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PubMed1989

Noncontiguous local recurrence of posterior uveal melanoma after cobalt 60 episcleral plaque therapy.

Four patients with posterior uveal melanomas treated by cobalt 60 episcleral plaque therapy developed the intraocular recurrence of choroidal melanoma at a site distant from and noncontiguous to their original lesions. Three of the four patients died of metastatic melanoma. The proportion of eyes with posterior uveal melanoma treated with cobalt 60 brachytherapy who subsequently develop this type of local recurrence appears to be low (0.68%).

Adult↗

PubMed1982

Computed tomography in purulent meningitis.

Of 102 patients with bacterial meningitis admitted to the Children's Hospital of Buenos Aires, 25 were selected for computed tomographic (CT) scans on the basis of altered consciousness for more than 96 hours after admission, persistent or recurrent seizures after 72 hours of antibiotic therapy, development of focal neurologic signs, increased intracranial pressure or prolonged fever. Scan findings included hydrocephalus, cerebritis, vasculitis, subdural effusion, cerebral atrophy, abscess, and ependymitis. Serial CT scans demonstrated the progression or regression of some complications. The CT scan was very useful in indicating the need for neurosurgical procedures.

Brain Edema↗

PubMed1977

Effectiveness of systemic BCG therapy in advanced melanoma.

The effect of systemic BCG therapy on advanced melanoma was studied in 42 patients with stage II and stage III disease. Evaluation of the immune response prior and during therapy revealed that patients who failed to convert a negative purified protein derivative (PPD) reaction and those having a low stimulation ratio of lymphocyte cultures had rapidly progressive disease and short survival. Neither tumor regression nor prolongation of survival could be appreciated in patients with stage III disease. Furthermore, aggravation of symptoms was observed in patients with visceral metastases. Fifty percent of the patients with stage II melanoma treated by operation and adjuvant immunotherapy had recurrent or metastatis disease within two years. No adverse effects were noted in patients with early disease who received adjuvant therapy. Two patients who had a full course of systemic BCG therapy developed severe reactions after intralesional injection of the vaccine. Further experience with various immunotherapeutic regimens and longer follow-up are necessary to evaluate its value in the early stages of melanoma.

Adult↗

PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗

PubMedDate not supplied

Merosin and congenital muscular dystrophy.

Merosin (also called as Laminin-2) is an isoform of laminin comprised of the alpha2, beta1 and gamma1 chains. In European populations, half of the patients with classical congenital muscular dystrophy have mutations of the LAMA2 gene (6q22-23) and present reduced or absence of laminin alpha2 chain. This form is generally referred to as merosin-deficient CMD. Merosin-deficient CMD is characterized by involvement of not only skeletal muscle but also central and peripheral nervous systems: Extensive brain white matter abnormalities are found by magnetic resonance imaging (MRI). However, most patients show no mental retardation. Recent case studies reported that some patients have several structural abnormalities such as abnormal cerebral cortical gyration, hypoplasia of cerebellum and pons, and dilation of ventricles. At present, functions of merosin related to muscle degeneration have not been fully elucidated. In addition, the mechanisms responsible for pathogenesis of diffuse brain white matter abnormalities remain to be determined. As mouse models for merosin-deficient CMD, three spontaneous mutants(dy, dy(2J), dy(PAS1)) and two mutants named dy(W) and dy(3K) by targeted gene disruption have been reported. These mice will help to elucidate the pathogenesis of merosin-deficient CMD and serve to develop therapy.

Animals↗

PubMed1997

Oral tolerance: elucidation of mechanisms and application to treatment of autoimmune diseases.

Oral tolerance is the phenomenon of systemic, antigen specific, immunological hyporesponsiveness that results from oral administration of a protein. The mechanism by which tolerance is generated depends on the amount of antigen administered; low doses favor induction of regulatory T cells while higher doses favor clonal deletion and anergy. The regulatory T cells induced by low doses of oral antigen are triggered by the same antigen to secrete cytokines that suppress, in an antigen nonspecific manner, inflammation in the microenvironment where the triggering antigen is located. This makes possible the targeted delivery of antiinflammatory cytokines to a specific tissue without the requirement for identifying the antigen causing the inflammation. This attribute makes active suppression an attractive mechanism for developing therapies for autoimmune diseases. Orally administered autoantigens have been shown to suppress a wide variety of experimental autoimmune diseases and have recently been applied to the treatment of human autoimmune diseases with promising early results.

Administration, Oral↗

PubMed1993

Enhancing the effectiveness of the specific serotonin antagonists. Combination antiemetic therapy with dexamethasone.

