Functional neurological disorder (FND) is a neuropsychiatric disorder that manifests with involuntary neurologic symptoms because of a brain network dysfunction, arising from variable biopsychosocial etiologies. Symptoms have positive clinical features of inconsistency, like tremor entrainment or distractibility, and incongruence with typical or well-understood neurophysiology/neuroanatomy. FND is not a diagnosis of exclusion and diagnostic criteria are available for many FND phenotypes.

Since the prognosis and treatment of nervous system tumors are still not beneficial to the patient, alternative therapies need to be investigated as primary or supplemental treatments to current methods. Hydrogel systems are well-known for their high-water absorption capacity, three-dimensional network composition, and biocompatibility, making them suitable as photosensitizers (PS) carriers for photodynamic therapy (PDT). A gelatin hydrogel system was synthesized via chemical cross-linking with varying glutaraldehyde concentrations, and the optimal hydrogel was encapsulated with methylene blue (MB). Scanning electron microscopy (SEM) analysis demonstrated that the formulation formed three-dimensional networks. The freeze-drying procedure increases the hydrogel's water-retention capacity, as shown by the swelling test. All spectroscopic results showed excellent photophysical properties of MB when incorporated into the system. The encapsulation efficiency was 95.35%. According to the trypan blue exclusion test, the cell viability in the PDT-treated groups was significantly lower (p < 0.05). Approximately 95% of 9L/lacZ cells died after PDT utilizing a concentration of 50μmol.mL-1 for the hydrogel with MB. Based on the data obtained, the system's viability has been confirmed, and it is expected to demonstrate potential in the treatment of neoplasms.

Erosive pustular dermatosis of the lower legs (EPDL) is a rarely diagnosed, chronic inflammatory skin disease that occurs predominantly in elderly people. Predisposing factors include skin atrophy, chronic venous insufficiency, and trauma. Although the pathogenesis of EPDL has not yet been conclusively clarified, there are ongoing discussions on its nature as a neutrophilic dermatosis in which exogenous triggers lead to immunological dysregulation with local skin damage. Clinically, EPDL manifests with superficial, sterile pustules from which sharply defined erosions develop. The predilection sites are the middle third of the lower leg extensor sides. It is a diagnosis of exclusion, which makes diagnostic differentiation more difficult. Potent topical glucocorticoids with a high therapeutic index (TIX) and calcineurin inhibitors are used therapeutically. Systemic immunomodulating therapies are reserved for refractory courses. Optimization of wound care is also important. In the long term, education and skin care are at the forefront of the complex and often long-term treatment. Due to the chronic recurrent course and the risk of secondary ulcerations and superinfections, early diagnosis and individual treatment planning is important. Interdisciplinary and interprofessional collaboration can make a decisive contribution to improve quality of life of affected patients and reduce the risk of complications.

The presence of an embryonal carcinoma in a cervical lymph node, in the absence of a palpable testicular mass, presents a diagnostic dilemma regarding whether this represents a rare primary extragonadal germ cell tumor (EGCT) of the neck or a metastasis from an occult spontaneously regressed testicular cancer. We report the case of a 34-year-old male presenting with isolated left cervical lymphadenopathy. Initial physical examination of the testes was unremarkable, potentially supporting a diagnosis of primary cervical origin. However, markedly elevated serum tumor markers (lactate dehydrogenase [LDH] and alpha-fetoprotein [AFP]), alongside a beta-human chorionic gonadotropin (beta-hCG) level within normal limits, prompted a search for a gonadal primary. Scrotal ultrasound revealed a calcified scar in the left testis, and subsequent orchiectomy confirmed a fibrotic nodule with no viable malignancy, consistent with the spontaneous regression of a primary tumor. The patient was treated for Stage IIIC non-seminomatous germ cell tumor (NSGCT) with bleomycin, etoposide, and cisplatin (BEP) chemotherapy and remains disease-free at 3 years. This case illustrates that primary cervical EGCT is a diagnosis of exclusion. The spontaneous regression phenomenon must be rigorously investigated via ultrasound and orchiectomy to avoid misdiagnosis and ensure appropriate multimodal therapy.

