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Biomedical subjects

M Ryan

Publications and source records attributed to M Ryan.

At least 109 records · Page 6Linked to original sources
PubMed1998

A kinematic and kinetic analysis of the sit-to-stand transfer using an ejector chair: implications for elderly rheumatoid arthritic patients.

Twelve elderly female rheumatoid arthritis patients (mean age = 65.5 +/- 8.6 yr) were assessed rising from an instrumented Eser Ejector chair under four conditions: high seat (540 mm), low seat (450 mm), with and without the ejector mechanism operating. Sagittal plane motion, ground reaction forces, and vertical chair arm rest forces were recorded during each trial with the signals synchronised at initial subject head movement. When rising from a high seat, subjects displayed significantly (p < 0.05) greater time to seat off; greater trunk, knee and ankle angles at seat off; increased ankle angular displacement; decreased knee angular displacement; and decreased total net and normalised arm rest forces compared to rising from a low seat. When rising using the ejector mechanism, time to seat off and trunk and knee angle at seat off significantly increased, whereas trunk and knee angular displacement, and total net and normalised arm rest forces significantly decreased compared to rising unassisted. Regardless of seat height or ejector mechanism use, there were no significant differences in the peak, or time to peak horizontal velocity of the subjects' total body centre of mass, or net knee and ankle moments. It was concluded that increased seat height and use of the ejector mechanism facilitated sit-to-stand transfers performed by elderly female rheumatoid arthritic patients. However, using the ejector chair may be preferred by these patients compared to merely raising seat height because it does not necessitate the use of a footstool, a possible obstacle contributing to falls.

Activities of Daily Living↗
PubMed1998

Double-blind crossover study of the interaction between perindopril and amlodipine on blood pressure and hormones related to fluid and electrolyte balance in patients with essential hypertension.

This study was to investigate the interaction between low doses of perindopril (2 mg daily) and amlodipine (2.5 mg daily) on ambulatory blood pressure (BP), clinic BP, serum angiotensin-converting enzyme (ACE), plasma levels of renin (PRA), angiotensin II (Ang II), aldosterone, and atrial natriuretic peptide (alpha-h ANP) in subjects with essential hypertension. The study design was a parallel, two-period, placebo-controlled, double-blind crossover design, with 11 subjects receiving perindopril and 10 receiving amlodipine during the run-in phase. The addition of amlodipine to perindopril had no effect on ambulatory BP, whereas the addition of perindopril to amlodipine reduced both systolic (P = 0.027) and diastolic (P = 0.049) ambulatory BP. By contrast, the opposite result was obtained for clinic BP at trough, whereby the addition of amlodipine to perindopril reduced erect systolic BP (P = 0.036) and both supine and erect diastolic BP (P = 0.038) whereas the addition of perindopril to amlodipine was without effect. The addition of perindopril to amlodipine decreased serum ACE by 72% and increased PRA two-fold, without change in plasma levels of Ang II, aldosterone or alpha-h ANP. The addition of amlodipine to perindopril increased plasma aldosterone 1.7-fold but did not affect serum ACE, PRA, Ang II, or alpha-h ANP. These interactions between perindopril and amlodipine may have been conditioned by the specific effects of the therapy first given, as well as by the different circumstances of BP measurement (ambulatory vs clinic).

Adult↗
PubMed1998

Successful use of protease inhibitors in HIV-infected haemophilia patients.

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group. Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 x 10(6)/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.

AIDS-Related Opportunistic Infections↗
PubMed1998

Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.

Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.

Antigens, Bacterial↗
PubMed1998

What precipitates deliberate self-harm? A cognitive behavioural formulation of attempted suicide presentations at an inner city hospital.

OBJECTIVE: To develop a working model that provides an understanding of the process of deliberate self-harm and a framework for psychological intervention in an emergency department setting. METHOD: A retrospective clinical audit of a consecutive series of 51 deliberate self-harm patients referred to the liaison psychiatry service by the emergency department of an inner city hospital. RESULTS: Patient characteristics were diverse. The age range was 17-92 years, with 79% between 15 and 35 years. Most were single and unemployed and the majority had a psychiatric disorder. Characteristically, there was at least one immediate stressor and intoxication immediately before the attempt. CONCLUSIONS: The diversity of deliberate self-harm patients requires strategic intervention in a setting such as the emergency department. The working model for intervention presented here may be transferable to other settings such as general practice or community mental health centres using an educational and skills development approach with ongoing supervision.

