the associations, including weighted linear regression, restricted cubic splines, weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR). Mediation analysis was performed to evaluate whether LDH mediated or partially explained these associations.

RESULTS: Among the 15 individual VOC metabolites, 8 were observed to have a significant association with specific liver function indicators. The WQS and BKMR models consistently identified significant associations between VOC mixtures and elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Additionally, AMCC [parent VOC (pVOC): N, N-dimethylformamide] and HMPMA (pVOC: crotonaldehyde) were identified as major contributors to the combined effect. Mediation analysis showed the potential mediation effect of serum LDH on these associations. Moreover, the adverse effect of VOC exposure on adolescent liver function was significantly mitigated with adequate vitamin D intake.

DISCUSSION: The results indicate that VOC exposure is positively associated with elevated liver function indicators in adolescents, with AMCC and HMPMA as main contributors. The mediating role of LDH suggests that oxidative stress may serve as a key mechanistic pathway underlying VOC-induced liver injury. Additionally, adequate vitamin D intake appears to mitigate these adverse effects.

CONCLUSION: Our findings revealed a positive association between exposure to VOC and liver function in adolescents, and suggest that LDH may be a potential mechanism for VOC-induced liver injury. Supplementing with vitamin D may help protect adolescent liver function from the effects of VOC exposure.

PMID:41832679 | DOI:10.2174/0113816128431488251204105511

Tunis Med. 2025 Aug 1;103(8):969-974. doi: 10.62438/tunismed.v103i8.5623.

ABSTRACT

INTRODUCTION: Role-playing are a subtype of simulation aimed at improving non-technical skills, such as delivering a cancer diagnosis. The use of this pedagogical method in teaching bad news delivery has been growing in recent years. However, data, particularly from Tunisia, on this topic are limited.

AIM: To evaluate learners’ perceptions of the usefulness of role-playing in delivering cancer diagnoses.

METHODS: We conducted a descriptive, cross-sectional study between January and October 2024. We included 4th-year medical students who had completed their gastroenterology rotations at Charles Nicolle Hospital. For each group, we conducted a role-playing session. A questionnaire was distributed to learners before and after the role-playing session to assess whether there was a change in students’ opinions.

RESULTS: We collected data from 61 students. According to the students, the most crucial step for successfully delivering a diagnosis was training doctors in delivering news about serious illnesses. Nearly half of the students (n=34) reported having difficulty communicating with patients or their families. All learners were convinced that simulation plays a major role in medical practice and medical education. Additionally, all students agreed that role-playing sessions are highly suitable for teaching the delivery of bad news, particularly cancer diagnoses. Participation in role-playing sessions allows doctors to understand patients better. The learners’ responses before and after the role-playing session were comparable.

CONCLUSION: Role-playing is a highly effective active learning method for teaching cancer diagnosis delivery. It helps learners approach reality more closely and acquire communication skills with patients and their families.

PMID:41832662 | DOI:10.62438/tunismed.v103i8.5623

Tunis Med. 2025 Aug 1;103(8):961-968. doi: 10.62438/tunismed.v103i8.5651.

ABSTRACT

AIM: To develop procedural documents of three gestures taught in endocrinology and to assess their contribution in the procedural learning of students.

METHODS: Prospective randomized controlled study, comparing a self-learning tool combining a video and a procedural document (PD), with a guided teaching (GT) of a technical gesture by a teacher. The study involved 89 students randomized into: an intervention group (I1;n=47) and a control group (I0;n=42). All the participants had GT regarding blood pressure measurement, thyroid examination, and waist circumference measurement. Then, the GroupI1 received three PD and three videos illustrating the same gestures. A week later, an assessment was performed. Group I0 received the documents after the assessment. The student satisfaction with the two methods was evaluated.

RESULTS: The percentage of students who used PD and videos was comparable between the two groups (68to79% in groupI1 and 76to86% in groupI0, p between0.161and0.827). The mean evaluation score respectively at the thyroid examination station, blood pressure and waist circumference measurement was 8.07±1.28 in groupI1 versus7.94±1.01 in group I0(p=0.634),7.51±1.11versus7.68±0.96(p=0.466) and7.41±1.37versus6.94±1.34(p=0.132). The mean satisfaction score of the two teaching tools was respectively in group I1 versus I0, of (9.38±1.53 and 8.88±1.63; p=0.195), (9.39±1,65 and 9.25±0.76, p=0.658) and (9.43±1.59 and9.24±0.82,p=0.543).The GT satisfaction score was 9.34±1.40 in I1group versus 9.62±0.46 in I0group, p=0.227. The power of the statistical test was less than 10%.

CONCLUSION: The lack of significant difference between the evaluation scores of the two groups could be explained by the low rate of consultation of the educational tools and the small sample size.

PMID:41832661 | DOI:10.62438/tunismed.v103i8.5651

Tunis Med. 2025 Aug 1;103(8):956-960. doi: 10.62438/tunismed.v103i8.5167.

ABSTRACT

Introduction In the emergency department (ED), learning by simulation provides a safe acquisition of procedural skills. This study’s objective was to evaluate the impact of the simulation-based learning on videolaryngoscope (VL) orotracheal intubation (OTI) skills among residents practicing in ED.

METHODS: evaluative, prospective study, including residents practicing in teaching hospitals ED in Tunis. They were novices in direct laryngoscopy. We scheduled a procedural simulation session. Residents were evaluated before and after the session. The primary endpoint was the rate of successful OTI after learning session.

