Biomedical subjects

K Andersson

Publications and source records attributed to K Andersson.

At least 145 records · Page 8Linked to original sources

PubMed1996

YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis.

The PTPase YopH of Yersinia is essential to the ability of these bacteria to block phagocytosis. Wild-type Yersinia pseudotuberculosis, but not the yopH mutant strain, resisted phagocytosis by J774 cells. Ingestion of a yopH mutant was dependent on tyrosine kinase activity. Transcomplementation with wild-type yopH restored the anti-phagocytic effect, whereas introduction of the gene encoding the catalytically inactive yopHC403A was without effect. The PTPase inhibitor orthovanadate impaired the anti-phagocytic effect of the wild-type strain, further demonstrating the importance of bacteria-derived PTPase activity for this event. The ability to resist phagocytosis indicates that the effect of the bacterium is immediately exerted when it becomes associated with the phagocyte. Within 30 s after the onset of infection, wild-type Y. pseudotuberculosis caused a YopH-dependent dephosphorylation of phosphotyrosine proteins in J774 cells. Furthermore, interaction of the cells with phagocytosable strains led to a rapid and transient increase in tyrosine phosphorylation of paxillin and some other proteins, an event dependent on the presence of the bacterial surface-located protein invasin. Co-infection with the phagocytosable strain and the wild-type strain abolished the induction of tyrosine phosphorylation. Taken together, the present findings demonstrate an immediate YopH-mediated dephosphorylation of macrophage phosphotyrosine proteins, suggesting that this PTPase acts by preventing early phagocytosis-linked signalling in the phagocyte.

Animals↗

PubMed1996

The concentrations of free amino acids in human liver tissue obtained during laparoscopic surgery.

The concentrations of the free amino acids in individual tissues gives information concerning amino acid, energy and protein metabolism. In muscle and intestinal mucosa, different metabolic states are distinctly characterized by an altered free amino acid pattern. Furthermore, the patterns are quite different in individual tissues. So far, liver tissue has not been investigated systematically in this respect. The aims of this investigation were to establish a standardized sampling procedure for liver tissue during laparoscopic surgery and to characterize the free amino acid concentrations in human liver tissue. Aspartate was the most abundant amino acid in the liver, followed by taurine, glutamine, glutamate, glycine and alanine. These six, and most abundant, amino acids constitute 90% of the total hepatic amino acid concentration. In the future, liver tissue sampling during laparoscopic surgery may be used as a model for investigating the influence of nutrition and hormones on hepatic amino acid and protein metabolism in man.

Adult↗

PubMed1996

Micturition in conscious rats with and without bladder outlet obstruction: role of spinal alpha 1-adrenoceptors.

1. In normal rats and rats with bladder hypertrophy secondary to outflow obstruction, undergoing continuous cytometry, we examined the responses to the selective alpha 1-adrenoceptor antagonist doxazosin given intrathecally (i.t.) and intra-arterially (i.a.). In addition, we investigated the effects of the drug on L-dopa-induced bladder hyperactivity in normal, unobstructed rats. 2. Doxazosin 50 nmol (approximately 60 micrograms kg-1), given i.t., decreased micturition pressure in normal rats and in animals with post-obstruction bladder hypertrophy. The effect was much more pronounced in the animals with hypertrophied/overactive bladders. Doxazosin did not markedly affect the frequency or amplitude of the unstable contractions observed in obstructed rats. In contrast, however, doxazosin reduced L-dopa-induced bladder overactivity. When tested, the enantiomers of doxazosin produced qualitatively similar effects to doxazosin, but there was no evidence of stereoselectivity. 3. The results suggest that in addition to the well documented action on prostatic and lower urinary tract smooth muscle, and an effect on the sympathetic outflow to the bladder, bladder neck, prostate, and external urethral sphincter, doxazosin may have an action at the level of the spinal cord and ganglia, thereby reducing activity in the parasympathetic nerves to the bladder. This effect is more pronounced in rats with bladder hypertrophy than in normal rats.

Adrenergic alpha-Antagonists↗

PubMed1996

Comparison of Two Questionnaires on Respiratory Symptoms in a Nicaraguan Population: Value in Diagnosis of Chronic Bronchitis.

