Persistent gynecomastia resulting from scalp inunction of estradiol: a model for persistent gynecomastia.
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Visible persistence duration for sine-wave gratings was measured in 9-year-old normal and specific-reading-disabled children. Experiment 1 investigated the influence of stimulus duration on visible persistence. The results demonstrated a Reading Group X Spatial Frequency interaction with disabled readers showing a smaller increase in persistence duration with increasing spatial frequency than controls. This interaction was greatest with stimulus durations longer than 80 msec. In Experiments 2a and 2b persistence was measured across a range of contrasts from .1 to .5. The stimulus durations employed were 100 msec in Experiment 2a and 300 msec in Experiment 2b. In both experiments, increasing contrast decreased persistence duration at 2 and 12 cycles per degree (c/deg) for the control group. In the specific-reading-disabled group, however, contrast had little effect on the persistence of 2-c/deg gratings in either experiment. In Experiment 2a the persistence of the 12-c/deg grating decreased with increasing contrast for both groups. In Experiment 2b contrast had significantly less effect on persistence duration in the specific-reading-disabled group, however, contrast had little effect on the persistence of 2-c/deg ratings in either experiment. In Experiment 2b contrast had significantly less effect on persistence duration in the specific-reading-disabled group than in the control group at 12 c/deg. Consequently, contrast had less effect on persistence in specific-reading-disabled children than in normal readers, especially at durations longer than the "critical duration" for each spatial frequency. Experiment 3 extended this finding to gratings with spatial frequencies of 4 and 8 c/deg. These results indicate a difference between normal and specific-reading-disabled children in cortical visible persistence. Two scores of visual processing were derived from the above experiments. On these scores the reading-disabled children were divided into Visual Disabled Readers (approximately 70%--eight subjects) and Nonvisual Disabled Readers (approximately 30%--four subjects). The percentages of disabled readers in each category remained constant when the sample size was increased to 61 normal and disabled readers.
Whether persister cells contribute to the evolution of antibiotic resistance and, if so, under what selective conditions this occurs, remain unresolved. Here, we examined whether repeated persister cycling itself promotes resistance evolution and how persister-associated minor variants are retained, lost, or fixed under distinct selective contexts. We compared five Escherichia coli cellular states: mutation-induced cells (M), persister-Amp cycling cells (A), persister cycling cells without selection (R), stationary-phase cells (S), and NaCl-stored persisters (P), using state-resolved whole-genome sequencing and phenotypic assays. Persister cycling without selection, stationary-phase cells, and NaCl-stored persisters maintained baseline MICs and showed no detectable high-frequency variant fixation. In contrast, mutation-induced cells fixed efflux-regulatory mutations in marR, acrR, and acrB, increasing MIC to 32 μg/mL. Persister-Amp cycling cells showed an intermediate MIC increase to 16 μg/mL without detectable quality-filtered genetic fixation, distinguishing this state from mutation-induced resistance. The stfE/stfP prophage background further shaped adaptive routes under mutation-inducing conditions. Exploratory analysis revealed sub-threshold low-frequency variant signals during persister cycling, but lineage tracking showed that these variants were not stage-specifically fixed and were instead stochastically retained or lost. These findings support a model in which persister cycling can reveal low-frequency genetic heterogeneity, but fixed resistance evolution requires selection that promotes variant retention and clonal expansion. Thus, resistance fixation was governed primarily by selective context during regrowth rather than by the persister state itself.
Transgenerational continuity (TC) describes the persistence of inherited molecular architectures across generations. Progress in identity-by-descent (IBD) detection, recombination dynamics, and epigenetic research highlights the growing need for a more comprehensive model of inheritance. This theoretical framework synthesizes evidence from genomics, population studies, and epigenetics to outline how inherited molecular architectures, which are transmitted through IBD, together with heritable epigenetic modifications, can preserve ancestral information across generations. IBD captures genomic continuity across three nested scales, where recent familial segments link close relatives, population-level haplotypes are shared across cohorts, and archaic fragments from Neanderthal and Denisovan admixture persist as molecular fossils of ancient lineages. Although recombination and selection reshape these regions, their persistence across time scales highlights the evolutionary durability of genomic continuity. Epigenetic memory reflects regulatory persistence, whereby molecular modifications can preserve functional states across cell divisions and sometimes across generations. Together with familial and population-level IBD persistence and the long-term retention of introgressed haplotypes, these findings demonstrate that inherited molecular architectures can persist across multiple timescales. Evolutionary processes shape this persistence. Purifying selection preferentially removes deleterious inherited variants, whereas positive selection can favor the persistence of functionally relevant genomic architectures. From this perspective, evolutionary dynamics arise not only from the generation of variation, but also from the differential persistence of inherited molecular architectures through selection. Transgenerational continuity therefore provides a conceptual framework in which persistence serves as an explanatory dimension of inheritance and evolution that complements variation and explains the persistence of biological identity across generations and evolutionary time.
