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PubMed1978

Comparative studies of intracellular transport of secretory proteins.

The physiology of protein intracellular transport and secretion by cell types thought to be free from short-term control has been compared with that of the pancreatic acinar cell, using pulse-chase protocols to follow biosynthetically-labeled secretory products. Data previously obtained (Tartakoff, A.M., and P. Vassalli. J. Exp. Med. 146:1332-1345) has shown that plasma-cell immunoglobulin (Ig) secretion is inhibited by respiratory inhibitors, by partial Na/K equilibration effected by the carboxylic ionophore monensin, and by calcium withdrawal effected by the carboxylic ionophore A 23187 in the presence of ethylene glycol bis (beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and absence of calcium. We report here that both inhibition of respiration and treatment with monensin slow secretion by fibroblasts, and also macrophages and slow intracellular transport (though not discharge per se) by the exocrine pancreatic cells. Attempted calcium withdrawal is inhibitory for fibroblasts but not for macrophages. The elimination of extracellular calcium or addition of 50 mM KCl has no major effect on secretory rate of either fibroblasts or macrophages. Electron microscopic examination of all cell types shows that monensin causes a rapid and impressive dilation of Golgi elements. Combined cell fractionation and autoradiographic studies of the pancreas show that the effect of monensin is exerted at the point of the exit of secretory protein from the Golgi apparatus. Other steps in intracellular transport proceed at normal rates. These observations suggest a common effect of the cytoplasmic Na/K balance at the Golgi level and lead to a model of intracellular transport in which secretory product obligatorily passes through Golgi elements (cisternae?) that are sensitive to monensin. Thus, intracellular transport follows a similar course in both regulated and nonregulated secretory cells up to the level of distal Golgi elements.

Calcimycin↗
PubMed2026

Distinct contributions of schizophrenia and neurotransmitter pathway genetic liability to neurocognition and antipsychotic efficacy in drug-naïve first-episode schizophrenia.

The genetic mechanisms underlying heterogeneity in symptom presentation and antipsychotic response in schizophrenia remain unclear, limiting the development of personalized treatment. We integrated genome-wide schizophrenia polygenic risk scores (SZ-PRS) and pathway-specific PRSs (pPRSs) for four major neurotransmitter systems to examine their associations with clinical phenotypes across the course of illness. Primary analyses were conducted in 394 drug-naïve, first-episode patients from the Chinese First-Episode Schizophrenia Trial (CNFEST) to investigate associations with baseline symptom severity, neurocognitive impairment, and longitudinal treatment response. The CNFEST cohort included 52-week longitudinal assessments of symptoms and neurocognition using the Positive and Negative Syndrome Scale and a modified version of the MATRICS Consensus Cognitive Battery. An independent case-control cohort evaluated associations with schizophrenia diagnosis, while a cohort of 514 healthy adults assessed whether PRS-cognition associations are specific to schizophrenia. Higher SZ-PRS predicted schizophrenia diagnosis (OR = 2.28, Pfdr = 0.003) and poorer baseline executive function (β = -0.44, Pfdr = 0.006) and working memory (β = -0.49, Pfdr = 0.018), but these associations were absent in healthy adults. In contrast, pPRSs showed weaker associations with diagnosis and baseline cognition but were more informative for treatment outcomes: higher serotonin-pPRS predicted greater improvement in depressive symptoms (Pfdr = 0.023-0.032), and higher GABA-pPRS predicted greater improvement in overall symptoms (Pfdr = 0.038-0.043) during weeks 4-24. Exploratory drug-specific analyses further suggested that treatment response varied across antipsychotics and was differentially associated with pPRSs. These findings demonstrate that genome-wide and pathway-specific PRSs contribute distinctly to schizophrenia phenotypes, supporting their integration for personalized stratification and treatment.

Humans↗
PubMed1977

Cholinergic mechanisms and short-term potentiation.

