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At least 19 recordsLinked to original sources
PubMed2022

Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.

BACKGROUND: The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking. RESULTS: We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%. CONCLUSIONS: Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.

Humans↗
PubMed2026

Genetic Associations with Temporal Modeling of Alzheimer's Disease Progression Supports a Novel Paradigm for Disease Risk.

A major challenge in Alzheimer's disease (AD) research is predicting who will develop AD, how it progresses, and how to slow, prevent, or reverse progression. Here, we apply a data-driven timeline inference framework to sparse longitudinal blood metabolomics data to reconstruct AD timelines and derive individual-specific timeline progression rates. Inferred temporal locations for each metabolomics sample along the AD timeline closely track clinical severity, while timeline progression rates capture inter-individual differences in the speed of pathophysiological progression. Genome-wide association studies of timeline progression rate identify novel loci distinct from those in AD case-control studies, notably showing no effect of the major risk locus APOE. These findings support a multidimensional paradigm of AD risk in which disease potential and progression act as partially independent factors. By explicitly modeling disease dynamics, this work reveals genetic contributions not captured by traditional approaches and provides a framework for studying AD and other progressive disorders.

Journal Article↗
PubMed2026

Symptom Networks and Core Symptoms in Patients with Solid Tumors Undergoing Chemotherapy: A Systematic Review.

OBJECTIVES: To summarize symptom network characteristics in patients with solid tumors undergoing chemotherapy and synthesize evidence on core symptoms, bridge symptoms, and temporal associations. METHODS: We systematically searched eight databases through October 2025 to identify studies that applied symptom network analysis to adults with solid tumors receiving chemotherapy. Eligible studies assessed symptoms using cross-sectional, longitudinal, or interventional designs. Two reviewers independently screened articles and extracted data on study characteristics, symptom assessment, and network outcomes. Methodological quality was assessed using the National Institutes of Health Study Quality Assessment Tool. RESULTS: Twenty-seven studies involving 13,452 participants were included, yielding 79 symptom networks. Fatigue was the most frequently identified core symptom (10/20, 50%), whereas sadness, lack of appetite, and nausea each occurred in 10% of studies, with variation across cancer types, treatment phases, and latent classes. Bridge symptoms included disturbed sleep, lack of appetite, and dry mouth (2/7, 28.6%). Studies evaluating temporal associations found that symptoms such as sadness, dyspnea, somnolence, and dry mouth predicted subsequent changes in appetite, distress, nausea, and other outcomes. Strength metrics showed acceptable stability (correlation stability coefficients: 0.28-0.83). CONCLUSIONS: Fatigue was frequently identified as a central symptom across studies, largely reflecting evidence from breast cancer studies. Core symptoms varied across cancer types, treatment phases, and latent classes, suggesting heterogeneity. IMPLICATIONS FOR NURSING PRACTICE: These findings highlight the importance of considering relationships among symptoms in clinical care. Focusing on key symptoms such as fatigue, while tailoring management strategies to cancer-specific symptom patterns, may support more effective symptom management.

Humans↗
PubMed1979

Shigella vaginitis: report of 38 patients and review of the literature.

Thirty-eight cases of Shigella vaginitis were identified in a retrospective review of records kept over the past 14 years. The cases of vaginitis were due to three subgroups of Shigella. Vaginitis varied in severity and duration, persisting for several months in some instances. In 47% of the cases, there was associated bloody vaginal discharge. Only two children had diarrhea temporally associated with vaginitis, but six others had had diarrhea. Many treatment modalities were used. Systemic antibiotic therapy appeared more effective than topical antimicrobials in the few patients who could be evaluated. Review of the literature revealed 32 additional cases, including four in adult women.

Child↗
PubMed1978

["Functional and anatomical organization of associative" cortical areas 7, 21 and 22 in monkeys. A study of the cortical projections from the pulvinar by means of HRP tracing technique (author's transl)].

The thalamic projections to the parietal and temporal associative areas (Brodmann's areas 7, 21 and 22) have been revealed by means of the retrograde axonal transport of horseradish peroxidase (HRP). The medial pulvinar (PM) was found to send afferents to the three studied areas. Labelled neurones of the PM appeared to be grouped in terms of their cortical target; indeed, neurones of origin of projection fibres to areas 7, 21 and 22 were respectively localized in the dorso-lateral, ventro-lateral and ventro-medial part of the PM. Although the multimodal sensory nature of the PM has been demonstrated by electrophysiological works, the function of PM neurones and the significance of their topographical repartition remain unknown. However PM could be involved in the transmission of specific sensory informations to the three associative areas 7, 21 and 22. Such an hypothesis is discussed according to the hitherto available data.