Two questionnaires about respiratory symptoms were evaluated for reliability and ability to diagnose chronic bronchitis in a study population of 129 Nicaraguans (110 workers and 19 patients with chronic bronchitis). The first questionnaire (AQ) had symptom questions that were based on British Medical Research Council (MRC) questions, adapted to local Spanish. The second questionnaire (MRCQ) contained MRC symptom questions translated directly into Spanish. The reliability of the questions was measured in a test-retest procedure. The questionnaire-based diagnosis of chronic bronchitis was compared with the diagnosis made by a physician (for workers) or from the hospital records (for patients). The questions concerning symptoms in both questionnaires were of acceptable reliability. For the diagnosis of chronic bronchitis in workers, the AQ showed similar sensitivity, a somewhat higher specificity, and a substantially higher positive predictive value (90%) than the MRCQ (57%). Among the patients, the AQ identified 17 patients as positive (sensitivity 89%), while the MRCQ identified 15 (sensitivity 79%). respiratory questionnaire; reliability; chronic bronchitis; Nicaragua Hanley & Belfus, Inc. Int J Occup Environ Health 1077-3525 2 2 1996 April/June Chronic Exposure to Cigarette Smoke Inhibits the Stimulating Effects of Mineral Fibers on the Production of Tumor Necrosis Factor by Alveolar Macrophages of Rats 95 98 EN Yasuo Morimoto Department of Environmental Health Engineering, University of Occupational and Environmental Health, Japan 1-1, Iseigaoka, Yahatanishiku, Kitakyushu 807, Japan. Ziro Nambu Hajime Hori Tohru Tsuda Hiroshi Yamato Toshiaki Higashi Yasuyuki Yokosaki Masamitsu Kido Isamu Tanaka The objective of this study was to evaluate the chronic combined effects of mineral fibers and cigarette smoke on the production of tumor necrosis factor (TNF) by alveolar macrophages. The authors chronically exposed ten rats to cigarette smoke in vivo and measured the production of TNF by alveolar macrophages in the presence of mineral fibers in vitro. For smoke exposure, rats were divided into two groups. Five rats were exposed daily to a concentration of 10 mg/m(3) of cigarette smoke for six hours a day, five days a week, for four weeks, and five rats (control) were not exposed to smoke. A broncho-alveolar lavage was performed after the smoke exposure, and the recovered alveolar macrophages were incubated with either chrysotile or ceramic fibers on a microplate for 24 hours. TNF activity in the supernatant was determined by the L929 bioassay. When alveolar macrophages were not stimulated by mineral fibers, TNF production tended to be lower in smoke-exposed alveolar macrophages than in unexposed ones, although the difference was not significant statistically. When alveolar macrophages were stimulated in vitro by chrysotile or ceramic fibers, both fibers stimulated TNF production, but TNF production in smoke-exposed alveolar macrophages was lower than that in unexposed macrophages. These results revealed that long-term exposure to cigarette smoke inhibited the stimulating effect of mineral fibers on the production of TNF.

Journal Article↗

PubMed1996

Symptomatic genital papillomavirus infection in a community. Incidence and clinical picture.

BACKGROUND: Incidence of condyloma acuminatum is not well known. Descriptive data are usually based on selected groups of patients. This study aims at giving incidence of the clinically defined disease in a well-defined area, thought to be representative for Sweden outside the capital city. METHODS: Data from people with condyloma acuminatum seeking medical attention were collected during a two-year period, 1989-90, in a middle-sized urban area in Sweden. A person with symptoms and a clinical picture consistent with condyloma was considered a case. RESULTS: Overall incidence was 2.4 per 1000. The highest age specific incidence occurred in the age group 20-24 years, 12 per 1,000. Women 15-19 years old had an incidence of 14 per 1,000. The total female to male ratio was 1.3. CONCLUSIONS: Women more often than men had a mixture of exo- and endophytic condylomata. Condyloma as another and complementary indicator of changing sexual behavior deserves further interest.

Adolescent↗

PubMed1996

Depletion of enterochromaffin-like cell histamine increases histidine decarboxylase and chromogranin A mRNA levels in rat stomach by a gastrin-independent mechanism.