Combinations of drugs have become standard therapy for the prevention of vomiting caused by anticancer drugs like cisplatin. Recently, a new class of antiemetic agents, the potent and specific 5-HT3 receptor antagonists such as ondansetron, granisetron, and tropisetron, have been shown to be more effective and better tolerated than metoclopramide. This report describes the rationale for combination antiemetic therapy, details the testing of metoclopramide-based regimens as a model for combination therapy development, reviews completed trials of ondansetron plus dexamethasone, and offers strategies to further alleviate vomiting during anticancer chemotherapy. The reported trials testing metoclopramide-based combinations were reviewed and that experience was applied to the ongoing studies of ondansetron when used with dexamethasone and other agents. Combinations of metoclopramide, dexamethasone, and lorazepam prevented acute emesis caused by high-dose cisplatin in 63% of patients, lessened side effects, and were convenient enough to administer to outpatients. Completed trials of ondansetron and dexamethasone demonstrated improved vomiting control over ondansetron alone while using less cumbersome schedules. Attempts to improve ondansetron-based antiemetic regimens by developing optimal drug doses and schedules and adding adjuvant and different classes of antiemetic agents are now in clinical testing. Based on previous experience and current results, combinations of a specific serotonin agonist and dexamethasone are the best treatment for prevention of vomiting induced by chemotherapy. Future clinical research should aim to refine antiemetic regimens and improve emetic control through the use of new antiemetic and adjuvant agents.

Antiemetics↗

PubMed2000

Patterns of prostate cancer biopsy grading: trends and clinical implications.

The predictive value of Gleason grading from prostate needle biopsy was examined and the patterns of grade discordance with surgical specimens are discussed in terms of their clinical implications. Gleason scores from biopsy and matched radical prostatectomy specimens were compared in 428 consecutive patients. Patterns of concordance were examined with respect to numerical agreement as well as to whether differences result in a change in group assignment with respect to Gleason score group 2-4, 5-6, 7, and 8-10. The coefficient of agreement, kappa, and accuracy were used to measure predictive value. An exact Gleason score match was present in 41% of the cases, while 48% were undergraded and 17% overgraded. With respect to group assignment, 51% remained unchanged while 35% were undergraded and 14% overgraded. Kappa analysis yielded a value of 0.26, which represents a poor agreement beyond chance. A Gleason score of 5-6, 7, or 8 was reproduced in 52%, 53%, and 58% of cases, respectively. A systematic bias toward progressive undergrading of more well-differentiated cancers and overgrading of more poorly differentiated cancers on biopsy is suggested by the data. A pooled analysis with nine additional series (n = 2,687) confirms this conclusion. No correlation was found between the amount of tumor in the biopsy specimen and grade discordance. Biases in pathologic interpretation and sampling effects are suggested as responsible for grade discordance. Predictable differences exist between the histologic grade in prostate needle biopsies and the surgical specimen. Clinical staging of organ-confined prostate cancer should include the likelihood of histologic upgrading or downgrading when used to stratify patients for clinical trials, in comparing results among therapies based on biopsy grading and when recommending a radical therapy. Developing a methodology which reduces both sampling effects and pathologic interpretation bias would likely result in significantly improved accuracy of Gleason grading of prostate biopsies. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 305-311 (2000).

Biopsy, Needle↗

PubMed1988

Immunotherapy of multiple sclerosis.

Based on the assumption that multiple sclerosis is an autoimmune disease, a number of clinical trials designed to suppress the immune system or to restore immune balance in multiple sclerosis have been attempted. Depending on the disease category, the clinical goals of immunotherapy differ. Therapeutic goals include improving recovery from acute attacks, preventing or decreasing the number of relapses, and halting the disease in its progressive stage. The ultimate goal of multiple sclerosis therapy is the early treatment of patients in an attempt to halt the onset of progression. Specific strategies of immunotherapy include generation of a suppressor influence, removal of helper/inducer cells, manipulation of activated T cells, manipulation of class II major histocompatibility complex-bearing cells, alteration of lymphocyte traffic, extracorporeal removal of serum factors or cells, and manipulation of antigen-specific cells. Present treatment modalities are beginning to show some efficacy of nonspecific immunosuppression, but these treatments are limited by their toxicities. As the immunotherapy of multiple sclerosis moves to the next stage in the coming years, patients at an earlier stage of their disease will have to be treated, nontoxic forms of therapy developed, clinical trials lengthened, and a laboratory monitor of the disease developed. Given the positive effects of immunotherapy seen thus far in the disease, it is possible that appropriate immunotherapeutic intervention may provide effective treatment for the disease in the future.

Autoantibodies↗

PubMed2026

Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.

OBJECTIVES: VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. METHODS: We conducted longitudinal deep phenotyping, including whole-blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. RESULTS: Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes upregulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, FDR < 0.05) and was upregulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 upregulation, all following the same graded pattern, recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathological features, including RNASE1 upregulation. CONCLUSIONS: Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.

Journal Article↗

PubMed2004

Structured model of influenza virus replication in MDCK cells.