Afferent Pathways↗
PubMed1978

Disseminated intravascular coagulation in childhood acute lymphocytic leukemia with poor prognostic features.

Three children with ALL having poor prognostic features developed clinical and laboratory evidence of disseminated intravascular coagulation (DIC). Two developed a bleeding diathesis associated temporally with a rapid drop in blast cell counts during induction therapy with L-asparaginase, prednisone, and vincristine. One of these children died of massive cerebral hemorrhage. The third patient developed episodes of superficial thrombophlebitis associated with relapses and rising blast cell counts which responded to chemotherapy and treatment with heparin. The unusual association of ALL with DIC and the fact that all 3 patients had multiple poor prognostic signs have led us to monitor carefully the coagulation system and withhold L-asparaginase in patients with massive disease until the white cell count and organomegaly have responded to prednisone and vincristine. The more common association of DIC with non-lymphocytic leukemia and recent reports of the presence of the Ph' chromosome in children with leukemia morphologically resembling ALL suggest that chromosomal evaluation be done in selected leukemic patients.

Adolescent↗
PubMed2025

Bistable Mutation-Selection Equilibria and Violations of Fisher's Theorem in Tetraploids: Insights from Nonlinear Dynamics.

Polyploidy and whole genome duplication (WGD) are widespread biological phenomena with substantial cellular, meiotic, and genetic effects. Despite their prevalence and significance across the tree of life, population genetics theory for polyploids is not well developed. The lack of theoretical models limits our understanding of polyploid evolution and restricts our ability to harness polyploidy for crop improvement amidst increasing environmental stress. To address this gap, we developed and analyzed deterministic models of mutation-selection balance for tetraploids under polysomic (autotetraploid) and disomic (allotetraploid) inheritance patterns and arbitrary dominance relationships. We also introduced a new mathematical framework based on ordinary differential equations and nonlinear dynamics for analyzing the models. We find that autotetraploids approach Hardy-Weinberg Equilibrium 33% faster than allotetraploids, but the different tetraploid inheritance models show little differences in mutation load and allele frequency at mutation-selection balance. Our model also reveals two bistable points of mutation-selection balance for dominant alleles with biased mutation rates over a wide range of selection coefficients in the tetraploid models compared to bistability in only a narrow range for diploids. Finally, using discrete time simulations, we explore the temporal dynamics of allele frequency and fitness change and compare these dynamics to the predictions of Fisher's Fundamental Theorem of Natural Selection. While Fisher's predictions generally hold, we show that the bistable dynamics for dominant mutations fundamentally alter the associated temporal dynamics. Overall, this work develops foundational theoretical models that will facilitate the development of population genetic models and methodologies to study evolution in empirical tetraploid populations.

Fisher’s Fundamental Theorem↗
PubMed2026

Genomic characterisation of ST233 Pseudomonas aeruginosa co-producing KPC-2 and VIM-2 in Northeastern Brazil during the COVID-19 pandemic: Evidence of independent horizontal acquisition events.

BACKGROUND: Dual-carbapenemase-producing Pseudomonas aeruginosa poses a major therapeutic and epidemiological challenge worldwide, yet systematic data on KPC and VIM co-production in Brazil remain limited. The COVID-19 pandemic intensified antimicrobial use, a period temporally associated with increased carbapenemase detection globally. OBJECTIVES: To characterise the molecular epidemiology and resistance profiles of KPC and VIM co-producing P. aeruginosa isolates from Brazil (2019-2023). METHODS: Between 2019 and 2023, 1489 multidrug-resistant P. aeruginosa isolates were screened by multiplex PCR for carbapenemase-encoding genes. Co-producing isolates underwent pulsed-field gel electrophoresis (PFGE) for clonal profiling, followed by whole-genome sequencing (WGS) for high-resolution phylogenomic analysis. Antimicrobial susceptibility testing and plasmid characterisation using next-generation sequencing platforms were also performed. RESULTS: Forty-two isolates (2.8%) harboured both blaKPC-2 and blaVIM-2, with detection occurring exclusively between 2020 and 2023, temporally coinciding with the COVID-19 pandemic. PFGE identified eight distinct clonal groups, providing evidence for independent horizontal gene transfer (HGT) events, whilst WGS confirmed all isolates as the high-risk ST233 lineage. Chromosomally integrated blaVIM-2 within class 1 integrons predominated; 2 isolates carried dual chromosomal copies. Plasmid-borne blaKPC-2 was identified across heterogeneous replicons (43.3-430.1 kb), suggesting multiple independent acquisition events. All co-producing isolates displayed extensive drug resistance, retaining in vitro susceptibility only to cefiderocol and colistin. CONCLUSIONS: ST233 co-producing KPC and VIM, represents a high-risk resistance phenotype of epidemiological significance. Divergent genomic architectures suggest active horizontal dissemination across diverse genetic backgrounds rather than clonal expansion, highlighting the need for enhanced surveillance and infection control strategies.