BACKGROUND: Gastrin activates histidine decarboxylase (HDC) and increases HDC and chromogranin A (CGA) mRNA levels in histamine-producing enterochromaffin-like (ECL) cells in the rat stomach. We have studied how histamine depletion by subcutaneous infusion of the HDC inhibitor alpha-fluoromethyl-histidine (alpha-FMH) affects how ECL cells respond to hypergastrinemia in terms of HDC and CGA mRNA levels. METHODS: In one experiment rats received alpha-FMH for 24 h. In another experiment rats received alpha-FMH, omeprazole (perorally), or a combination of the two drugs for 10 days. In a third experiment antrectomized rats were treated with alpha-FMH for 48 h. The circulating gastrin level, oxyntic mucosal histamine concentration, HDC activity, and HDC and CGA mRNA levels were determined. RESULTS: alpha-FMH for 24 h increased the HDC and CGA mRNA levels without increasing the serum gastrin concentration. alpha-FMH for 10 days increased the serum gastrin concentration twofold. alpha-FMH + omeprazole resulted in the same serum gastrin concentration as after omeprazole alone (eightfold increase). HDC mRNA levels were higher after alpha-FMH + omeprazole than after omeprazole alone. alpha-FMH alone induced an HDC mRNA level that was similar in magnitude to that observed after omeprazole, although the serum gastrin concentration after alpha-FMH was much lower. In antrectomized rats alpha-FMH increased the HDC and CGA mRNA levels without increasing the serum gastrin concentration. CONCLUSION: ECL-cell histamine depletion will increase mRNA levels for HDC and CGA by a gastrin-independent mechanism, possibly involving abolished histamine autofeedback inhibition.

Animals↗

PubMed1996

Gastric acid secretion after depletion of enterochromaffin-like cell histamine. A study with alpha-fluoromethylhistidine in rats.

BACKGROUND: Histamine is thought to play a central role in the regulation of gastric acid secretion. In the rat oxyntic mucosa most of the histamine is synthesized and stored in enterochromaffin-like (ECL) cells, and the rest resides in mast cells. The present study examines the role of ECL-cell histamine in the control of acid secretion in the intact, conscious rat. METHODS: Rats were treated with alpha-fluoromethylhistidine (alpha-FMH) to inhibit histamine synthesis. alpha-FMH was given by continuous subcutaneous infusion (3 mg/kg/h) for up to 9 days. An additional oral dose of alpha-FMH (50 mg/kg) was given 2 h before each acid secretion test. Acid secretion was studied in pylorus-ligated rats and in chronic gastric fistula rats stimulated with histamine, gastrin-17, or insulin after 2-6 days of alpha-FMH infusion. RESULTS: Treatment with alpha-FMH lowered oxyntic mucosal histamine synthesis by 80%. From previous observations this is thought to reflect depletion of histamine from the ECL cells. The remaining 20% resides in mucosal and submucosal mast cells, which seem to be resistant to alpha-FMH. Basal acid secretion was inhibited by more than 60% after alpha-FMH treatment and by more than 80% by ranitidine. Histamine-stimulated secretion was unaffected by alpha-FMH and abolished by the histamine H2-receptor antagonist ranitidine. The acid response to gastrin-17 was almost abolished in histamine-depleted rats and abolished by ranitidine. Vagally induced acid secretion (provoked by the injection of insulin or by pylorus ligation) was unaffected by alpha-FMH treatment but abolished by ranitidine and by the muscarinic M1-receptor antagonist pirenzepine. CONCLUSION: The results suggest that gastrin stimulates acid secretion by releasing histamine from ECL cells. Vagally induced acid secretion is also dependent on a histaminergic pathway but not on ECL-cell histamine.

Animals↗

PubMed1996

Significance of indoor environment for the development of allergic symptoms in children followed up to 18 months of age.