Acutely prepared rabbits were used to study, electrophysiologically, tetanic and post-tetanic potentiation of the pathway from the medial septal region to hippocampal field CA1. It was found that tetanic potentiation, evoked by short stimulus trains, was maximal at 6--8 Hz. Responses recovered from post-tetanic potentiation in 5--35 seconds. Acetylcholine, physostigmine, and cyclic GMP each had an excitatory effect on pyramidal cell responses when applied in stratum radiatum. The time course studies showed that these effects outlasted the duration of the injection current by many minutes. Phosphodiesterase inhibitors (e.g., isobutyl methyl xanthine) prolonged the time course of recovery with test responses which were post-tetanically potentiated. K+, on the other hand, selectively enhanced tetanic potentiation. It is suggested, with respect to the potentiation phenomena, that K+ acted primarily presynaptically to facilitate transmitter release, whereas cyclic GMP acted primarily postsynaptically for the enhancement of pyramidal cell excitability.

Acetylcholine↗
PubMed1978

Short-term increase and long-term reversion of striatal cell activity after degeneration of the nigrostriatal dopamine system.

The spontaneous activity of neurons in the head of the striatum was studied in rats 3 days and more than 1 year after a 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine system in comparison to unlesioned animals. Cells were detected and tracked by stimulating the excitatory corticostriatal pathway. In unlesioned animals striatal cells discharged at very low frequencies, with a median of 0.04 impulse/second. The activity was increased to 0.28 impulses/second 3 days after the lesion. This increase was related to the degree of dopamine depletion. More than 1 year after the lesion, the frequency had decreased to a level indistinguishable from that measured in unlesioned animals, with a median of 0.03 impulses/second. Cells in 3-day lesioned animals discharged a higher number of bursts at shorter intervals as compared to unlesioned animals, while in long-term denervated animals the bursting pattern was similar to that in unlesioned animals. This demonstrates that removal of the dopaminergic input results in increased activity only during an initial phase and that adaptive processes subsequently occur. The data from this Parkinsonian model suggest that symptoms of this disease cannot simply be related to an increased striatal cellular activity. The fact that the initially increased spontaneous activity adapted indicates that functional effects of a lesion can only be evaluated when studying the resulting changes throughout a time course.

Action Potentials↗
PubMed1978

The measurement of change in endogenous affective disorders.

Psychopathological syndromes, as originally revealed by clinical observation, can also be detected by multivariate statistical analyses of symptom ratings. Changes in the course of psychiatric syndromes may be rated simply by improvement scales or by consecutive quantifications of symptoms and their comparison in chronological order. For the latter approach, which is less liable to bias, clinical ratings of psychopathology by staff members, self-ratings by the patients, analyses of patients' overt behavior (including video and speech records), or objective measurements of psychological and/or physiological variables can be used. Advantages and limitations of these different methods are discussed and illustrated by examples from ongoing clinical research in affective disorders. Generally, the combined use of different rating procedures is recommended. Self-ratings are economical, but they may represent aspects of psychopathology other than clinical ratings. In endogenous depression, mood scales are valid (supplementary) tools for the quantification of long-term as well as short-term changes, including diurnal variations. In severe conditions of mania, however, clinical rating has been--until now--the only valid basis for quantifying the degree of psychopathology and its changes with time. Precise evaluation of changes in psychopathology is essential in longitudinal investigations of endogenous affective disorders, since psychopathology up to now seems to have been the most sensitive and the most specific indicator of the hypothetical underlying abnormalities of cerebral functioning.

Affect↗
PubMed1992

Antithyroid drug and Graves' hyperthyroidism. Significance of treatment duration and TRAb determination on lasting remission.