Hepatorenal toxicity is one of the most life-threatening adverse effects of methotrexate (MTX). The present study investigated the potential protective effects of glutamine (GLU), glycine (GLY), methionine (MET), and leucine (LEU) in MTX-induced hepatorenal toxicity in vitro and in vivo. Freshly isolated hepatocytes and renal slices of rats were used to investigate the effect of these amino acids in vitro, while male Sprague-Dawley rats were used to evaluate their effects in vivo. Rats were assigned into 6 equal groups: a negative control, MTX (20mg/kg/day, i.p., 3days), MTX + (GLU 25mg/kg/day i.p., 6days), MTX + (GLY 0.5 gm/kg/day, i.p., 3days), MTX + (MET 1mg/kg/day, i.p., 6days) and MTX + LEU (50mg/kg/day, i.p., 6days). These amino acids showed enhanced viability of liver and kidney cells assessed by trypan blue exclusion and lactate dehydrogenase leakage tests, respectively. Besides, pre-incubation of suspended hepatocytes or renal slices with GLU (25mM and 10mM, respectively), GLY (25mM and 5mM, respectively), MET (12.5mM and 5mM, respectively) or LEU (25mM and 10mM, respectively), 30min before MTX, significantly down-regulated caspase-3 and TNF-α levels as compared with MTX-intoxicated groups. MTX-induced hepatorenal toxicity was manifested by increasing liver and kidney enzymes, oxidative stress and severe histopathological alterations. Amino acids pre-treatment abrogated MTX-induced alteration in hepatorenal toxicity indices as evidenced by amelioration in oxidative stress, inflammatory mediators, and histopathological changes. Amino acids may serve as a promising adjuvant therapy with MTX as it may ameliorate its hepatorenal toxicity through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.

Understanding the gap: How much do healthcare professionals know about functional neurological disorders?

Aim: Granulomatous mastitis is a benign inflammatory condition of the breast, typically of idiopathic origin. This case report seeks to examine the diagnosis and management of granulomatous mastitis with erythema nodosum (GMEN), a rare manifestation, and to offer insight for clinicians encountering comparable cases. Case: A 34-year-old woman presented with right breast swelling and chest pain persisting for two months. On physical examination, two palpable masses were detected in the lower outer quadrant of the right breast, along with increased temperature and tenderness. Additionally, several erythema nodosum lesions were observed on both lower extremities. Breast ultrasound revealed heterogeneity in the fatty tissue of the outer half of the right breast, with a significant increase in the ductal diameter (6.1 millimeters at its widest point) and dense content within the lumens, raising suspicion for mastitis. On the seventh day of treatment with ciprofloxacin and teicoplanin, the mass areas in the breast fistulized to the skin, initially discharging tissue fluid, followed by ulceration. A Tru-cut breast biopsy was performed on the affected area, revealing mixed inflammatory infiltrates consisting of neutrophils, lymphocytes, histiocytes, granulomatous formations, and giant cells, leading to a diagnosis of idiopathic granulomatous mastitis. After thorough evaluation for differential diagnoses, the patient was started on methylprednisolone and methotrexate. Following six months of treatment, the patient showed clinical improvement. Three months later, due to recurrence, the patient was followed up at an external center, where treatment with azathioprine and methylprednisolone was continued. Conclusion: Idiopathic granulomatous mastitis is a diagnosis of exclusion, and thorough evaluation for other potential causes, particularly malignancy, is crucial. It is also possible to prevent unnecessary antibiotic use with suspicion of infectious mastitis by keeping it in mind in differential diagnoses. Early diagnosis is essential due to the requirement for prolonged treatment with immunosuppressive agents.

Triadimefon (TF) and triadimenol (TN) are triazole fungicides widely used to prevent fungal infections in cereals, fruits, and other economically important crops. Their harmful effects on non-target organisms have been reported. This study investigated the cytogenotoxic effects of TF and TN, isolated and combined, at environmentally relevant concentrations (TF: 0.006, 0.012, and 0.024 mg/mL; TN: 1.5, 3.0, and 6.0 mg/mL; and 0.012 mg/mL TF + 3.0 mg/mL TN) on human lymphocytes using the trypan blue exclusion test and the comet assay. Additionally, in silico tools, BioTransformer and DIGEP-Pred, were employed to elucidate metabolic pathways more effectively for detoxifying these xenobiotics and to evaluate their putative effects on gene transcription, respectively. Exposure to TF and TN, either alone or in combination, did not affect lymphocyte viability at the tested concentrations. However, both compounds induced an increase in the percentage of DNA strand breaks after treatment. The in silico predictions suggested that the interaction with the cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C9, and CYP2D6) differed for each compound analyzed. Gene expression prediction indicated that TF and TN may up-regulate genes involved with hormonal alterations, Alzheimer’s disease risk, and cancer progression (SF1, SPON1, ADGRF5, and RORB). While they may down-regulate a gene involved with changes in heart rhythm and neurotoxicity (HCN1). In conclusion, our findings reinforced that the triazole fungicides TF and TN, while effective in agriculture, may pose risks to genomic stability in humans, highlighting the importance of biomonitoring studies in exposed populations.