Bacterial genomic characterisation↗
PubMed1977

Periodic lateralized epileptiform discharges (PLED's) and nystagmus retractorius.

A 57-year-old diabetic woman presented with focal right-sided seizures and hyperglycemia. She later showed periodic lateralized epileptiform discharges (PLEDs), originating in the left hemisphere, which were temporally associated with nystagmus retractorius. It appears that the left hemisphere epileptiform activity diffusely excited brainstem structures via polysynaptic pathways to produce the nystagmus.

Diabetic Neuropathies↗
PubMed1979

Ultrastructural studies on the evolution of amyloidosis in the cyclic hematopoietic (CH) dog.

Electron microscopy studies were made on tissues of cyclic hematopoietic (CH) dogs of various ages presenting a high incidence of spontaneous amyloidosis. The distribution and morphologic characteristics of amyloidosis in this animal model closely correspond to the secondary and familial forms of the disease in humans. Plasma cells and, particularly, macrophages presented marked changes during the evolution of amyloid deposition. Residual bodies in the macrophages contained abundant cell debris, a result of both endocytic and autophagocytic activities. Intracellular amyloid fibrils were not observed by conventional electron microscopy. A few reticular cells contained intracytoplasmic fibrils which were morphologically different from amyloid. There was no correlation between the amount of intracellular fibrils and the size of the extracellular amyloid deposits. On the contrary, a temporal association between the magnitude of the amyloid deposits and cytoplasmic changes in the macrophages at sequential stages of the evolution of the disease was evident. It is suggested that the hematopoietic defect in the CH dog could play an important role in the production of amyloidosis, making this animal an excellent experimental model for studies of that disease.

Amyloidosis↗
PubMed2026

Reversible exacerbation of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PTEN hamartoma tumor syndrome and young-onset Parkinson's disease.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS), caused by germline loss-of-function variants in PTEN, typically manifests as macrocephaly, neurodevelopmental disorders, and cancer susceptibility. Parkinson's disease has not been recognized as part of its known neurological spectrum. METHODS: We describe the clinical course of a patient with a germline PTEN nonsense variant (p.Arg130Ter) who developed young-onset Parkinson's disease before being diagnosed with bilateral breast cancer. RESULTS: The patient developed asymmetric, levodopa-responsive parkinsonism at 35 years of age, with reduced bilateral striatal dopamine transporter uptake. During two cycles of epirubicin-cyclophosphamide chemotherapy, her previously well-controlled parkinsonism showed reproducible and severe exacerbations. Symptoms began several days after chemotherapy, reached their maximum severity approximately one week after treatment, and resolved completely within approximately two weeks without modification of her antiparkinsonian medications. No dehydration, electrolyte disturbance, infection, or exposure to dopamine-receptor antagonists was identified. The chemotherapy regimen was discontinued after the second episode because of the reproducible temporal association. CONCLUSIONS: This case demonstrates reproducible, fully reversible exacerbations of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PHTS and young-onset Parkinson's disease. These episodes may reflect transient vulnerability of dopaminergic neurons to chemotherapy-related systemic stress, although the causal role of PTEN haploinsufficiency remains uncertain.

Humans↗
PubMed1977

Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.

Friend leukemia virus (FLV) erythroleukemic cells cultured in medium containing FLV-immune serum from dormant FLV-infected mice undergo modulation of FLV cell surface antigens. Modulation was determined by an increased resistance to FLV antibody-mediated complement-dependent lysis and was associated temporally with the capping of FLV-immune complexes at the cell surface. Modulated cells regained their susceptibility to FLV antibody-mediated complement-dependent lysis when transferred to medium containing normal mouse serum. After 48 h of culture in FLV-immune serum, 26% of the FLV erythroleukemic cells were devoid of FLV cell surface antigens as demonstrated by immunofluoresence. Antigenic modulation occurred to a greater extent in cells maintained in logarithmic growth than in cells in GO or resting phase. FLV-antigenic modulation is discussed as a possible mechanism by which antibody induces and maintains FLV-transformed cells in a dormant state.