OBJECTIVE: To investigate the significance of treatment with antithyroid drugs longer than 12 months on lasting remission in Graves' hyperthyroid patients, and to study clinical and laboratory parameters of prognostic value. PATIENTS: Fifty-two untreated Graves' hyperthyroid patients were assigned at random to two therapeutic groups. They were treated with carbimazole during 12 and 24 months in Group I (n = 28) and Group II (n = 24), respectively. MEASUREMENTS: Serum levels of FT4, T3, sTSH and TSH receptor antibody (TRAb) were measured before starting treatment and at regular intervals during treatment and follow-up after drug withdrawal. We compared the relapse rate in both groups of patients, at short (2-yr) and long-term (5-yr) periods after drug withdrawal. Also, we compared clinical and biochemical parameters between patients who stayed in remission and who had relapse. RESULTS: At the end of the short-term period, relapse had occurred in 13 (46.4%) Group I patients and in 13 (54.1%) Group II patients, p = 0.36. At the end of the long-term period, relapse had occurred in 24 (85.7%) Group I and 20 (83.3%) Group II patients, p = 0.78. No difference could be observed between patients who had stayed in remission and who had suffered relapse, within the 5-yr follow-up period regarding to goiter size, frequency of ophthalmopathy, TSH and TRAb levels. CONCLUSIONS: The high relapse rate observed could be due to high iodine intake in our country. In this study and in a review of the available data, we have been unable to find any rational basis for courses of antithyroid drugs longer than twelve months for the treatment of Graves' hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

Long-term course of chloroquine retinopathy after cessation of medication.

Seven patients with chloroquine retinopathy were examined ten years after their therapy with chloroquine or hydroxychloroquine, or both, had been discontinued and an additional five patients with chloroquine retinopathy were similarly examined from two to eight years after their therapy had been discontinued. Visual acuity, visual fields, and ophthalmoscopic examinations were compared to those performed at the time therapy was discontinued. These long-term observations confirmed the previously published observations based on short-term studies that chloroquine retinopathy tends to remain stable after therapy is discontinued, although a few patients in the early stages of retinopathy may show regression and occasionally a patient with a more advanced stage of the disease may show progression.

Adult↗
PubMed1977

Effect of short-term cyclic administration of cyproterone acetate on pituitary-ovarian function in the human.

Short courses of cyproterone acetate, a compound with progestational and antiandrogenic activities, were administered to normally menstruating women during different phases of the menstrual cycle to suppress growth and maturation of the follicles and corpus luteum function. Postovulatory administration of 20 mg of the drug daily for 8 days to two women delayed menstruation by 4 to 6 days, followed by prolonged bleeding and short post-treatment cycles. Plasma levels of progesterone were suppressed temporarily during therapy, but increased immediately after cessation of treatment. Administration of 10 mg of the drug for 8 days during the early follicular phase to two women resulted in irregular bleeding, short cycles, and decreased plasma levels of progesterone throughout the cycle. Reduction of the dose to 2.5 mg during the early follicular phase in two other women also resulted in irregular cycles. When the 2.5-mg dose was administered to three women from the 8th to the 15th days of the cycle, vaginal bleeding and cycle length were normal. Plasma levels of luteinizing hormone and progesterone were suppressed during therapy. In one subject, cervical mucus was found to be hostile to sperm penetration in all three treatment cycles. The results indicate that, with cyclic administration of low doses of cyproterone acetate to women during the late follicular phase, it may be possible to interrupt pituitary-ovarian function, as well as sperm transport through the cervical mucus.

Body Temperature↗
PubMed2026

Adverse pregnancy outcomes and long-term cardiovascular disease risk.