Peripartum cardiomyopathy (PPCM) is a rare, but potentially life-threatening condition that typically presents during the final month of pregnancy, or within the first few months postpartum. PPCM is characterized by a decrease in left ventricular function that leads to heart failure in pregnant women with no previous history of cardiovascular disease, and for which the etiology of heart failure cannot be identified. Despite advances in understanding its molecular and clinical underpinnings, PPCM remains a diagnosis of exclusion. This review provides an overview of PPCM, including discussions on clinical presentation, population incidence, the potential role for genetic mutations, existing animal models, and candidate biomarkers.

Cancer of unknown primary (CUP) is evolving from a diagnosis of exclusion treated with empirical chemotherapy to a molecularly defined entity amenable to precision-based interventions. This heterogeneous entity, comprising 2-3% of all metastatic malignancies, encompasses diverse cancers with clinically occult primary sites at diagnosis after a thorough workup. Recent landmark trials including CUPISCO and Fudan CUP-001 have demonstrated significant survival improvements with molecularly guided therapies compared to empirical chemotherapy, fundamentally enhancing and complementing traditional organ-centric treatment paradigms. This review synthesizes the current evidence supporting molecular diagnostics, tumor-agnostic therapies, and precision-based approaches in CUP management. We examine the clinical utility of comprehensive genomic profiling, gene expression profiling, and liquid biopsy technologies, while addressing implementation challenges and future directions. The integration of molecular tumor boards and the emergence of tissue/tissue-of-origin agnostic therapies herald a new era where CUP transitions from therapeutic nihilism to personalized oncology. As molecular technologies advance and targeted therapies proliferate, CUP may no longer represent a diagnosis of exclusion but rather an opportunity for molecularly informed precision care.

Introduction: Primary central nervous system vasculitis (PCNSV) is a rare, heterogenous and polymorphic disorder affecting the blood vessels of the CNS. It is a diagnosis of exclusion with no disease specific clinical features, serological or imaging findings. Historically, the presence of hemorrhages was considered rare in PCNSV. However, with the advent of susceptibility weighted imaging (SWI) sequences of MRI, the presence of microhemorrhages has been found to be common despite macrohemorrhages being uncommon. Hypothesis: The presence of microhemorrhages in the cerebellar tonsils on SWI sequences of MRI brain in a patient with an unexplained neurological deficit are indicative of PCNSV. Methods: We retrospectively evaluated our biopsy proven PCNSV patients and patients with hypertensive cerebellar hemorrhage who underwent an MRI (1.5T or 3T) between 2020-2024. All clinic-radiological and histopathological details of these patients were entered into a predesigned proforma. A senior neuroradiologist evaluated the MRI scans for the presence of tonsillar microhemorrhages. Results: Twenty-nine patients of PCNSV (15- granulomatous vasculitis; 14 – lymphocytic vasculitis) and 44 patients with hypertensive cerebellar ICH fulfilled the study criteria. The clinical characteristics of the patients are mentioned in table 1. All PCNSV patients (100%) were found to have tonsillar microhemorrhages along with supratentorial and infratentorial lesions (T2/ FLAIR/ SWI) and 27/29 (93.1%) revealed punctate or linear enhancement of these tonsillar lesions (Figure 1). There was no difference in the microhemorrhage pattern between granulomatous and lymphocytic vasculitis subtypes of PCNSV. In comparison, only 9/44 (20.4%) patients with cerebellar hemorrhage had tonsillar microhemorrhages. Amongst them, all of them had pontine microhemorrhages while 6/9 (66.7%) and 5/9 (55.5%) had concomitant midbrain and medullary microhemorrhages respectively. Most patients with concomitant pontine microhemorrhages had no cerebellar tonsil involvement. Conclusions: Cerebellar tonsillar microhemorrhages in PCNSV may be a marker of its intrinsic microangiopathy. The presence of cerebellar tonsillar microhemorrhages in patients with an unexplained neurological deficit may be an imaging marker for diagnosing PCNSV.

Fasciitis-like primary breast pyoderma gangrenosum: A rare case report

Limited availability of live CBA for AQP4-IgG testing and its consequences for the diagnosis and treatment of NMOSD in Latin American countries.

Immune gene correlation networks differentiate both chronic lung allograft dysfunction and survival.