Adolescent↗
PubMed1998

Pertussis toxin potentiates Th1 and Th2 responses to co-injected antigen: adjuvant action is associated with enhanced regulatory cytokine production and expression of the co-stimulatory molecules B7-1, B7-2 and CD28.

Pertussis toxin (PT) is a major virulence factor of Bordetella pertussis which exerts a range of effects on the immune system, including the enhancement of IgE, IgA and IgG production, delayed-type hypersensitivity reactions, and the induction of experimental autoimmune diseases. However, the mechanism by which PT mediates adjuvanticity remains to be defined. In this investigation we have shown that PT can potentiate antigen-specific T cell proliferation and the secretion of IFN-gamma, IL-2, IL-4 and IL-5 when injected with foreign antigens. A chemically detoxified PT and a genetic mutant with substitutions/deletions in the S-1 and B oligomer components that abrogate enzymatic and binding activity displayed no adjuvant properties. In contrast, a non-toxic S-1 mutant devoid of enzymatic activity but still capable of receptor binding retained its adjuvanticity, augmenting the activation of both Th1 and Th2 subpopulations of T cells. In an attempt to address the mechanism of T cell activation, we found that PT stimulated the production of IFN-gamma and IL-2 by naive T cells and IL-1 by macrophages. Therefore potentiation of distinct T cell subpopulations may have resulted in part from the positive influence of IFN-gamma on the development of Th1 cells and the co-stimulatory role of IL-1 for Th2 cells. Furthermore, PT augmented expression of the co-stimulatory molecules B7-1 and B7-2 on macrophages and B cells, and CD28 on T cells, suggesting that the adjuvant effect may also be associated with facilitation of the second signal required for maximal T cell activation. This study demonstrates that the immunopotentiating properties of PT are largely independent of ADP-ribosyltransferase activity, but are dependent on receptor binding activity and appear to involve enhanced activation of T cells.

Adjuvants, Immunologic↗
PubMed1998

Antibodies to oxidized lipoproteins and their relationship to myocardial infarction.

The inflammatory process and autoimmunity in the form of antibodies to oxidized LDL are important factors in the formation of the atherosclerotic plaque. We examined the time relationship of oxidized lipoprotein antibodies to the acute oxidative stress of myocardial infarction (MI). We also examined the relationship of C-reactive protein, an index of inflammation, and therefore of free radical production, to oxidized low-density lipoprotein (LDL) antibodies. We examined five groups of patients in a cross-sectional study: group 1, within 48 h of MI; group 2, two days to 1 week; group 3, 1-4 weeks; group 4, 1-3 months; and group 5, 3-6 months post MI. Nine patients with high antibody levels were re-examined 12 months after their first assessment. Malondialdehyde (MDA)-LDL and MDA-HDL antibodies were determined by an ELISA method. The highest MDA-LDL antibodies were found within 48 h of MI, but there was no significant difference in MDA-HDL antibodies between the groups. When 9/10 patients with LDL antibodies greater than the mean of 2.7 were re-examined 1 year later, there was a significant decrease in the mean antibody levels (5.2 +/- 1.7 vs. 3.2 +/- 0.6, p < 0.02). There was no correlation between antibodies to MDA-LDL and antibodies to MDA-HDL. There was a positive correlation between serum HDL cholesterol and antibodies to MDA-LDL (r = 0.4, p < 0.02) and a positive correlation between serum triglycerides and MDA-HDL antibodies (r = 0.39, p < 0.02). Acute MI appears to be associated with significantly higher C-reactive protein and antibodies to MDA-LDL, suggesting a possible acceleration of the atherosclerotic process immediately prior to MI.

Aged↗
PubMed1998

A murine model in which protection correlates with pertussis vaccine efficacy in children reveals complementary roles for humoral and cell-mediated immunity in protection against Bordetella pertussis.