Pregnancy provides a unique physiological stress test for the cardiovascular system, during which, adverse pregnancy outcomes (APOs) can unmask latent susceptibility to future disease. Common complications, including hypertensive disorders of pregnancy (HDP), gestational diabetes, and preterm birth (delivery before 37 weeks' gestation), identify women at substantially higher long-term risk of cardiovascular morbidity and mortality compared with women without a history of APOs. These excess risks likely reflect the combined effects of pre-existing cardiometabolic and genetic susceptibility, as well as the haemodynamic and metabolic stressors of pregnancy, heralding accelerated risk factor trajectories, relative impairment in endothelial and microvascular function, and early disease onset. This final Review in the Series extends the focus from cardiovascular disease during pregnancy and HDP to the long-term cardiovascular implications of APOs after delivery. We synthesise epidemiological data quantifying cardiovascular risk across major APO phenotypes and emerging evidence linking maternal APO history with cardiometabolic risk trajectories in offspring. We also delineate putative mechanistic pathways and summarise guidelines and consensus-informed recommendations for short-term and long-term follow-up after APOs. Finally, we propose practical approaches for integrating APO history into cardiovascular disease risk assessment and guideline-directed prevention across the female life course. We highlight key knowledge gaps, including uncertainty about optimal follow-up models, the limitations of current risk-stratification tools, and the absence of APO-specific prevention trials. We also outline priorities for mechanistic and implementation research. Positioning APOs as early, sex-specific indicators of cardiovascular risk offers a key window of opportunity to shift prevention upstream and improve cardiovascular health outcomes for women.

Humans↗
PubMed2026

Short-Term Success, Long-Term Failure: Strain Turnover and Virulence Re-Emergence May Drive Relapse in Pouchitis.

BACKGROUND & AIMS: Pouchitis, de-novo small intestinal inflammation is the most common complication developing in patients with ulcerative colitis after total large bowel resection and ileal pouch-anal anastomosis (IPAA) reconstruction. While the first line treatment is antibiotics, the microbial properties underlying flare, remission, and relapse remain vague. We aimed to investigate how antibiotic treatment drives microbial shifts that underlie remission and contribute to relapse. METHODS: Patients after IPAA were prospectively recruited during clinical flare (active pouchitis defined by the pouchitis disease activity index) and received a two-week course of metronidazole with either ciprofloxacin or doxycycline. Longitudinal follow up was conducted during a year. Clinical data were recorded, and fecal samples were obtained during consequent flares, recovery, and relapses. Microbial gene repertoire, strains, and resistance to antibiotics were determined. Metagenomic sequencing was integrated with whole-genome sequencing of Escherichia coli isolates, providing strain-specific virulence and antibiotic resistance profiles. RESULTS: Patients (n=21) recruited provided 130 samples over one-year follow-up. Both antibiotic regimens induced rapid but transient clinical improvement, reflected by a decrease in fecal calprotectin (728 to 265 &#x3bc;g/g, p<.05), and a marked reduction in bacterial exotoxin genes (p<.05), yet both parameters rebounded by 6 weeks post-treatment. Antibiotic resistance gene abundance significantly increased during treatment (p<.05), without expansion of resistance gene diversity, indicating that pre-existing resistant strains increased. CONCLUSIONS: Antibiotic-induced remission in pouchitis likely results from a temporary suppression of exotoxin-producing bacteria, enabling resistant, low-virulence strains to transiently dominate; The fact that harmful strains quickly rebound after treatment cessation highlights the need for targeted approaches to achieve sustained microbial control.

Inflammatory bowel disease↗
PubMed1976

Reduplicative paramnesia.

A striking behavioral abnormality is described in three individuals who had severe head trauma. At a point when general mnestic capabilities had returned to a near normal level, the patients persistently relocated the hospital at another geographical site, even in the face of compelling counter-evidence. The strong parallels in the etiology and course of the three cases justify the positing of a syndrome, here termed reduplicative paramnesia. A neuropsychologic analysis of the disorder stresses the cognitive operations entailed in geographical localization and confabulation. Clinical-pathologic considerations underline the role of right hemisphere and frontal lobe structures in the syndrome.

Adult↗
PubMed1976

[Tetanic fatigue and proximate post-tetanic recuperation in sartorius and flexor carpi radialis muscles of the male frog. Effects of iodoacetic acid (author's transl)].