Drug treatment of hydatid cysts is usually carried out using benzimidazole compounds such as albendazole and mebendazole. However, limited efficacy, the need for long-term use, and side effects such as liver damage and gastrointestinal problems have made the use of these drugs challenging. The present study aimed to evaluate the antiparasitic effects of Baicalein (BC) on Echinococcus granulosus protoscoleces (PTS) and its inhibitory effects on the expression level of antioxidant genes. The antiparasitic effects of BC on PTS was evaluated using eosin exclusion test. The effects of BC on the expression level of antioxidant genes glutathione glutathione S-transferase (GST), thioredoxin (Trx), and thioredoxin peroxidase (TPx) in PTS was performed using Real-time PCR. For cytotoxicological tests, two human cell lines including normal liver cells (THLE-2) and liver cancer cells (HepG2) were used for MTT assay. The findings demonstrated that both the lethality and subsequent mortality of E. granulosus PTS increased significantly with rising concentrations of BC and prolonged exposure time (p < 0.001). Among the concentrations evaluated, BC exhibited the most pronounced antiparasitic activity against PTS at 64 and 128 µM/mL, achieving complete protoscolicidal effects after 30 and 20min, respectively. Furthermore, the calculated CC50 values were 161.3 µM/mL for THLE-2 cells and 75.6 µM/mL for HepG2 cells. Treatment of PTS with the BC dose-dependently reduced the relative expression level of the GST, TRx, and TPx genes (P < 0.001); while significantly increased the reactive oxygen species in the PTS. The results of the study showed that BC had a significant protoscolicicidal effect on E. granulosus PTS, which increased parasite death by reducing the expression of antioxidant genes, indicating a direct effect on their defense system and metabolic pathways. Also, BC had a favorable selective effect on HepG2 cancer cells and showed less toxicity than normal THLE-2 cells, which confirms its high selectivity index. Future studies can focus on developing novel drug delivery formulations and investigating signaling pathways related to oxidative stress and apoptosis in parasites to optimize the antiparasitic and anticancer effects of BC.

Idiopathic hypersomnia (IH) is a rare chronic neurological condition that may be characterized by excessive daytime sleepiness (EDS), and/or prolonged nocturnal sleep, and also sleep inertia, yet its underlying mechanisms and diagnostic boundaries remain poorly defined. A key challenge is distinguishing excessive sleep duration from EDS, as patients may present one or both features, and similar symptoms can arise from diverse medical, psychiatric, and sleep disorders. Current diagnostic criteria rely heavily on the multiple sleep latency test, which frequently underestimates hypersomnia in patients with long sleep need, demonstrates poor test-retest reliability, and separates IH from narcolepsy type 2 based on an unstable count of sleep-onset REM periods. Accurate measurement of long sleep is an unmet need. Actigraphy and sleep diaries frequently misestimate true sleep duration, while extended polysomnography, the gold standard, is rarely feasible outside research. Defining abnormal sleep quantity remains difficult given individual variability and the heterogeneity of IH phenotype. The pathophysiology of IH remains largely speculative. No definitive biomarker has been identified, and proposed mechanisms, including genetic susceptibility, circadian alterations, abnormal slow-wave dynamics, and neurobiology disturbances lack consistent validation. Clinical overlap between IH and hypersomnolence associated with depression suggests potential shared disruptions in arousal and circadian-homeostatic systems, though their neurobiological bases remain unclear. Therapeutic approaches are still limited. Low-sodium oxybate offers symptomatic improvement, and orexin receptor agonists represent an encouraging emerging class. Advancing the field will require better phenotyping, standardized sleep extension methods, and biomarkers to define IH as a distinct multidimensional disorder rather than a diagnosis of exclusion.

Background: Physical activity is important for prevention of some of the most common diseases worldwide: cardiovascular disease, type 2 diabetes mellitus, and certain types of cancers. However, extremely strenuous exercise performed over a prolonged period can lead to Overtraining Syndrome (OTS), especially in athletes competing at elite levels. This is characterized by psychological, neuroendocrine and immunological disturbance, and a prolonged decrease in exercise tolerability. Although many theories have emerged about the etiology of this condition, the pathophysiology is still unknown. That makes it difficult to diagnose OTS, as the resulting symptoms, including fatigue and diminished exercise performance, are common in athletes and largely nonspecific. Aim: The goal of this study was to synthesize current evidence on possible hormonal biomarkers that may assist in the diagnosis of OTS. Materials and methods: The search was conducted via PubMed, Science Direct, NCBI, and Google Scholar databases for articles with a focus on human studies. The keywords included “overtraining syndrome”, “OTS”, “overreaching syndrome”, “hormonal biomarkers”, “testosterone cortisol ratio”, “testosterone estradiol ratio”, “hypothalamic pituitary axis”, “hypothalamic dysfunction”, “EROS-HPA axis”. Results: Certain studies suggest that basal and dynamic hormone measurements may aid in the diagnosis of OTS. The Cadegiani and Kater EROS studies (2017-2020) [9, 10, 11] have proposed diagnostic tools composed of clinical and biological markers that, in the tested cohort, showed 100% diagnostic accuracy in distinguishing between OTS and non-OTS athletes. However, without an established pathophysiological pathway, many researchers remain sceptical. Conclusions: There is a definite need for validation of proposed diagnostic tools and reaching a consensus on the diagnostic process of OTS, instead of having it be a diagnosis of exclusion.