UNLABELLED: The emergence of multidrug-resistant Klebsiella pneumoniae (KPN) and antibiotic-tolerant persister cells poses a significant challenge to existing anti-infection therapies. Given the urgent need for sustainable alternatives to antibiotics, phage cocktails are emerging as a promising alternative to control K. pneumoniae infections. We isolated three lytic phages vB_KpnM_NB (1-3) from Ningbo environmental samples, classified them into the Drexlerviridae family, and determined the biological characteristics of two representative phages. Genomic analysis confirmed that these phages are closely related and lack resistance and virulence genes, ensuring biosafety. Subsequently, a stable KPN persister model was established using amikacin, with a biphasic killing pattern observed during treatment. At a multiplicity of infection of 10, the phage cocktail eliminated 99.00% of persister cells, while individual phages were less effective. The phage cocktail also inhibited persister-derived biofilm formation, showing improved results when combined with amikacin. This combination significantly reduced capsule polysaccharide production in persisters, weakening the outer membrane barrier. These findings demonstrate that the phage cocktail-amikacin combination effectively targets planktonic cells, persister cells, and biofilms, providing a promising strategy against persisters and recurrent K. pneumoniae infections. IMPORTANCE: This study fills the critical gap in understanding how phage cocktails synergize with amikacin against K. pneumoniae persister cells. By constructing a highly specific phage vB_KpnM_NB cocktail, establishing a stable persister model, and performing in vitro bactericidal and biofilm assays, we demonstrate that the cocktail effectively eliminates planktonic cells, persisters, and biofilms. We clarify the core synergistic mechanism: inhibiting capsular polysaccharide synthesis, improving phage adsorption, and disrupting the bacterial outer membrane barrier. These findings provide experimental evidence for the prevention and control of multidrug-resistant and carbapenem-resistant K. pneumoniae persister infections, establishing a safe and effective phage-antibiotic combination therapy. The results are crucial for addressing antibiotic tolerance and controlling chronic, recurrent infections. They hold significant theoretical and translational value for the treatment of refractory infections in clinical settings and offer new insights into the development of novel antimicrobial strategies.
BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold ≤30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0·0001) and individuals older than 60 years (p=0·0027). The median within-host genome-wide evolutionary rate was 7·9 × 10-4 substitutions per site per year (IQR 7·0-9·0 × 10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.
The course and prognosis of persistent pain are largely unknown. In addition, follow-up studies of chronic pain sufferers have come from specialized pain clinics and have ignored the question of how representative this special group is to the general population who suffer persistent pain. Because health care planners are assumed to require these data for projection of health care needs, it is important to determine the course of persistent pain in those persistent pain sufferers in the general population as well as those referred to a specialty clinic. An epidemiological study compared 2 groups of self-reported persistent pain sufferers from a Family Practice Clinic and a Specialty Pain Clinic over a 2 year period. All subjects reporting a persistent problem with pain at the time of the initial survey were contacted 2 years later to determine whether the initial differences between the 2 groups remained constant over time and whether there were any changes within each group over time. Despite the similarities between the study groups on multiple socioeconomic and demographic variables, the Specialty Pain Clinic group remained distinctly different from the Family Practice pain sufferers on many pain behavior and emotional variables. Thirteen percent of the persistent pain sufferers from the Pain Clinic group and 36% of the persistent pain sufferers from the Family Practice group no longer reported pain as a problem at follow-up. Of those pain sufferers from either group who continued to experience pain at 2 years follow-up, their pain became more intermittent, psychological distress factors improved, and the use of health services decreased. The implications are that persistent pain does not necessarily continue forever and that persistent pain sufferers in the general population have a better prognosis than those who are referred to a Specialty Pain Clinic. All follow-up studies need to be interpreted in light of these findings.