The time-course of the isometric tension output, at 20 degrees C, during a long tetanus and after a short period of rest, was investigated in two isolated frog muscles : the sartorius and flexor carpi radialis muscles. To prevent aerobie and glycolytic recovery processes, some muscles were poisoned with 0,4 mM iodoacetic acid (IAA) and nitrogen, for 20 or 40 min. 1. For the unpoisoned sartorius muscle, tetanic tension declined quickly, but after a 0,8 sec period of rest, the muscle was able to develop high tension. Poisoning with IAA-N2 increased fatigue without suppressing the property of a proximate post-tetanic recuperation. 2. In the flexor carpi radialis muscle resistance to fatigue was very large before poisoning and diminished after poisoning. Proximate recuperation was very weak. 3. The results show that the recovery processes are not a primary factor of the development of the short-term fatigue ; they enhance the hypothesis that a failure of the electromechanical coupling can explain the rate of the tension fall in tetanized sartorius muscles.

Anaerobiosis↗
PubMed1975

[Special pharmacokinetic aspects in newborns and young infants].

The safety of drug therapy in the newborn period and early infancy is endangered for two main reasons: 1. The relative distribution volume of drugs during maturation and in pathological states varies greatly and thus makes conventional dosage in short-term therapy ineffective. 2. During early childhood, the rate of elimination of many drugs is slow hence there is a risk of overdosage in long-term therapy with doses considered safe in older children. The example of two drugs demonstrates, that the course of blood levels is not only dependent on the elimination half life and on the relative distribution volume, but may also be modified to a large extent by the process of invasion. This increases the risk of iron-dextrane but contributes to the safety of Cephalexine. If drug therapy is to be safe and effective in childhood at least the basic elements of a most simple pharmacokinetical model consisting of Invasion, Volume of Distribution and Elimination must be known as can be shown by the mathematical extrapolation of blood level curves gained from single applications for long-therm therapy.

Age Factors↗
PubMed1975

Protein bound radioactivity in neuronal and glial fractions following intra-carotid 3H-leucine perfusion.

Brain proteins in one cerebral hemisphere were labeled by means of intracarotid perfusion with 3H-leucine by a 40 s pulse. Recirculating precursor contributed little to the protein bound radioactivity. This radioactivity reached a peak level 30 min after perfusion. Fractions enriched in neuronal perikarya and glial cells showed a similar time course of labeling, but the neuronal fraction demonstrated the highest level of protein bound radioactivity. Subcellular fractions from whole brain were studied by the same system. The highest protein bound radioactivity was observed in the nuclear and microsomal fractions. The brain entry of the precursor by means of a controlled intracarotid pulse of short duration offers particular advantages in short-term experiments since the systemic metabolism of the labeled precursor is largely avoided. The easily achieved high labeling of proteins facilitates assay of the radio-activities in different cellular and subcellular fractions and also allows analyses of relative turnover rates in electrophoretically separated proteins.

Animals↗
PubMed1975

[Certain hemodynamic indicators during rest and after intensive physical exercise at high altitude].

For 5 years 364 normal males, aged 19--25, were studied at the altitude of 3800--4200 m, along with local inhabitants of the mountain region; the hemodynamic shifts and arterial blood oxygenation were studied with the base metabolism conditions preserved both at rest, and after intensive physical exercises performed according to the step-test method with the maximum tempo of the work (cardiological motion test, WHO, 1967). The initial reaction of the cardiovascular system to the high altitude conditions manifested itself in an increased stroke volume and cardiac output, of the volume speed of blood ejection, of the cardiac index in a decrease of the total peripheral resistance and oxygen saturation of the arterial blood. This reaction was interpreted as a compensatory one. In the course of acclimatizing, the cardiac output and the pulse amplitude of the arterial pressure gradually decreased, and the total peripheral resistance increased. These hemodynamic changes must be of an adaptative nature. The maximum physical workload caused a distinct intensification of the circulatory reactions, especially in those living for considerable periods of time at high altitude and in local inhabitants. The general state of the examined remained good. Hence, these persons have a considerable reserve of functional capacities of their cardiovascular system, and can perform hard muscle work at high altitude. Individuals staying at high altitude for only short periods of time react to intensive physical workloads by a less distinct intensification of the contractile capacity of the heart and by a sharp decrease of blood oxygenation, considerable acceleration of the heart rate and respiration rate, as well as by a deterioriation of their general state. Such muscular efforts cause overloading of the heart only in persons with a short-term acclimatizing.