Adverse Childhood Experiences (ACEs) and Positive Childhood Experiences (PCEs) are each independently associated with a range of adult outcomes, including mental health, substance use, and criminal justice involvement. However, few studies have examined how the balance between these experiences influences outcomes. This study explores the predictive utility of a PCE:ACE ratio. Unlike previous measures of resiliency and risk protection scales that treat risk and protective factors as parallel dimensions, the ratio is population-level heuristic intended to capture the relative balance of positive versus adverse experiences using a single relational metric. Using data from a representative sample of 1,203 adults in Northern Ireland, participants completed validated measures of 13 ACEs and 10 positive childhood experiences (PCEs) A weighted PCE:ACE ratio was calculated, and participants were categorised into high, moderate, or low ratio groups. Findings showed that a higher ratio was significantly associated with reduced odds of arrest, incarceration, school exclusion, substance use, and mental health diagnosis, even after adjusting for age, gender, and deprivation. Those in the low-ratio group had the highest rates of adverse outcomes. While the ratio offers an intuitive and accessible framework for understanding developmental balance, limitations include the potential for oversimplification of distinct ACE-PCE profiles. These findings support the feasibility of a ratio-based approach that standardises balance rather than the independent accumulation of risks and strengths, and suggests that a stronger balance of protective experiences may buffer the impact of adversity. Further research is needed to explore threshold effects and interaction dynamics. However, the ratio provides a useful metric and sound basis for capturing population health and the extent to which public investment is tipped in favour of positive or less positive outcomes.

Bone pain is a frequent yet challenging complaint encountered in paediatric practice. While most cases are benign and attributable to growing pains, a significant minority may represent serious underlying conditions such as infection, inflammatory disease, metabolic disorders, or malignancy. Growing pains remain a diagnosis of exclusion, and inappropriate reassurance without adequate clinical assessment may lead to delayed diagnosis of life-threatening disorders. Conversely, indiscriminate investigations contribute to parental anxiety and unnecessary healthcare expenditure. This review provides a comprehensive and evidence-based overview of growing pains and bone pain in children, emphasizing epidemiology, pathophysiology, clinical features, red-flag signs, differential diagnoses, rational investigative strategies, and management principles. The aim is to guide paediatricians toward a structured, safe, and cost-effective approach while ensuring early recognition of pathological causes.

Arthrofibrosis after total knee arthroplasty (TKA) is the result of excessive scar formation because of the inflammatory insult of surgery. This formation can lead to significant loss of range of motion, pain, and functional deficits requiring further treatment. Although much has been researched on arthrofibrosis, it continues to lack definitive diagnostic testing. This has led to an array of approaches and treatments to relieve patients of this complication. In response to the inflammatory insult caused by TKA, arthrofibrosis occurs because of an overactivation and proliferation of myofibroblasts. This leads to an abundant deposition of type I collagen and scar tissue formation. This general cascade has been found to be associated with multiple signaling pathways involving primarily transforming growth factor-beta. Additionally, there is a multifactorial component of risk factors and comorbidities, which contribute to the formation of arthrofibrosis. Arthrofibrosis is diagnosed as both a clinical diagnosis and a diagnosis of exclusion. Using the patient's history, clinical examination, and diagnostic testing to rule out other etiologies, one can obtain the diagnosis of arthrofibrosis. While stiffness is an umbrella term that is commonly used interchangeably with arthrofibrosis, it is imperative to use the diagnostic testing to systematically rule out other causes of stiffness. There is no definitive imaging, biopsy, or biomarker test specific for arthrofibrosis currently, which makes obtaining a definitive diagnosis difficult. Nonoperative and operative treatment options are available for the treatment of arthrofibrosis. Most conservative approaches begin with physical therapy, appropriate pain management, and oral anti-inflammatory medication. Treatment options rise in invasiveness with manipulation under anesthesia, arthroscopic lysis of adhesions, open lysis of adhesions, and ultimately revision TKA. This review will focus on the role of manipulation under anesthesia in the setting of arthrofibrosis.