Animals↗
PubMed1979

The tumor dormant state. Quantitation of L5178Y cells and host immune responses during the establishment and course of dormancy in syngeneic DBA/2 mice.

Subcutaneous implantation of DBA/2-derived L5178Y cells into DBA/2 mice followed 10 d later by nodule excision protected 100% of mice from the rapid outgrowth of an intraperitoneal challenge of L5178Y cells given 7 d postexcision. Challenged mice remained clinically normal for 48--250 d before onset of an ultimately fatal tumor outgrowth. The numbers of L5178Y cells in the peritoneal cavity increased logarithmically for 4 d after challenge and then declined to low but detectable levels which persisted throughout the clinically normal period. Cells active in 18-h in vitro cytolytic assays against 51Cr-labeled L5178Y target cells were found in the peritoneal cavity. The effector cells were determined to be Thy1.2 positive. Their activity was tumor specific and reached peak levels 4 d after tumor challenge and then gradually declined to undectable levels during the following 70 d. Tumor emergence occurred most frequently during the period when CMC activity was no longer demonstrable in the remaining clinically normal mice. A transient peak of low level cytophilic antitumor antibody was detected about 30 d after tumor cell challenge. The temporal associations between the numbers of tumor cells and the levels of cell-mediated lysis against L5178Y cells indicate the importance of the cell-mediated cytolysis response in limiting initial tumor outgrowth and suggest its role as one of the factors responsible for long-term tumor suppression during tumor dormancy.

Animals↗
PubMed1976

Induction of increased graft-versus-host disease by mouse spleen cells sensitized in vitro to allogeneic tumor.

The aim of our study was to sensitize cells in vitro, follow their proliferative and cytotoxic responses, and determine their ability to cause lethal graft-versus-host disease (GVHD). C57BL/6 (H2b) spleen cells were incubated with irradiated BALB/C (H2d) Moloney lymphoma cells (LSTRA) in mixed leukocyte culture conditions for 2, 4, or 6 days and then tested. The maximal proliferative response occurred after 4 days. In vitro cytotoxic reactivity against 51Cr-labeled LSTRA was generated by 4 days (76.3+/-3.1% 51Cr released) and 6 days (133.0+/-4.8%) of sensitization but not by 2 days (-0.2+/-1.1%). Induction of fatal GVHD was assayed by injecting graded doses of the C57BL/6 spleen cells i.v. into adult BALB/c mice pretreated with cyclophosphamide, 180 mg/kg. Cells sensitized for 2 days were effective but no more so than were (control) cells cultured with irradiated C57BL/6 spleen cells. However, cells sensitized longer were far more active than the control cells. Cells sensitized for 4 days killed 70 of 88 mice (80%), and those sensitized for 6 days killed 37 of 48 mice (77%), whereas control cells killed only 42 of 90 mice (47%) (P less than 0.005). Thus, cells sensitized in vitro exhibited an increased ability to induce GVHD in vivo, which was temporally associated with the development of cytotoxicity in vitro.

Animals↗
PubMed1977

The natural discharges of Purkinje cells in paravermal regions of lobules V and VI of the monkey's cerebellum.

1. Conscious monkeys were trained with food rewards to perform movement tasks with the left hand and to accept manipulation of the joints and muscles and natural non-noxious stimulation of the skin of both forelimbs.2. Recordings were made from 230 Purkinje cells situated in the paravermal region of lobules V and VI or immediately adjacent folia of the left cerebellum in a region from 2 to 7 mm from the mid line. These neurones were all in a zone which was demonstrated to receive inputs from the ipsilateral hand and which is known to receive projections, via the pontine nuclei from the ;arm area' of motor cortex in the right hemisphere.3. Modulation of the natural activity of 182 of these 230 Purkinje cells (79%) occurred in a reproducible manner in temporal association, each with a particular phase of the self-paced movement tasks performed by the animal using the ipsilateral arm and hand. The patterns of modulation of Purkinje cell firing in this limited zone of cerebellar cortex could be classified into one of four groups, and each cell's discharge was associated with a particular aspect of movement such as general arm flexion, shoulder retraction, elbow extension or elbow flexion whenever it occurred.4. The cells were spontaneously active at rest. Most commonly, marked accelerations of the discharge were related to one direction of the particular aspect of movement and a reduction of activity or even total silence accompanied movement in the opposite direction.5. Variation of the amount of discharge demonstrated during a movement performance with which this discharge was characteristically associated could be related to the range of the movement or its duration, more activity being characteristic of more prolonged movement performance through larger angles of joint displacement.6. Both simple spikes and complex spikes of some cells showed characteristic modulation of their activity during the monkey's self-initiated movements. Cells whose simple spikes did not change in frequency during the movement task, also showed no modification of complex spike discharge.7. Of the 182 neurones whose discharges changed during active movement performance, 105 (roughly 60%) were demonstrated to be in receipt of an input from peripheral receptors in the hand which could be activated by brisk tapping of the skin or brushing of hairs. In contrast, none of the Purkinje cells whose discharges were unchanged during arm movements could be demonstrated to receive such an input.8. Movement of joints through their full range and prodding of muscles were completely ineffective stimuli for causing changes in Purkinje cell firing in this zone of the cerebellar cortex while the animal was passive and relaxed. Imposed perturbations of movement performance injected unexpectedly during the execution of a movement task were also ineffective in modifying the discharge of these Purkinje cells in relation to the task.

