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PubMed1975

The immature HPO axis.

One cause or anovulation may be an immature hypothalamic-pituitary-ovarian axis. The fact that initial menstrual cycles are usually irregular and often anovulatory implies that a maturation process is taking place in the HPO axis and that cyclic ovulatory menstruation begins only when adequate maturation occurs. Moreover, the external appearance of the ovary of a severely oligomenorrheic or amenorrheic female frequently is similar to that of a prepubertal female--this is, the ovary appears normal in size of slightly smaller, has a smooth, glistening surface without convolutions, and its capsule-like outer surface reveals few, if any, underlying follicles. A reasonable assumption is that there is inadequate gonadotropin stimulation of these ovaries possibly as a result of an immature HPO axis. The studies by radioimmunoassay of FSH and LH levels in prepubertal and pubertal females offer no statistical data by which to measure the maturity of the HPO axis, although consistently low FSH and LH levels may prove meaningful. Studies of FSH and LH in patients exhibiting gonadal dysgenesis neither support or disprove the immature HPO axis theory, but studies of idiopathic sexual precocity tend to support it. Studies using LH-RF in prepubertal and pubertal females indicate a pattern of response which may give useful information in the area.

Adolescent↗
PubMed1975

The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO.

The use of trimethadione (TMO) as a protector in hyperbaric oxygen toxicity in the conscious rat has been examined in detail. The oxidation-reduction state of pyridine nucleotides was measured simultaneously with the EEG activity from the surface of the brain cortex. From the data obtained, a few parameters were calculated. The results show that in TMO-treated animals the time to the onset of convulsions, the time to the onset of NADH oxidation-reduction cycles, and the survival time were significantly longer than in the control group. The effect of TMO on the EEG shows that the tonic phase of the convulsive activity was almost completely abolished.

Animals↗
PubMed1979

Effect of hyperbaric oxygen on the cytotoxicity of adriamycin and nitrogen mustard in cultured Burkitt's lymphoma cells.

The effects of hyperbaric oxygen (HPO) exposure on the cytotoxicity of Adriamycin (ADM) and nitrogen mustard have been examined in Burkitt's lymphoma cells (P3J) in vitro. Exposure of cells to 3 atmospheres of pressure HPO for 2 hr produces inhibition of DNA synthesis and mitosis. Simultaneous exposure to HPO and ADM results in decreased cytotoxicity compared to drug treatment alone. However, exposure to ADM (0.15 microgram/ml) 2 to 8 hr before or after HPO produces an increase in drug effect. There is no potentiation of lower ADM concentrations. Cytotoxicity is increased when cells are exposed to HPO during, before, or after exposure to nitrogen mustard (NSC 762) (0.15 and 0.25 microgram/ml). Lower nitrogen mustard (NSC 762) concentrations are not potentiated. HPO potentiation of antineoplastic agents appears to depend upon the agent studied, the concentration of the agent, and the scheduling of the drug and HPO exposure.

Burkitt Lymphoma↗
PubMed1991

Evidence that 3 alpha-hydroxy-5 alpha-pregnan-20-one is a physiologically relevant modulator of GABA-ergic neurotransmission.

3 alpha-Hydroxy-5 alpha-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABAA receptor binding, by determining the allosteric properties of HPO on the in vitro binding of 3H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of 3H-muscimol to GABAA receptor sites by 52% and enhanced the number of accessible binding sites from 5.5 +/- 0.5 to 7.5 +/- 1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABAA receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.

Animals↗
PubMed1978

Cytochemical study on uptake of exogenous peroxidase by Vx2 carcinoma cells transplanted into the rabbit.

When horse-radish peroxidase (HPO) was administered iv to Vx2 carcinoma-bearing rabbits, an HPO reaction product was detected in the lumina of blood vessels and the extracellular spaces between tumor cells in the first few minutes after administration. HPO was also seen in vesicles in tumor cells. Fifteen minutes to 1 hour after administration, the HPO reaction product was found mainly in the large membrane-bound vacuoles. Within 6--12 hours, the HPO activity gradually diminished in large membrane-bound vacuoles (lysosomes). In conclusion, exogenous HPO was rapidly incorporated into Vx2 carcinoma cells by pinocytosis, and then pinocytotic vesicles were fused with lysosomes.