Acclimatization↗
PubMed1979

Effect of short-term administration of cyproterone acetate on the reproductive tract histology, ovarian and serum cholesterol contents of female monkey (Presbytis entellus entellus).

Short courses of cyproterone acetate, a compound with progestational and antiandrogenic activities were administered to normally cycling female monkeys to investigate into the effects of cyproterone acetate on the reproductive tract. In little earlier follicular stage 20 mg of the drug daily for 30 days increased the cholesterol contents in the gonads. Serum cholesterol contents were slightly increased. When the reproductive tract was examined histologically, the gonads showed reduction in size, along with widespread degeneration of the young follicles as well as other growing follicles. Uterus showed progestational endometrial proliferation and sloughing of the vaginal productive tract.

Animals↗
PubMed1992

Marital discord and early child development.

As part of a prospective study on the neuropsychiatric development of children born at varying degrees of organic and psychosocial risk, the effect of marital discord on the cognitive and social-emotional development of 315 first-born children into two parent households was investigated. Both the children and the quality of the parental relationship were evaluated when the children were 3 months and 2 years of age. The findings show that marital discord at 3 months does not affect child performance at 3 months, or at 24 months. Marital discord at 2 years does affect the emotional well-being of the 2 year olds, i.e. it is accompanied by a significant rise in psychopathological symptoms. When the effect of the stability of marital strife from the first assessment to the second was studied, a significant increase of behaviour problems and decrease in cognitive performance was found in the group of children whose parents' marital situation had deteriorated and failed in the meantime but surprisingly not in the group with chronic discordant relationships. Conversely, poor child performance and emotional adjustment improved with a positive change in the parental relationships. Analysis shows that negative marital change goes hand in hand with a decrease in parenting skills which affect children more adversely than their counterparts whose parents had a history of marriage and child-rearing problems. Further study of the course of marital relationships and child development at the next research waves (4.5 and 8 years) will show which results are of long-term versus short-term relevance.

Adolescent↗
PubMedDate not supplied

[Modification of the body's resistance to acute ionizing radiation by synthetic beta-carotene].

Radiomodifying efficiency of short-term and chronic medicinal and treatment-prophylactic enrichment of rations with artificial beta-carotene, administered at single doses of 0.1-10.0 mg, were studied after acute external gamma-irradiation of adult nonlinear and Wistar rats (0.029 Gy/s) or female SBA mice (0.0037 Gy/s), where the absorbed dose was equal to 8-3 Gy or 9.9-9.5 Gy, respectively. Suspension of beta-carotene paste in olive oil accelerated death of rats irradiated at doses of 8 and 7 Gy (P = 0.04), and shortened their lifespan. At a dose of 6 Gy single and long-term enrichment of rations with beta-carotene decreased the rate of rat death within 30 days from 33.3% to 16.7% (P = 0.14) and 3.3% (P = 0.01), while their life time was increased from 48 days to 67 days (P = 0.05) and 508 days (P = 0.01). beta-Carotene was found to affect favourably the radiation-induced (5 Gy) leukocytopenia, and decreased thymus mass (6 Gy) and body weight (8 Gy). In treatment-prophylactic enrichment with beta-carotene of mice (9.9 Gy) ration their survival was increased from 15% to 30% and lifespan from 14.4 days to 28.9 days (P = 0.05). During medicinal or treatment-prophylactic courses of beta-carotene death of mice (9.7 Gy) was decreased from 75% to 35% (P = 0.01) or 60% and life time was increased from 16.7 days to 22.17 days or 39.9 days (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