Intracellular events that take place during influenza virus replication in animal cells are well understood qualitatively. However, to better understand the complex interaction of the virus with its host cell and to quantitatively analyze the use of cellular resources for virion formation or the overall dynamic for the entire infection cycle, a mathematical model for influenza virus replication has to be formulated. Here, we present a structured model for the single-cell reproductive cycle of influenza A virus in animal cells that accounts for the individual steps of the process such as attachment, internalization, genome replication and translation, and progeny virion assembly. The model describes an average cell surrounded by a small quantity of medium and infected by a low number of virus particles. The model allows estimation of the cellular resources consumed by virus replication. Simulation results show that the number of cellular surface receptors and endosomes, as well as other resources, such as the number of free nucleotides or amino acids, is not significantly influenced by influenza virus propagation. A factor that limits the growth rate of progeny viruses and their release is the total amount of matrix proteins (M1) in the nucleus while other newly synthesized viral proteins (e.g., nucleoprotein NP) and viral RNAs accumulate. During budding, synthesis of vRNPs (viral ribonucleoprotein complexes) represents another limiting factor. Based on this model it is also possible to analyze effects of parameter changes on the dynamics of virus replication, to identify possible targets for molecular engineering, or to develop strategies for improving yields in vaccine production processes. Furthermore, a better insight into the interactions of viruses and host cells might help to improve our understanding of virus-related diseases and to develop therapies.

Animals↗

PubMed2005

Percutaneous balloon aortic valvuloplasty: antegrade transseptal vs. conventional retrograde transarterial approach.

Percutaneous balloon aortic valvuloplasty (BAV) has been limited predominantly to a palliative treatment for poor surgical candidates with critical aortic stenosis and multiple high-risk or comorbid conditions. The most commonly used technique for BAV is the retrograde approach, in which the balloon is passed via the femoral artery using 12-14 Fr sheaths. We compared an antegrade transseptal approach using the Inoue balloon vs. the retrograde transarterial approach using conventional balloons. The antegrade group had an improved acute hemodynamic outcome, including 20% additional increase of aortic valve area and 20% greater reduction of transaortic valve gradient compared to the retrograde approach. Preclosure with the Perclose device was used for the 14 Fr venous access sites, resulting in immediate hemostasis, minimizing the need for transfusion, and diminishing the period of bed rest. The improved acute efficacy and relative ease of venous access for the antegrade approach facilitate BAV by eliminating the need for large-caliber arterial access sheaths. The antegrade approach also incorporates technical elements necessary for percutaneous aortic valve replacement and may have expanded applications as an adjunct to this developing therapy. The impact of improved acute results on the long-term clinical outcome for this patient group will require further study.

Age Factors↗

PubMed2003

Temporal and spatial distribution of activated caspase-3 after subdural kainic acid infusions in rat spinal cord.

The molecular events initiating apoptosis following traumatic spinal cord injury (SCI) remain poorly understood. Soon after injury, the spinal cord is exposed to numerous secondary insults, including elevated levels of glutamate, that contribute to cell dysfunction and death. In the present study, we attempted to mimic the actions of glutamate by subdural infusion of the selective glutamate receptor agonist, kainic acid, into the uninjured rat spinal cord. Immunohistochemical colocalization studies revealed that activated caspase-3 was present in ventral horn motor neurons at 24 hours, but not 4 hours or 96 hours, following kainic acid treatment. However, at no time point examined was there evidence of significant neuronal loss. Kainic acid resulted in caspase-3 activation in several glial cell populations at all time points examined, with the most pronounced effect occurring at 24 hours following infusion. In particular, caspase-3 activation was observed in a significant number of oligodendroglia in the dorsal and ventral funiculi, and there was a pronounced loss of oligodendroglia at 96 hours following treatment. The results of these experiments indicate a role for glutamate as a mediator of oligodendroglial apoptosis in traumatic SCI. In addition, understanding the apoptotic signaling events activated by glutamate will be important for developing therapies targeting this cell death process.

Animals↗

PubMed2005

Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature.

BACKGROUND: Oral mucosa squamous cell carcinoma (OSCC) has locoregional evolution, with frequent neck involvement (the most important parameter for prognosis). There are still many doubts concerning the best way to approach N0 neck disease in early-stage lesions (T1 and T2). Many parameters have been studied to identify N0 patients with a high likelihood of harboring occult node metastases or of having them develop. METHODS: A review of the studies analyzing "tumor thickness"/"depth of invasion" in predicting regional metastases and survival was undertaken. RESULTS: The literature suggests that "tumor thickness"/"depth of invasion" is a reliable parameter for predicting regional nodal involvement and survival in OSCC. CONCLUSIONS: Authors are in substantial agreement regarding the reliability of tumor thickness. The lack of comparable study groups, measurement techniques, and cut-off values points to the need for further studies so as to reach a consensus and to develop therapy protocols that include tumor thickness.