The results of phase 3 efficacy trials have shown that acellular and whole-cell pertussis vaccines can confer protection against whooping cough. However, despite the advances in vaccine development, clinical trials have not provided significant new information on the mechanism of protective immunity against Bordetella pertussis. Classical approaches based on measurement of antibody responses to individual antigens failed to define an immunological correlate of protection. A reliable animal model, predictive of acellular and whole-cell pertussis vaccine potency in children, would facilitate an elucidation of the mechanism of immune protection against B. pertussis and would assist in the regulatory control and future development of pertussis vaccines. In this study, we have shown that the rate of B. pertussis clearance following respiratory challenge of immunized mice correlated with vaccine efficacy in children. Using this model together with mice with targeted disruptions of the gamma interferon (IFN-gamma) receptor, interleukin-4 or immunoglobulin heavy-chain genes, we have demonstrated an absolute requirement for B cells or their products in bacterial clearance and a role for IFN-gamma in immunity generated by previous infection or immunization with the whole-cell pertussis vaccine. The results of passive immunization experiments suggested that protection early after immunization with acellular pertussis vaccines is mediated by antibody against multiple protective antigens. In contrast, more complete protection conferred by previous infection or immunization with whole-cell pertussis vaccines reflected the induction of Th1 cells. Our findings suggest that the mechanism of immunity against B. pertussis involves humoral and cellular immune responses which are not directed against a single protective antigen and thus provide an explanation for previous failures to define an immunological correlate of protection.

Animals↗
PubMed1998

Menopausal status: subjectively and objectively defined.

This study aims to assess the relationship between self-rated and menstrually defined menopausal status, assesses criteria women use in perceiving their own menopausal status and compares symptom reporting and hormonal levels for self-rated and menstrually defined menopausal status. Women in the third year of the longitudinal phase of the Melbourne Women's Midlife Health Project (n = 332) were asked to assess their own menopausal status and the basis for this assessment. They were also specifically questioned on current menstrual cycle characteristics and levels of follicle-stimulating hormone (FSH), estradiol and inhibin were measured. For 67% of the women, the two definitions of menopausal status were in agreement. In women menstrually defined as premenopausal, self-rated menopausal status of peri- or postmenopausal appeared to be based on the occurrence of symptoms. In women menstrually defined as postmenopausal, persistence of hot flushes was taken to mean that 'the menopause was still in progress' despite absence of menses for more than 12 months. In women menstrually defined as perimenopausal yet who self-rated as premenopausal, FSH was lower (p < 0.01) and inhibin higher (p = 0.05) than women who self-rated as peri- or postmenopausal. Women's perceptions of the menopause are based on symptoms. Self-rated menopausal status appears to relate more closely to a women's endocrine status than definitions based on purely menstrual cycle characteristics.

Attitude to Health↗
PubMed1997

Atypical squamous cells of undetermined significance: a comparative review of original and automated rescreen diagnosis of cervicovaginal smears with long term follow-up.

BACKGROUND: There is an increasing number of articles regarding the long term follow-up of Papanicolaou (Pap) smears with the diagnosis of atypical squamous cells of undetermined significance (ASCUS). Much controversy exists regarding the management of patients with this diagnosis. In a prior study in 1992, the authors performed automated rescreening of 101 ASCUS cases and 91 negative (control) cases. They found that through PAPNET-directed rescreening, 35 of 101 ASCUS cases (35%) could be reclassified as a squamous intraepithelial lesion (SIL). METHODS: These 192 women were followed since 1992 through manual look backs of subsequent Pap smears and surgical biopsies over a 4-year period. The population studied was comprised of predominantly black women between the ages of 14 and 85 years. The majority were considered a high risk population because many had a history of several sexual partners and multiple pregnancies. RESULTS: Eighteen of 74 patients (24.3%) with an original diagnosis of ASCUS were found on subsequent Pap smears to have an SIL. Only 4 of 64 patients (6%) who originally had a negative Pap smear subsequently were found to have a low grade squamous intraepithelial lesion (LGSIL) within 4 years. Through ordinal logistic regression analysis, it was found that patients with an ASCUS diagnosis had a risk of developing SIL that was 2.6 times greater than the risk for patients with a negative smear diagnosis. Comparing the surgical biopsies in the control and ASCUS groups, there was no statistically significant difference in the risk of developing SIL. This may be because the number of follow-up biopsies were small. CONCLUSIONS: A statistically significant difference of the risk of developing SIL exists between patients with a negative smear versus those with an ASCUS smear. Long term follow-up is essential in the management of the patients with an ASCUS smear because there is clearly an increased risk of developing SIL.