The development of symptoms possibly related to allergy or other forms of hypersensitivity was studied in a group of 638 children on two occasions: when the children were 3 and 18 months of age. Standardized questions were used to collect basic information about the child, technical characteristics of the home, and the mother's perception of the indoor climate. All reported exposure factors were analyzed in relation to the child's symptoms at 18 months of age, by logistic regression techniques. A family history of atopy was associated with a high incidence of most of the investigated symptoms. Attendance at a day nursery before 18 months of age increased the risk of recurrent colds and the need for several courses of treatment with antibiotics. If the mother smoked, the children more often suffered from protracted coughing episodes. If the child has a sibling, the risk of developing a wheeze, repeated colds, and the need for antibiotic treatment increased. No building factors, such as size of the home, heating and ventilation system, type of foundation, dampness, or presence of wall-to-wall carpets, showed a significant correlation to symptoms reported in the children. However, if the mothers reported symptoms that are often connected with "sick buildings", the children more often had eczema, dry skin, or reactions to food. The mothers' complaints about indoor air quality and climate and mucous membrane symptoms were significantly related to the type of building and presence of condensation on the windows in winter, a finding which may indicate that indoor climate factors also have some effect on the health of the children. This study reports the prevalences of symptoms until the age of 18 months. At this age, the allergic manifestations are usually nonspecific, and follow-up examinations to 4-5 years of age are needed before any definite conclusions can be drawn about the development of atopic diseases due to indoor climate factors.

Age Factors↗

PubMed1996

[Prevention of female genital mutilation in Sweden].

A three-year pilot study of female genital mutilation has been carried out at Gothenburg. There is increasing awareness of this issue, and discussions have started between immigrants and health-care professionals. By means of further information and education it is hoped to improve care of the victims, and in the long-term to eliminate a pernicious tradition. It is estimated that there are approximately 115 million victims of female genital mutilation in Africa alone. As a result of emigration, about 5000 young women from areas where it is practised are now to be found in Europe, and 16,000 in Sweden.

Adolescent↗

PubMed1995

Mouse and rat B-myc share amino acid sequence homology with the c-myc transcriptional activator domain and contain a B-myc specific carboxy terminal region.

B-myc is a member of the myc gene family. Previous studies indicate that the rat B-myc gene contains a single exon which shows 77% nucleotide homology to the second exon of the rat c-myc gene. Its open reading frame (ORF) encodes a polypeptide with a predicted molecular weight of 20 kD. We have isolated a new, larger rat B-myc genomic clone. Sequence analysis of this clone confirmed the presence of one single coding exon. Furthermore, a genomic mouse B-myc clone was identified and compared to the rat homolog. Nucleotide analysis of B-myc coding and non-coding sequences suggests that it may be a functional gene evolved by selective duplication of part of the second c-myc exon. Analysis of the rodent B-myc open reading frames revealed two in-frame amino acid duplications in mouse B-myc and a 96% conservation at the amino acid level. Both rat and mouse B-myc proteins contain an identical and unique stretch of 14 carboxy terminal amino acid residues not found in other myc proteins. In vitro translation of rat and mouse B-myc ORF's yielded proteins that migrated as 26 kD bands in SDS-PAGE and could be immunoprecipitated by a polyclonal panmyc antiserum. Immunostaining of human lymphoma cells transiently transfected with a B-myc expression vector showed that the protein was mainly localized to the nucleus.

Amino Acid Sequence↗

PubMed1995

Peroxisome proliferation and associated effects caused by perfluorooctanoic acid in vitamin A-deficient mice.

Vitamin A-deficient male mice were treated for 10 days with 0.02% perfluorooctanoic acid (PFOA) in their diet. The effects of this highly potent peroxisome proliferator on peroxisomal palmitoyl-CoA oxidation and lauroyl-CoA oxidase activities were reduced by 3.1-7.5 times in comparison to the values obtained with mice receiving a vitamin A-adequate diet. The activity of peroxisomal catalase was virtually unaffected by vitamin A deficiency and treatment with PFOA had no significant effect on this activity in vitamin A-adequate or vitamin A-deficient mice. However, vitamin A deficiency itself caused a more than 800% increase in cytosolic catalase activity. Thus, the percentage increase caused by PFOA on cytosolic catalase activity was reduced 12.6 times in vitamin A-deficient mice compared to the increase in vitamin A-adequate mice, although the total absolute activities were similar. These findings suggest that the peroxisome proliferation caused by this peroxisome proliferator is highly dependent on the vitamin A status of the mouse.

Acyl-CoA Oxidase↗

PubMed1995

Immunoaffinity column clean-up for the high-performance liquid chromatographic determination of aflatoxins B1, B2, G1, G2, M1 and Q1 in urine.