RESULTS: 32 residents were enrolled. The mean age was 28 ± 2.5 years. Gender ratio was 0.18. The mean exercise seniority was 1.53 ± 0.7 years. The rate of successful OTI before and after the training was observed in 4 residents (12.5%) vs 23 (71.8), p=0.689. The average time of OTI was respectively 149.81±108 seconds (sec) vs. 51±96 sec (p<0.001). The rate of esophageal intubation was n (%): 16 (50%) vs 9 (28%) (p=0.49) and the mean number of attempts was 3.81 vs. 1.84 (p<0.001). Intubation time after the session more than 12 sec was an independent factor of intubation failure (Adjusted OR= 3.5, p=0.001 and 95%CI [1.018-10.69]).

CONCLUSION: Learning by simulation in the ED provides residents with a skill that allows complete OTI in less time and a smaller number of attempts. Intubation time is an independent factor predicting intubation failure among doctors learning intubation by VL.

PMID:41832660 | DOI:10.62438/tunismed.v103i8.5167

Tunis Med. 2025 Aug 1;103(8):1087-1091. doi: 10.62438/tunismed.v103i8.5966.

ABSTRACT

INTRODUCTION: Thyroid nodules are a frequent and mostly benign pathology. Failure to recognize a cancer remains a major concern for any physician confronted with this pathology. Fine needle aspiration cytology (FNAC) is the reference examination when managing thyroid nodules. The aim of our study was to evaluate the role of FNAC in determining the histological nature of thyroid nodules.

METHODS: We conducted a cross-sectional, retrospective, and descriptive study, spread over a 5-year period from January 2016 to December 2020, carried out in our Department of Otolaryngology and Head and Neck Surgery.

RESULTS: The median age of the 200 patients was 46 years. Female predominance was evident, with a sex ratio of 0.09. All our patients underwent FNAC followed by surgical excision. FNAC was non diagnostic in 8 cases (4%) and benign in 53 cases (20.50%). It revealed atypia of undetermined significance in 33 cases (16%), a follicular neoplasm in 45 cases (21.50%) and a malignant suspicion in 47 cases (22.50%). FNAC was malignant in 22 cases (10.5%). Pathological examination showed malignancy in 115 cases. FNAC has an overall sensitivity of 84% and a specificity of 71.6% in predicting thyroid nodules diagnosis.

CONCLUSION: Combining clinical and ultrasonographic criteria with cytological results improves the sensitivity of thyroid carcinoma screening.

PMID:41832648 | DOI:10.62438/tunismed.v103i8.5966

Tunis Med. 2025 Aug 1;103(8):1073-1079. doi: 10.62438/tunismed.v103i8.5408.

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, destructive inflammatory rheumatic disease reported in populations of African origin. The aim of this study was to evaluate the epidemiological, clinical and paraclinical data of RA in Guinea with a registry from 2018 – 2022.

METHOD: This was a longitudinal, retrospective study conducted in the rheumatology department of CHU Ignace Deen between January 2018 and December 2022. The diagnosis of RA was based on the ACR and EULAR 2010 criteria.

RESULTS: During the study period we collected 528 cases of RA out of 4213 observations (12.5%). There were 433 (82%) women with an average age of 47.3 years. The average number of painful joints was 8, ranging from 4 to 28, and the average number of swollen joints was 2 (ranging from 2 to 20). Rheumatoid factors were positive in 396 (75%) of cases, while anti-CCP antibodies were positive in 380 (72%) of patients. With DAS28, remission was noted in 53 (10%) of our patients, activity was low in 137 (26%) of cases, moderate in 259 (49%) and high in 79 (15%). Quality of life was assessed by the HAQ score, the mean value of which was 48 out of 60 (range 0 to 60).

CONCLUSION: Rheumatoid arthritis is the most common form of arthritis in Guinea. It mainly affects housewives, with significant functional repercussions.

PMID:41832646 | DOI:10.62438/tunismed.v103i8.5408

Tunis Med. 2025 Aug 1;103(8):1061-1066. doi: 10.62438/tunismed.v103i8.5888.

ABSTRACT

BACKGROUND: Acute pancreatitis (AP) is acute inflammatory process of the pancreas, commonly attributed to biliary or alcoholic causes. Drug-induced AP, although rare, is increasingly recognized as a potential etiology. However, there is limited literature on this topic.

AIM: This study aims to review the epidemiological, clinical, radiological, and management characteristics of drug-induced AP based on data from Tunisian databases.

METHODS: A retrospective study was conducted at the Department of Digestive and Visceral Surgery, spanning five years. Thirteen cases of drug-induced AP out of 1580 admitted patients with AP were analyzed. Data collection included clinical characteristics, diagnosis methods, therapeutic approaches, and outcomes.

RESULTS: We report a series of 13 cases of drug-induced acute pancreatitis (AP). Due to the rarity of this event, our small sample size limits the statistical power of our findings. However, each case provides valuable insight into potential drug associations with AP. The mean age of affected patients was 55.62 years, with a male predominance (77%). Common symptoms included sudden onset epigastric abdominal pain (100% of cases) and elevated lipase levels (92.3%). Implicated medications included captopril (38.5%), atorvastatin (23.1%), azathioprine (23.1%), metformin, and olanzapine (7.7% each). Management involved pain management and proton pump inhibitors, with favorable outcomes in 84% of cases.

CONCLUSION: Drug-induced pancreatitis is a recognized entity requiring multidisciplinary management. Early recognition and reporting of suspected cases are essential for improved pharmacovigilance.

PMID:41832644 | DOI:10.62438/tunismed.v103i8.5888