Action Potentials↗
PubMed1979

Discharges of intracerebellar nuclear cells in monkeys.

1. Conscious monkeys were trained with food rewards to perform movement tasks with the left forelimb and to accept manipulation of the joints and muscles and natural non-noxious stimulation of the skin of all four limbs. 2. Recordings were made from 217 cells situated in the left interpositus and dentate nuclei of the cerebellum. The identity of seventy-seven cells as cerebellar projection neurones was definitively established by activating them antidromically from the brachium conjunctivum near the contralateral red nucleus. 3. Modulation in the natural activity of 129 of these crebellar nuclear cells (sixty in interpositus; sixty-nine in dentate) occurred in a reproducible manner in temporal association with a phase of the self-paced movement tasks performed by the animal using the ipsilateral arm and hand. The discharges during motor performance of forty-two dentate and forty-five interpositus cells were shown to be associated with movement about a particular joint or region of the forelimb whenever that movement occurred. 4. Cells whose discharges were related to proximal joint movements (shoulder, elbow) and cells related to distal joint movements (wrist, fingers) were encountered in both the dentate and interposed nuclei. 5. The cells were tonically active at rest. Most commonly, accelerations in the discharge were related to movement of a joint or the limb in one direction and a reduction or cessation of activity accompanied movement in the opposite direction. 6. For some cells, variation of the amount of discharge demonstrated during movement performance could be related to the range of the movement or its duration, more activity being characteristic of more prolonged movement performance through larger angles of joint displacement. 7. The dentate and interpositus cells whose discharges were most strongly and consistently related to movements of the forelimb were concentrated in the mid region and caudal half of either nucleus. 8. None of seventy-three dentate neurones examined showed appreciable responses to stimulation of the skin or manipulation of joints and muscles of the fore- or hind limbs and only two cells responded to unexpected perturbation of movement performance. 9. No influence resulting from peripheral afferent input from the ipsilateral forelimb was detected in any interpositus cell whose firing was unchanged during ipsilateral arm movements. 10. Of the sixty interpositus cells whose discharge rates changed during motor performance, twenty-eight were demonstrated to be in receipt of input from receptors in the ipsilateral hand or arm, which could be activated by brisk tapping of the skin and sometimes by gentle squeezing of the forearm. 11. In the passive relaxed animal, manipulation of joints was ineffective in modifying the discharges of most interpositus neurones and, in all cases, prolonged pressure upon the skin elicited only transient responses...

Action Potentials↗
PubMed1978

A neurophysiological analysis of the effects of hypercapnia on the embryonic spinal cord.

Progressive hypercapnia in the normal chick embryo late in incubation (14-19 days) is temporally associated with a gradual decline in motor activity and the corresponding frequency of polyneuronal (burst) activity in the spinal cord. We have studied the possible correlation between the increasing hypercapnia and the declining frequency of burst activity seen during these later stages of incubation by systematic manipulation of CO2 levels. Burst frequency was seen to decrease as a result of a 5-min exposure to different carbon dioxide environments at all ages studied. The magnitude of this inhibition and the ability to recover from consecutive bouts of hypercapnia (pulses) is pulse and age dependent. These short-term (less than 5.0 min) changes differ qualitatively from the long-term (greater than 2.5 h) effects of subsequent hypercapnic episodes. This evidence suggests a role for metabolic factors in the normal developmental changes in motility and electrophysiological activity in the chicken embryo spinal cord.

Age Factors↗