Human observers continue to experience a visual stimulus for some time after the offset that stimulus. The neural activity evoked by a visual stimulus continues for some time after its offset. The information extracted from a visual stimulus continues to be registered in a visual form of memory ('iconic memory') for some time after its offset. We may thus distinguish three distinct senses in which a visual stimulus may be said to persist after its physical offset: there is phenomenological persistence, neural persistence and informational persistence. Various assumptions have been made about the relation between these forms of visual persistence. The most frequent assumption is that they correspond simply to three different methods for studying a single entity. Detailed consideration of what is known about the properties of these three forms of persistence suggests, however, that this assumption is not correct. It can reasonably be proposed that visible persistence is the phenomenological correlate of neural persistence occurring at various stages of the visual system: photoreceptors, ganglion cells and the stereopsis system. Iconic memory on the other hand, does not correspond to visible persistence, nor to neural persistence in any stage of the visual system. Recent work, in fact, suggests that iconic memory is a property of some relatively late stage in the visual information-processing system, rather than being a peripheral sensory buffer store. This suggestion raises some fundamental theoretical issues concerning the psychology of visual perception, issues with which cognitive psychology has yet to come to grips.
1. Transient and persistent tetrodotoxin-sensitive sodium currents were recorded in response to depolarizing voltage pulses in voltage clamped segments of rat extensor digitorum longus muscle fibres at 20-25 degrees C in a triple Vaseline gap. 2. Appreciable persistent sodium current but little or no transient current was seen in response to depolarizations of up to 15 mV from a holding potential of -100 mV. 3. The maximum amplitude of both transient and persistent sodium currents occurred with depolarizations to -40 mV: the average peak amplitude of the transient current in fibres with a holding potential of -90 mV was -0.22 +/- 0.03 mA/microF (mean +/- 1 S.E.M., seven fibres) and the average amplitude of the persistent current was -0.94 +/- 0.10 microA/microF (mean +/- 1 S.E.M., twelve fibres). With a holding potential of -100 mV, the average amplitudes of the transient and persistent currents were -0.46 +/- 0.10 mA/microF (four fibres) and -1.4 +/- 0.22 microA/microF (five fibres), respectively. 4. The average maximum persistent sodium conductance in seven fibres held at -90 mV was 0.13 +/- 0.0078 microS and the potential for half-maximum conductance was -53 +/- 0.74 mV (mean +/- 1 S.E.M.). 5. When the transient sodium current was completely inactivated with 100 ms conditioning depolarizations to potentials more positive than -50 to -60 mV, there was little inactivation of the persistent current. 6. In six denervated fibres, the average amplitudes of the transient and persistent sodium currents generated by pulses to -40 mV from a holding potential of -90 mV were -0.11 +/- 0.01 mA/microF and -0.88 +/- 0.12 microA/microF, respectively (mean +/- 1 S.E.M.). It was concluded that there was a decrease in transient current but not persistent current amplitude following denervation and that the persistent current in denervated fibres with an increased input resistance could give rise to the spontaneous action potentials responsible for fibrillation.
In order to determine the descriptive epidemiology of persistent diarrhoea in rural northern India, a cohort of 963 children aged 0-71 months was followed prospectively for 12 months through weekly household visits. The incidence of persistent diarrhoea was 6.3 per 100 child-years among those aged 0-71 months, and was highest (31 per 100 child-years) among those aged 0-11 months. There were no significant sex-related differences in the incidence of the disease, and the overall seasonal distribution of acute and persistent diarrhoea was similar. The persistence of diarrhoeal symptoms was significantly correlated with a higher initial mean stool frequency (P less than 0.01) and passage of gross blood with stools (P less than 0.001). Persistent diarrhoea was an important problem among children during the first 2 years of life. Established enteric pathogens were isolated during the initial illness in 46.4% of persistent and 55.4% of acute episodes. Pathogens isolated during persistent episodes included enterotoxigenic Escherichia coli (ETEC 9.3%), Salmonella spp. (4.7%), as well as campylobacter (4.7%), Shigella spp. (2.3%), Entamoeba histolytica (2.3%), and rotavirus (2.3%). Similar proportions of these pathogens were isolated also during episodes of acute diarrhoea. Multiple pathogens were isolated in 7% of the persistent and 5% of the acute episodes. E. coli that manifested aggregative adherence (EAEC-A) was more common (34.9% versus 12.3%) in persistent than acute episodes (P less than 0.01), and initial faecal excretion of EAEC-A was significantly associated with the persistence of a diarrhoeal episode.