Adolescent↗
PubMed1997

Probing the roles of active site residues in phosphatidylinositol-specific phospholipase C from Bacillus cereus by site-directed mutagenesis.

The role of amino acid residues located in the active site pocket of phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus[Heinz, D. W., Ryan, M., Bullock, T., & Griffith, O. H. (1995) EMBO J. 14, 3855-3863] was investigated by site-directed mutagenesis, kinetics, and crystal structure analysis. Twelve residues involved in catalysis and substrate binding (His32, Arg69, His82, Gly83, Lys115, Glu117, Arg163, Trp178, Asp180, Asp198, Tyr200, and Asp274) were individually replaced by 1-3 other amino acids, resulting in a total number of 21 mutants. Replacements in the mutants H32A, H32L, R69A, R69E, R69K, H82A, H82L, E117K, R163I, D198A, D198E, D198S, Y200S, and D274S caused essentially complete inactivation of the enzyme. The remaining mutants (G83S, K115E, R163K, W178Y, D180S, Y200F, and D274N) exhibited reduced activities up to 57% when compared with wild-type PI-PLC. Crystal structures determined at a resolution ranging from 2.0 to 2.7 A for six mutants (H32A, H32L, R163K, D198E, D274N, and D274S) showed that significant changes were confined to the site of the respective mutation without perturbation of the rest of the structure. Only in mutant D198E do the side chains of two neighboring arginine residues move across the inositol binding pocket toward the newly introduced glutamic acid. An analysis of these structure-function relationships provides new insight into the catalytic mechanism, and suggests a molecular explanation of some of the substrate stereospecificity and inhibitor binding data available for this enzyme.

Amino Acid Sequence↗
PubMed1997

Stress response decreases NF-kappaB nuclear translocation and increases I-kappaBalpha expression in A549 cells.

The stress response and stress proteins confer protection against diverse forms of cellular and tissue injury, including acute lung injury. The stress response can inhibit nonstress protein gene expression, therefore transcriptional inhibition of proinflammatory responses could be a mechanism of protection against acute lung injury. To explore this possibility, we determined the effects of the stress response on nuclear translocation of the transcription factor NF-kappaB, an important regulator of proinflammatory gene expression. In A549 cells induction of the stress response decreased tumor necrosis factor-alpha (TNF-alpha)-mediated NF-kappaB nuclear translocation. TNF-alpha initiates NF-kappaB nuclear translocation by causing dissociation of the inhibitory protein I-kappaBalpha from NF-kappaB and rapid degradation of I-kappaBalpha. Prior induction of the stress response inhibited TNF-alpha-mediated dissociation of I-kappaBalpha from NF-kappaB and subsequent degradation of I-kappaBalpha. Induction of the stress response also increased expression of I-kappaBalpha. We conclude that the stress response affects NFkappaB-mediated gene regulation by two independent mechanisms. The stress response stabilizes I-kappaBalpha and induces expression of I-kappaBalpha. The composite result of these two effects is to decrease NF-kappaB nuclear translocation. We speculate that the protective effect of the stress response against acute lung injury involves a similar effect on the I-kappaB/NF-kappaB pathway.

Adenocarcinoma↗
PubMed1997

Monocyte chemotactic protein-3 (MCP-3)/fibroblast-induced cytokine (FIC) in eosinophilic inflammation of the airways and the inhibitory effects of an anti-MCP-3/FIC antibody.