Animals↗
PubMed2025

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Humans↗
PubMed1978

Clinical trials of radiotherapy in hyperbaric oxygen at Portsmouth, 1964--1976.

For 12 years randomised clinical trials have been run at Portsmouth in collaboration with the Medical Research Council's Working Party on radiotherapy and high pressure oxygen to determine the survival rate of patients treated by megavoltage radiotherapy in high pressure oxygen (HPO) compared with those treated in air at atmospheric pressure. Five hundred and five patients have been included, 280 with carcinoma bronchus, 163 with carcinoma bladder and 62 with carcinoma cervix stage III. With conventional small fraction daily radiotherapy, the use of HPO has not improved survival in carcinoma of the bronchus and of the bladder. When six fractions of 600 rad maximum tissue dose are given in HPO, some improved survival is shown in carcinoma of the bronchus and of the cervix compared with the same dose in the air series. In the cervix, the survival rate in HPO is almost the same as that of a retrospective series treated by an intrauterine radium tube followed by 6000 rad central depth dose to the whole true pelvis in air. Large fraction radiotherapy has not given improved survival when using adjuvant HPO in carcinoma of the bladder. The bladder trial has now been abandoned.

Air↗
PubMed2026

Robust replication of associations across patient-mediated and provider-sourced EHR data in the All of Us research program.

The All of Us Research Program is assembling a nationwide cohort with electronic health record (EHR) resources through two complementary pathways: healthcare provider organization (HPO)-sourced EHRs and patient-mediated EHR (PME) contributed through patient portal linkages. The comparative research utility of these two data sources has not been systematically evaluated. Here, we compared PME and HPO EHRs with respect to disease prevalence, phenotype-phenotype associations, and replication of established genotype-phenotype associations using data from 19,703 PME and 373,887 HPO participants. We benchmarked disease prevalence against national estimates, conducted phenome-wide association studies for 10 commonly studied diseases, and tested replication of more than 5000 established genotype-phenotype associations across multiple ancestral groups. Disease prevalence was consistently lower in PME than in HPO, although prevalence of most diseases in both cohorts exceeded national estimates. Both data sources reproduced known phenotype-phenotype associations and showed moderate-to-strong concordance in effect sizes across the phenome. The overall genotype-phenotype replication rate was 49.1% (5399/10,999) in HPO and 5.9% (381/6482) in PME across ancestral groups, with effect sizes strongly correlated among well-powered associations (R&#x2009;=&#x2009;0.84, P&#x2009;<&#x2009;0.001). To disentangle the impact of sample size from data quality, we performed 1:1 propensity score matching. After matching, the replication gap in genotype-phenotype associations narrowed from 8.3-fold to 1.3-fold, with equivalent replication rates among adequately powered associations and strongly concordant effect sizes; comorbidity patterns were also consistent across all 10 diseases tested. These findings demonstrate that both data sources are valuable for clinical and genomic research and can inform other cohorts integrating provider-derived and patient-mediated EHRs.

Computational biology and bioinformatics↗
PubMed2026

Selective and sensitive colorimetric sensing of carbosulfan based on BiO2-x/Bi2O2.75 nanosheets with excellent haloperoxidase-like activity.