A method for the determination of aflatoxins B1, B2, G1, G2, M1 and Q1 in human urine has been developed. The 10-ml urine samples were automatically cleaned up on immunoaffinity columns and analysed by high-performance liquid chromatography (HPLC), including post-column derivatization with bromine and fluorescence detection. Average aflatoxin recoveries were: B1 103%, B2 106%, G1 98% and G2 96% in the range 6.8-73 pg/ml of urine and M1 103% and Q1 100% in the range 18-97 pg/ml of urine. The relative standard deviations were all between 1% and 21%. The determination limits of aflatoxins in urine were 6.8 pg/ml for B1, B2, G1 and G2 and 18 pg/ml for M1 and Q1.

Aflatoxin B1↗

PubMed1995

Synergistic induction of acyl-CoA oxidase activity, an indicator of peroxisome proliferation, by arachidonic acid and retinoic acid in Morris hepatoma 7800C1 cells.

Morris hepatoma 7800C1 cells (a Wistar rat cell line) were exposed to 100 microM arachidonic acid in the medium for seven days. This treatment resulted in 150% and 60% increases (above control activities) in acyl-CoA oxidase (which catalyzes the first step in peroxisomal beta-oxidation) and catalase activities, respectively. Arachidonic acid (C20:4) can be metabolized to 20- and 19-hydroxy-arachidonic acid by cytochrome P-450IVA and it was shown that our cells are capable of forming 20-hydroxyarachidonic acid. However, 20-hydroxyarachidonic acid (0.1-0.8 microM, 4 days) had no effects on lauroyl-CoA oxidase and catalase activities in Morris hepatoma cells. Treatment of 7800C1 cells with 100 microM all-trans-retinoic acid resulted in inductions of catalase (160% above the control activity) and carnitine acetyltransferase (140% above the control activity) activities. The activity of lauroyl-CoA oxidase was often, but not always, slightly induced by treatment with all-trans-retinoic acid. When all-trans-retinoic acid was administered together with arachidonic acid, these two compounds had a synergistic effect on the induction of acyl-CoA oxidase activity (almost 700% above the control activity). However, treatment of Morris hepatoma cells with the man-made peroxisome proliferator, perfluorooctanoic acid, together with all-trans-retinoic acid did not result in any synergistic effect on this same enzyme activity. In summary, this study (1) corroborates findings from transfection experiments indicating that the heterodimer PPAR-RXR alpha activates transcription of the acyl-CoA oxidase gene using the Morris hepatoma cell line; (2) shows that arachidonic acid induces the activity of lauroyl-CoA oxidase; (3) suggests that transcription of the catalase gene is not regulated by a PPAR-RXR alpha heterodimer in this system; and (4) demonstrates that peroxisome proliferation in Morris hepatoma cells by perfluorooctanoic acid is not as dependent on the level of retinoic acid as is the same process caused by arachidonic acid.

Acyl-CoA Oxidase↗

PubMed1995

Determination of intracellular glutathione in human skeletal muscle by reversed-phase high-performance liquid chromatography.

A chromatographic method for the specific determination of cellular low molecular mass thiols has been applied to human muscle tissue. The method is based on the derivatisation of thiols using monobromobimane, which is a specific reagent for the sulphydryl group. The glutathione and cysteine bimane adducts were separated by reversed-phase HPLC, whilst quantitation of the cysteine and glutathione adducts was achieved by fluorescence spectroscopy. The method was found to yield a quantitative recovery of glutathione (ca. 96%), to be sensitive (down to 20 pmol glutathione/per injection) and reveal a low intra-individual coefficient of variation (C.V. < 5%) of the glutathione concentrations in human skeletal muscle. The concentrations of reduced and total glutathione were 1320 +/- 37 mumol/kg wet weight (mean +/- S.E.M.) and 1525 +/- 66 mumol/kg wet weight, respectively. The method was also applied to tissues from nine healthy volunteers to determine if fluctuations in glutathione level occurred over a 24-h period. No diurnal variation of glutathione level in human skeletal muscle was observed.

Adult↗

PubMed1995

Perinatal asphyxia increases bFGF mRNA levels and DA cell body number in the mesencephalon of rats.