Peritoneal macrophages from mice that are resistant to Mycobacterium bovis (strain BCG) [Gros et al., J. Immunol. 127,2417, 1981] can be induced to express persistently or transiently major histocompatibility complex (MHC) class II glycoproteins. The induction of persistent expression is dependent on the dose of recombinant interferon-gamma (rIFN-gamma). High doses of rIFN-gamma (100 U) induce persistent Ia expression, whereas lower doses induce only transient Ia expression. Once induced, the persistent expression of Ia does not require its continued synthesis. We show that the expression of Ia by macrophages that transiently express MHC class II glycoproteins is reduced by the addition of cycloheximide or monensin, whereas Ia expression by macrophages that persistently express Ia is not affected. The differential sensitivity of Ia expression to cycloheximide was used to study the induction of persistence that is linked to the Bcg gene. Macrophages were primed with low doses of rIFN-gamma in order to induce transient, cycloheximide-sensitive Ia expression. The cells were then treated with high doses of rIFN-gamma in order to induce persistent, cycloheximide-resistant Ia expression. We found that the induction of persistent Ia expression requires at least 3 hr of exposure to rIFN-gamma. Furthermore, the addition of rIFN-gamma to primed macrophages is followed by a short burst of protein synthesis that is independent of the production of new mRNA. The rapidity with which persistent Ia expression is induced is consistent with the rapid onset of innate resistance to Mycobacterium following injection of BCG.
Persistent defects on serial thallium scans are commonly thought to represent fibrosis or scar. However, such a pattern may also represent severe ischemia. To better understand persistent defects, exercise thallium and resting gated blood pool scans were reviewed in 52 patients pre and post coronary angioplasty for single-vessel left anterior descending (LAD) coronary artery disease, and the fate of persistent defects after successful revascularization was determined. Persistent and transient defects were defined from the average scores of three observers. Ten patients with 16 myocardial segments with persistent defects were compared to another 11 patients with 20 myocardial segments with transient defects. After angioplasty (PTCA), 75% of the regions that had persistent defects and 85% of the regions that had transient defects were normal by visual assessment. In the persistent defect group, only regional wall motion on the resting gated blood pool scan pre PTCA helped to distinguish those segments that would or would not revert to normal. We conclude that regions of persistent defect on thallium scan often revert to normal after PTCA (75%), suggesting that persistent defects may represent hypoperfusion of viable myocardium, and should not preclude consideration of an intervention.
A persistent infection (persistent infection I) of baby hamster kidney (BHK) cells with the WSN (H1N1) strain of influenza A virus was established using a virus stock which contained a high proportion of defective-interfering (DI) particles. Virus recovered from passage 92 (388 days) of persistent infection I was used to establish a second persistent infection (persistent infection II) in BHK cells. A number of phenotypic changes were identified in the virus isolated during the first 50 passages of persistent infection I (early pi virus). These included a decrease in the size of plaques, the appearance of temperature-sensitive mutants, and a decreased ability of amplified pi virus to agglutinate chicken erythrocytes. The decreased ability to cause hemagglutination was associated with a 20- to 30-fold increase in viral neuraminidase activity. Virus isolated after passage 63 of persistent infection I could not be amplified in eggs or in a number of cell lines. Although very little infectious virus was produced when cells were infected with these late pi viruses, cytopathology frequently occurred and an unusual pattern of viral protein synthesis was observed. The NP protein was the predominant protein synthesized, while the synthesis of M protein was drastically reduced relative to its synthesis in cells infected with parental WSN virus. The HA, NS1, and NS2 proteins were not detected; however, a virus-specific protein which migrates faster than NS2 was observed. Virus recovered from persistent infection II interfered with the replication of parental WSN virus in a mixed infection. The pattern of protein synthesis in such mixed infections resembled that in cells singly infected with late pi virus. DI particles did not appear to play a significant role either in the maintenance of the persistent infection, in the expression of the pi protein synthesis phenotype, or in the pi virus-mediated interference.
In order to measure visual persistence of figures that were solely defined by relative motion (motion-defined figures or motion figures), random-dot kinematograms were used to form stimulus figures in the two-frame, missing element task introduced by Di Lollo, V. (1977 Nature, 257, 241-243). Experiment 1 showed that motion-defined figures persisted for about 130 msec after the termination of the stimulus presentation (i.e. after the dots stopped moving). This was similar to but several tens of milliseconds longer than the visual persistence of figures which were defined by a luminance difference (luminance-defined figures or luminance figures) in the same random-dot pattern. Since motion detectors are not found in the retina or lateral geniculate in primates, our results strongly suggest that visual persistence is not only a retinal phenomenon but also a cortical one. Experiment 2 investigated the possible influence of motion aftereffects on the visual persistence of motion figures. The results showed that coherent movement of the dots over the whole display after the stimulus offset did not reduce the visual persistence of motion figures, suggesting that the source of this persistence is not a motion aftereffect. In Experiment 3, visual persistence for the motion-defined figures was shown to be longer than that for luminance-defined figures independently of the contrast of the stimulus figure as long as the stimuli could be seen clearly enough. This suggests that different mechanisms are involved in the visual persistence of motion-defined and luminance-defined figures.