The development of colorimetric methods based on directly inhibiting nanozyme activity for pesticide detection has attracted considerable attention. In this study, we report a novel colorimetric sensing strategy utilizing BiO2-x/Bi2O2.75 nanosheets (BiO2-x/Bi2O2.75 NSs) with haloperoxidase (HPO)-like activity for the rapid and sensitive detection of carbosulfan (CBS) in foods. Oxygen-vacancy-rich BiO2-x/Bi2O2.75 NSs with HPO-like activity were rationally constructed. Kinetic studies revealed a remarkable Michaelis-Menten constant (Km) of 0.014&#xa0;mM for I-, indicating a higher affinity for iodide ions than other reported HPO-like nanozymes, as evidenced by its lower Km. Under acidic conditions, CBS tends to be hydrolyzed to produce reductive sulfide species, which directly inhibit the iodoperoxidase-like activity of BiO2-x/Bi2O2.75 NSs, enabling selective detection with a limit of detection (LOD) of 0.18&#xa0;&#x3bc;g/mL and a linear range of 0.20-100&#xa0;&#x3bc;g/mL. When the concentration of interfering pesticides and substances was 5 times that of CBS, the sensor remained unaffected, exhibiting excellent stability and specificity. This work contributes to the detection of CBS in complex food matrices, bridging the application gap of HPO-like nanozymes in pesticide detection and providing a promising method for food safety detection.

Colorimetry↗
PubMed1977

Complexes of inorganic pyrophosphate, orthophosphate, and calcium as stimulants of 3T3 cell multiplication.

Addition of 0.1-0.5 mM sodium PP(i) for 17 hr to confluent cultures of BALB/c 3T3 cells in low serum concentrations stimulated the incorporation of [(3)H]thymidine into DNA to an extent equal to that produced by high serum concentration. PP(i) prevented much but not all of the cell detachment that accompanies decreasing the serum concentration of confluent cultures and it increased the saturation density of cultures in high serum concentrations. The stimulation had a sharp concentration dependence and was associated with the appearance in the medium of a flocculent precipitate. Stimulation and precipitate formation were dependent on Ca(2+) and inorganic orthophosphate (HPO(4) (2-)) and were inhibited by Mg(2+). More than half the Ca(2+) requirement could be met with Sr(2+). In the absence of PP(i), supranormal concentrations of either Ca(2+) or HPO(4) (2-) caused graded increases in [(3)H]thymidine incorporation and total cell yield. The effect of supranormal [Ca(2+)] depended on [HPO(4) (2-)] and vice versa, and the Ca(2+) requirement could be partially met by Sr(2+). The stimulation was associated with increasing turbidity of the medium. Various other complexing agents of Ca(2+), including the divalent cation ionophore A 23187, failed to produce stimulation of 3T3 cells. We conclude that water insoluble complexes of PP(i), HPO(4) (2-), and Ca(2+) or, at much higher concentrations, the latter two together, stimulate 3T3 cells and we speculate that this is brought about by the association of these complexes with the cell membrane.

Calcium↗
PubMed1977

Pulmonary osteoarthropathy. Association with mesenchymal tumor metastases to the lungs.

Six of 18 patients with sarcomatous tumors metastatic to the lung had hypertrophic pulmonary osteoarthropathy (HPO), and, in three patients in whom tumor regression was achieved by cytotoxic chemotherapy or surgery, the clinical and radiologic changes of HPO were reversed. All six patients had large mass lesions (greater than 5 cm) that impinged on the pleural surface, and the pathophysiologic mechanism resulting in the clinical syndrome of HP may be related to the anatomic relationship of the tumor and the pleura. The use of radionuclide scanning to detect HPO in the absence of roentgenographic signs or clinical symptoms is discussed.

Adult↗
PubMed1977

Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced cancer of the uterine cervix: preliminary results of a randomized trial.

From September 1968 to March 1974, a randomized clinical trial was carried out, using conventional fractionation, i.e., five treatments per week, in 233 patients with advanced cancers of the uterine cervix--Stages IIB, IIA, IIIB and IVA. The age limit was 70 years and all patients had medical clearance. Lymphangiography and, in some patients, an exploratory laparotomy with selective lymphadenectomy, were done prior to treatment to determine the extent of nodal disease. The staging has not been changed either by lymphangiogram or lymphadenectomy findings. A few patients with bulky Stage I and IIA lesions were entered into the trial because of extensive nodal disease demonstrated either by lymphangiogram and/or lymphadenectomy. First, the patients were grouped according to the clinical stage. The secondary stratification was according to the lymphangiogram and/or selective lymphadenectomy findings. The patients were then randomized to air or hyperbaric oxygen within each group. The patients were pressurized in a Vickers chamber at 3 atmosphere absolute, using a 20-minute soak time prior to the irradition. The size of the external beam portal was determined by the status of the nodes. The difference in absolute NED (no evidence of disease) survival rates for both groups as a whole and by stages is not statistically significant. There is no difference in the incidence of failures in the irradiated area between the HPO and air patients. There is no increase in distant metastases in the HP group. It does not seem that the HPO has had an effect on the major complications. However, there was an increase in the incidence of complications with extended fields. The addition of lymphadenectomy had increased the incidence of fatal complications, even with routine pelvic portals. The negative results of this trial with conventional fractioantion should not lead to the conclusion that HPO could not be useful with schemes using a few high dose fractions.