Monocyte chemotactic protein-3 (MCP-3)/fibroblast-induced cytokine (FIC), a CC chemokine, is chemotactic for cells that typically infiltrate the late-phase allergic reaction. We developed a mouse model of airway inflammation to study the role of MCP-3/FIC. The immunization of mice with OVA resulted in Ag-specific IgE Ab production and the expression of mRNA for IL-4 in the lung tissue. Two weeks after immunization mice were challenged with the allergen by inhalation. Lungs were lavaged, and the tissue was examined at 2 or 24 h. Allergen challenge resulted in the increased recovery of leukocytes in the lavage fluid, but saline challenge did not. There was a significant increase in eosinophils (29 +/- 8% vs 1.2 +/- 0.2%) and lymphocytes (25 +/- 4% vs 5 +/- 2%) in the bronchoaveolar lavage fluid. Histologic examination of the lung demonstrated intense airway inflammation following OVA challenge. The expression of MCP-3/FIC and other CC chemokines (MCP-1, macrophage inflammatory protein-1alpha, and RANTES) was investigated by reverse transcription-PCR followed by densitometric analyses. The allergen challenge up-regulated the expression of mRNA for MCP-1, MCP-3/FIC, and macrophage inflammatory protein-1alpha at 2 and/or 24 h. Immunocytochemical staining for MCP-3/FIC showed that the allergen challenge induced the expression of MCP-3/FIC predominantly in the airway epithelium. Pretreatment of mice with an anti-MCP-3/FIC Ab significantly inhibited the OVA-induced airway inflammation and the bronchoalveolar lavage eosinophilia (8 +/- 2% vs 46 +/- 11% after control Ab, p < 0.03). We conclude that MCP-3/FIC plays a significant role in the allergen-induced eosinophilic inflammation of the airways.

Animals↗
PubMed1997

Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients.

OBJECTIVE: The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients. DESIGN: SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography. RESULTS: For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001) ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006]. CONCLUSIONS: For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.

Adult↗
PubMed1997

The heat shock response inhibits inducible nitric oxide synthase gene expression by blocking I kappa-B degradation and NF-kappa B nuclear translocation.

We investigated the mechanisms by which the heat shock response inhibits inducible nitric oxide synthase (iNOS) gene expression. Incubation of cultured murine lung epithelium (MLE-15) at temperatures ranging from 39 to 43 degrees C, for 1 h, demonstrated that only severe thermal stress (41 to 43 degrees C) was sufficient to induce the heat shock response. Thermal stress inhibited cytokine-mediated iNOS gene expression only when associated with induction of the heat shock response. Transient transfection assays with an iNOS promoter-reporter gene construct demonstrated that the heat shock response inhibited cytokine-mediated iNOS promoter activity. Electromobility gel shift assays demonstrated that the heat shock response inhibited cytokine-mediated NF-kappa B nuclear translocation. The heat shock response also inhibited cytokine-mediated I kappa-B degradation. These data suggest that the heat shock response inhibits iNOS gene expression by transcriptional mechanisms involving the NF-kappa B/ I kappa-B pathway.

Animals↗
PubMed1997

Determination of pKa values of the histidine side chains of phosphatidylinositol-specific phospholipase C from Bacillus cereus by NMR spectroscopy and site-directed mutagenesis.

Two active site histidine residues have been implicated in the catalysis of phosphatidylinositol-specific phospholipase C (PI-PLC). In this report, we present the first study of the pKa values of histidines of a PI-PLC. All six histidines of Bacillus cereus PI-PLC were studied by 2D NMR spectroscopy and site-directed mutagenesis. The protein was selectively labeled with 13C epsilon 1-histidine. A series of 1H-13C HSQC NMR spectra were acquired over a pH range of 4.0-9.0. Five of the six histidines have been individually substituted with alanine to aid the resonance assignments in the NMR spectra. Overall, the remaining histidines in the mutants show little chemical shift changes in the 1H-13C HSQC spectra, indicating that the alanine substitution has no effect on the tertiary structure of the protein. H32A and H82A mutants are inactive enzymes, while H92A and H61A are fully active, and H81A retains about 15% of the wild-type activity. The active site histidines, His32 and His82, display pKa values of 7.6 and 6.9, respectively. His92 and His227 exhibit pKa values of 5.4 and 6.9. His61 and His81 do not titrate over the pH range studied. These values are consistent with the crystal structure data, which shows that His92 and His227 are on the surface of the protein, whereas His61 and His81 are buried. The pKa value of 6.9 corroborates the hypothesis of His82 acting as a general acid in the catalysis. His32 is essential to enzyme activity, but its putative role as the general base is in question due to its relatively high pKa.

Bacillus cereus↗
PubMed1997

Sports drinks: research asks for reevaluation of current recommendations.

Results of two clinical studies support the use of a carbohydrate-electrolyte beverage to improve performance of intermittent moderate- to high-intensity exercise, such as soccer and ice hockey. Two other studies documented that such beverages improved performance during steady-state moderate- to high-intensity exercise, although the mechanism by which carbohydrate improved performance in these protocols is yet to be determined.

Beverages↗