The present investigation was undertaken in order to study the long-term effects of perinatal asphyxia on basic fibroblast growth factor (bFGF) gene expression and the number of dopamine nerve cell bodies in the mesencephalon of the rat. Asphyxia was induced during birth for 19-20 min. A 30% increase in the number of tyrosine-hydroxylase immunoreactive (TH-IR) nerve cell bodies (i.e. dopamine-containing neurones) as well as a 50% increase in bFGF gene expression following asphyxia was found in the substantia nigra/ventral tegmental area 4 weeks after birth. The increase in bFGF mRNA levels may underlie the increase found in the number of dopamine cell bodies. The present results indicate that asphyxia during birth can prime the long-term development of the central nervous system.

Animals↗

PubMed1995

The influence of the Gyne-T 380S IUD on menstrual blood loss and iron status.

The influence of the Gyne-T 380S intrauterine contraceptive device (IUD) on menstrual blood loss (MBL) and iron status (hemoglobin, hematocrit, red cell count and indices, and serum ferritin) was evaluated. MBL was determined objectively by the alkaline hematin method in 18 women (mean age 37.1 +/- 1.6 yr, range 22-46 yr) before and 3, 6 and 12 months after insertion of a Gyne-T 380S IUD. MBL prior to IUD insertion was 59 +/- 8 ml and increased to 91 +/- 11 ml (p < 0.01) 3 months after insertion. MBL then remained largely unchanged during the remainder of the observation period (6 months, 94 +/- 12 ml; 12 months, 92 +/- 13 ml). The percentage increase in MBL at the respective measurement points ranged between 54 and 59% which is comparable with previous reports regarding the increase in MBL associated with the use of a copper IUD. There were no significant changes recorded in iron status parameters during the 12-month observation period following IUD insertion. Based on the results of the present study, women from developed countries apparently tolerate an increased MBL of approximately 55% without developing iron deficiency anemia. Iron stores were unchanged indicating an adequate adaptive increase in intestinal iron absorption.

Adult↗

PubMed1995

Short-term effects of perinatal asphyxia studied with Fos-immunocytochemistry and in vivo microdialysis in the rat.

In the present study, the short-term consequences of various perinatal asphyctic periods were studied at the peripheral and CNS levels in the rat. Perinatal asphyxia was induced in rat pups delivered by caesarean section within the last day of gestation, by placing the uterus horns including the fetuses in a water bath at 37 degrees C for various periods of time (0-23 min). Following asphyxia, the uterus horns were opened. The pups were then removed and stimulated to breathe. Subcutaneous levels of pyruvate (Pyr), lactate (Lact), glutamate (Glu), and aspartate (Asp) were monitored with microdialysis 40 min after delivery. In parallel experiments, the pups were sacrificed 80 min after delivery. The brains were removed, fixed, cut, and processed for Fos immunocytochemistry. The number of Fos-immunoreactive (IR) cells in different brain structures was counted under light microscopy. Subcutaneous levels of Pyr, Lact, Glu, and Asp increased following perinatal asphyxia, as compared to caesarean-delivered pups or to spontaneously delivered controls. A maximum increase in Pyr levels (approximately threefold) was observed with 2-3 min of asphyxia, while Lact levels increased along with the length of asphyxia. A maximum increase in Glu and Asp levels (approximately threefold) was observed with 10-11 min of asphyxia. Fos-IR nuclei were predominantly found in the piriform cortex, and in the cortical amygdaloid complex. In some cases, mainly in pups exposed to asphyxia, Fos-positive cells were also seen in other tele-diencephalic structures.

Amino Acids↗

PubMed1995

Optimization of the intestinal lavage procedure for determination of intestinal immune responses.

Optimal conditions to process, concentrate and store intestinal lavage fluid were studied in samples collected from volunteers before and after oral immunization with a prototype vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhoea. Total IgA and specific IgA antibody titres against enterotoxin and colonization factor antigen were determined in 22 lavage samples which were either enzyme-inhibited or heat-inactivated and then subjected to different long-term storage conditions. Samples were analysed within 1 month of collection and also after 3, 6 and 24 months of storage. Total IgA concentrations and specific IgA antibody levels were higher in lavage samples treated with enzyme inhibitors (soybean trypsin inhibitor and phenylmethylsulfonyl fluoride) than in those heat-inactivated. Similarily, concentration of the lavage fluid by freeze-drying was superior to concentration against polyethylene glycol. Specific antibody titres remained elevated after storage for at least 6 months but declined after 2 years in frozen compared with freeze-dried samples.

Administration, Oral↗