Adult↗
PubMed1991

Improvement in the proliferative activity of human-human hybridomas at low cell density by transfection with bFGF gene.

Highly purified recombinant basic fibroblast growth factor (rbFGF) and acidic FGF (aFGF) stimulated the proliferation of human-human (h-h) hybridomas to the extent of over four-fold from a low cell density such as 1 x 10(3) cells per ml in a serum-free medium in 24-well plates. The stimulatory effect of rbFGF was also observed in various lymphoid cell lines. Expecting that FGF could be an autocrine growth factor, we introduced bFGF gene into a h-h hybridoma using an expression plasmid induced by dexamethasone. The transformed cells thus obtained, HPO-75.11 bFGF-7, were able to grow well from a low inoculum density in a serum-free medium and antibody production was also increased when bFGF gene expression was induced. The transformed cells could grow at clonal density in a serum-free medium in 96-well plates, though the original cells could not. We also obtained a more practical transfectant, HPO-75.29-H74, using a high-shear stress adapted clone as the recipient and an expression plasmid having bFGF gene under the control of metallothionein-I promoter. The HPO-75.29-H74 cells were capable of growing and producing human monoclonal antibody against hepatitis B virus surface antigen from an inoculum density of 1 x 10(3) cells per ml in an agitation vessel without addition of an inducer.

Animals↗
PubMed1976

Tests of the hypothalamic-pituitary-ovarian axis.

The availability of RIA to measure the pituitary gonadotropins and ovarian sex steroids has greatly helped in the development of tests of hypothalamic-pituitary-ovarian function. The use of estimates of basal gonadotrophin and sex steroid hormones together with dynamic tests such as the LH-RH test, oestrogen provocation test, clomiphene tests and exogenous gonadotrophins can now test the integrity and functional capacity of each of the components of the HPO axis. Figure 4 demonstrates how these tests can be used in a logical sequence to investigate patients with a disorder of the HPO axis after having first excluded any other endocrine abnormality. Screening of serum for elevated levels of gonadotrophins, prolactin and progesterone is an important initial step. Interpretation of the oestrogen provocation and clomiphene tests requires a normally functioning pituitary gland and hence the response to an LH-RH test also plays a ket role. The flow chart also demonstrates the points at which specific ovulation induction treatment can be instituted and should be useful in saving patient and doctor investigative time. Using these types of tests it should be possible to reclassify disorders of the HPO axis on the basis of their underlying pathology.

Androgens↗
PubMedDate not supplied

The protective action of certain anaesthetics and tranquilizers against the effects of hyperbaric oxygen.

The protective effects of pentobarbitone, hydroxydione and diazepam against acute and chronic toxicity of high-pressure oxygen (HPO) were studied in rats. During exposure to hyperbaric oxygen body temperature was measured and ECG as well as EMG tracings from the diaphragm were obtained. Long term observations of animals after the exposure to HPO were conducted. Pentobarbitone and hydroxydione reduced the manifestations of acute toxicity but increased those of chronic toxicity. Diazepam reduced the manifestations of acute toxicity and seemed to counteract those of chronic toxicity. Lowering of body temperature of the animals which occurred during exposure to HPO was probably connected with manifestations of chronic toxicity. Observation of the cardiorespiratory functions suggested a possible connection between their disturbances and an onset of seizures and development of oxygen-induced paralysis.

Animals↗