K virus, a murine papovavirus, produces a lethal pneumonia in newborn mice. Animals surviving acute illness develop a persistent infection which reactivates under conditions of immunosuppression. The present study was conducted to identify the cell populations which support persistent K virus infection and to determine the cell populations in which this persistent infection is reactivated during immunosuppression. Mice inoculated by the oral route with 100 50% newborn mouse lethal doses (LD50) of K virus at 14 days of age were followed over a period of 7 months. The distribution of infection was studied by virus assay, immunohistochemistry, and in situ nucleic acid hybridization methods. Viral replication during the acute phase of infection was confined to pulmonary and systemic vascular endothelial cells, as well as to scattered, apparently lymphoid cells within spleens. Beginning 2 months after inoculation, however, specific hybridization for K virus nucleic acids was detected in rare renal tubular epithelial cells, and by 6 months after inoculation renal tubular epithelial cells represented the major site of viral persistence. Positive cells were frequently present in groups of two or more, and a minority of positive cells also expressed viral capsid (V) antigen. Immunosuppression with cyclophosphamide resulted in reactivation of infection, with highest titers of virus being detected in kidneys and with increased numbers of renal tubular epithelial cells expressing viral capsid antigen. Capsid antigen was also detected in rare endothelial cells in kidneys, livers and lungs of these immunosuppressed mice. Although K virus behaves as an endotheliotrope during acute infection, the major site of K virus persistence and reactivation, the renal tubular epithelial cell, is similar to that involved during persistent infection by polyoma virus in mice, SV40 virus in monkeys, and BK and JC viruses in man. The observation that persistently infected renal tubular epithelial cells occur in groups of two or more and occasionally express capsid antigen suggests that virus may persist as a productive infection which is confined by antiviral antibody but maintains itself by cell-to-cell-spread. The present study represents the first instance in which the cell populations which support infection by a member of the polyomavirus subgroup in its natural host have been defined during acute, persistent, and reactivated infection.
A Vero cell line with a long-term rubella virus persistent infection was maintained for 45 weeks in the presence of anti-rubella virus antibody of sufficient titer to completely neutralize the virus in the culture fluid to determine the effect of the presence of antibody on the maintenance of the persistent infection. Prior to antibody treatment, virus was continuously detected as plaque-forming units in the persistently infected culture fluid. Virus clones that were plaque purified from the persistently infected culture fluid were temperature sensitive and exhibited a reduced efficiency of replication and ability to induce cytopathic effects in Vero cells at the persistently infected culture temperature compared with the standard virus used to initiate the persistently infected culture. Defective interfering RNAs were the major intracellular virus-specific RNA species present in the persistently infected cells. Treatment with antibody failed to cure the persistently infected culture of virus, and the cells retained the ability to release virus after antibody treatment was discontinued. Interestingly, the presence of antibody led to the selection of a population of virus which was markedly less cytopathic for Vero cells than the virus population which was selected during persistent infection in the absence of antibody.
Peritoneal macrophages (M phi) from mice that are resistant to infection by Mycobacterium bovis (strain BCG) (Bcgr) can be induced to express major histocompatibility complex (MHC) class II glycoproteins (I-A) continuously upon treatment with 100 units of recombinant interferon-gamma (rIFN-gamma). In contrast, M phi from mice that are susceptible to BCG (Bcgs) express I-A transiently. Persistent expression of I-A does not require the continued synthesis of the glycoprotein. Thus, treatment with cycloheximide (CHX) reduces I-A expression by M phi that express I-A transiently but does not affect the expression of I-A that is persistently expressed. It was not possible, in these studies, to characterize the induction of persistence independent of MHC class II expression because of the 24-48 h required for MHC class II synthesis and cycling to the cell surface. During this time, persistence was also induced. To characterize persistence independent of MHC class II induction we have produced M phi-M phi somatic cell hybrids that express I-A constitutively by fusing cells from a Bcgs M phi cell line with M phi from Bcgr mice. Treatment of some of the hybrids with CHX reduced MHC class II expression. The M phi hybrids required treatment with high doses of rIFN-gamma to induce CHX-resistant I-A expression. The induction of the persistence of I-A, following the addition of rIFN-gamma, required a short burst of protein synthesis as well as the presence of rIFN-gamma for at least 3 h. The addition of actinomycin D simultaneously with rIFN-gamma did not prevent the induction of the persistence of I-A expression by one of the M phi hybrids (F6.4). In contrast, the induction of persistence of I-A expression required a longer period of induction than was observed for hybrid F6.4, which was attributed to the requirement for new RNA and protein synthesis by the A1.8 hybridoma.