Carcinoma, Squamous Cell↗

PubMed1988

The efficacy results and safety profile of imipenem/cilastatin from the clinical research trials.

Imipenem/cilastatin is highly effective for infections in many body sites against a broad range of gram-positive and gram-negative aerobic and anaerobic bacteria. During therapy, development of resistance is uncommon except in the case of Pseudomonas aeruginosa in which the incidence appears similar to that for other beta-lactam antibiotics. There appears to be a very low probability of cross-resistance. The clinical and laboratory adverse reactions are similar in type to those for other beta-lactam antibiotics. The frequency of colonization and superinfection during treatment with imipenem/cilastatin has been comparable to other antibiotics in comparative trials and to literature reports for other antibiotics for noncomparative trials.

Bacterial Infections↗

PubMed2006

Treatment of extensive chronic graft-versus-host disease with extracorporeal photochemotherapy.

Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory therapy developed for cutaneous T-cell lymphoma, has shown promise in treating chronic graft-versus-host disease (cGvHD) in uncontrolled studies. The purpose of this study was to further examine the effects of ECP on cGvHD. ECP (administered initially 3 times weekly on alternating days) was retrospectively evaluated in 14 patients with extensive cGvHD following allogeneic hematopoietic stem cell transplantation. The median time from transplantation to ECP initiation was 29 months (range, 5-96 months). The median number of concomitant baseline treatments per patient was 3 (range, 0-5). During a median ECP duration of 17 months (range, 3-44 months), 3 patients (21%) achieved a complete cutaneous response (100% improvement), 4 patients (29%) achieved a partial cutaneous response (> or =50% improvement), and 7 patients (50%) had stable skin disease. The median time to response was 6 months (range, 2-15 months), and the median response duration was 5 months (range, 1-31 months). At endpoint, responses were ongoing in 4 patients. Resolution or improvement was noted in arthralgia (5/7 patients), oral changes (3/7), elevated liver enzymes (3/5), dry eyes (2/5), joint stiffness (3/3), pulmonary disease (1/3), and thrombocytopenia (1/1). Because of a favorable response, 11 of 13 patients (85%) who received prednisone at baseline were able to taper (7/13; 54%) or discontinue (4/13; 31%) this medication, and 12 of 14 patients (86%) were able to taper (11/14; 79%) or discontinue (1/14; 7%) ECP. Five-year posttransplantation survival was 77%. Our results suggest that adjunctive ECP improves cutaneous and extracutaneous manifestations of cGvHD and has a steroid-sparing effect.

Adult↗

PubMed2006

Future prospects for fMRI in the clinic.

Functional MRI (fMRI) has tremendous clinical potential that is as yet unrealized. There are tremendous unmet medical needs that fMRI could address with significant benefit to human health. However, both medical and technical barriers prevent this benefit from accruing today. Technical barriers may be the reflexive focus of the current practitioners of fMRI, a technically savvy group. However, the real challenge lies in the medical realm, and this will require multidisciplinary and interdisciplinary work since the technical aspects of fMRI are ahead of the medical aspects. This can be seen in a range of diseases from Alzheimer's disease to schizophrenia to ischemic stroke: in each case our ability to image changes with fMRI outstrips our ability to do anything useful for the patient with them. Diagnostic imaging will always be linked in the clinic to therapeutic choices, and therefore the most powerful approach to link fMRI more directly to the clinic will be to tie fMRI to therapy development and implementation.

Brain Mapping↗

PubMed2002

Death and survival of neuronal cells exposed to Alzheimer's insults.

Neuronal cell death is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD is a disease caused by loss of neurons points toward suppression of neuronal death as the most important therapeutic target. Nevertheless, the mechanisms for neuronal death in AD are still relatively unclear. Three known mutant genes cause familial AD (FAD): amyloid precursor protein, presenilin 1, and presenilin 2. Detailed analysis of cytotoxic mechanisms of the FAD-linked mutant genes reveals that they cause neuronal cell death at physiologically low expression levels. Unexpectedly, cytotoxic mechanisms vary depending on the type of mutations and genes, suggesting that various mechanisms for neuronal cell death are involved in AD patients. In support of this, activity-dependent neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor-I can completely protect neurons from beta-amyloid (A beta) cytotoxicity but exhibit incomplete or little effect on cytotoxicity by FAD mutant genes. By contrast, Humanin, a newly identified 24-residue peptide, suppresses neuronal cell death by various FAD mutants and A beta, whereas this factor has no effect on cytotoxicity from AD-irrelevant insults. Studies investigating death and survival of neuronal cells exposed to AD insults will open a new horizon in developing therapy aimed at neuroprotection.

Alzheimer Disease↗