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Biomedical subjects

N R Saunders

Publications and source records attributed to N R Saunders.

At least 37 records · Page 2Linked to original sources

Development of walking, swimming and neuronal connections after complete spinal cord transection in the neonatal opossum, Monodelphis domestica.

Development of coordinated movements was quantitatively assessed in adult opossums (Monodelphis domestica) with thoracic spinal cords transected by (1) crushing 7-8 d after birth [postnatal days 7-8 (P7-P8)]; at 2-3 years of age, systematic behavioral tests (e.g., climbing, footprint analysis, and swimming) showed only minor differences between control (n = 5) and operated (n = 10) animals; and (2) cutting on P4-P6; at 1 month these opossums exhibited coordinated walking movements but were unable to right themselves from a supine position, unlike controls (n = 6). When tested at 2 or 6 months, they could right themselves and showed remarkable coordination, albeit with more differences from controls than after a crush. No animals with spinal cords that were crushed at P14-18 survived because of cannibalism by the mother. Morphological studies (n = 10) 3 months-3 years after crush at 1 week showed restoration of structural continuity and normal appearance at the lesion site. Animals with cut rather than crushed cords showed continuity but greater morphological deficits. That lesions were complete was demonstrated by examining morphology and nerve impulse conduction immediately after crushing or cutting the spinal cord in controls. After lumbar spinal cord injection of 10 kDa dextran amine, retrogradely labeled cells were found rostral to the lesion in hindbrain and midbrain nuclei. Conduction was restored across the site of the lesion. Thus complete spinal cord transection in neonatal Monodelphis was followed by development of coordinated movements and repair of the spinal cord, a process that included development of functional connections by axons that crossed the lesion.

Animals↗

Inflammatory mediators in adults undergoing cardiopulmonary bypass: comparison of centrifugal and roller pumps.

BACKGROUND: The nonocclusive centrifugal pump is used for cardiopulmonary bypass (CPB) and mechanical cardiac assistance. This study examined its impact on proinflammatory cytokine release. METHODS: Forty-one patients undergoing elective coronary artery bypass grafting were randomized prospectively to either a standard roller pump group (n = 21) or a centrifugal vortex pump group (n = 20) for CPB. The two groups were well matched in age, sex, severity of disease, and duration of CPB and aortic cross-clamping. Plasma levels of the cytokines tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8, as well as terminal complement, neutrophil counts, and leukocyte elastase, were analyzed before, during, and after CPB. RESULTS: In both groups, traces of tumor necrosis factor-alpha were observed infrequently and interleukin-1beta was not detected. Plasma levels of interleukin-6 and interleukin-8 increased during and after CPB, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. The release of interleukin-6 was significantly greater in the centrifugal group (p < 0.05), whereas the interleukin-8 concentration did not differ between the groups throughout the study period. Levels of terminal complement increased in both groups perioperatively, reaching a peak 30 minutes after protamine administration, whereas neutrophil counts and elastase peaked 2 hours after protamine administration. Plasma terminal complement, neutrophil counts, and elastase release were significantly higher in the centrifugal group (p < 0.05). Peak terminal complement correlated (r = 0.64, p < 0.01) with peak elastase in the centrifugal group only. CONCLUSIONS: This study confirms the proinflammatory nature of CPB in adults and demonstrates that use of the centrifugal pump induces a greater systemic inflammatory response than use of the standard roller pump.

Adult↗

Modification of macrophage response to lipopolysaccharide by fetuin.

The physiological role(s) of fetuin, a protein present in plasma and many tissues of developing animals at levels much higher than in the adult, is unknown. Here we show that fetuin can modify the responses of macrophages to lipopolysaccharide (LPS) stimulation. At concentrations of fetuin in the medium, corresponding to fetal levels of this protein in plasma, the production and secretion of interleukin 1beta (IL-1beta) and nitric oxide (NO) is almost abolished, tumour necrosis factor-alpha (TNF-alpha) reduced, while that of IL-6 is not affected. On the other hand, concentrations of fetuin corresponding to adult plasma levels (i.e. 40-60 mg/100 ml) were without much effect on macrophage synthesis and secretion of these cytokines.

Animals↗

Permeability of the developing and mature blood-brain barriers to theophylline in rats.

1. In the present study, the uptake of theophylline and L-glucose into the adult and neonatal rat brain has been investigated. Steady state cerebrospinal fluid (CSF) and brain concentrations of theophylline were reached within 1 h following a single intraperitoneal (i.p.) injection, whereas steady state CSF and brain concentrations of L-glucose were not approached until after 5 h. 2. Steady state brain:plasma and CSF:plasma concentration ratios for theophylline and L-glucose in neonatal rats were significantly higher than ratios in adult rats. Erythrocyte:plasma ratios for theophylline in neonatal rats were also significantly higher than ratios in adult rats. Steady state ratios for theophylline were significantly higher than those for L-glucose in both neonatal and adult rats. 3. Respiratory acidosis (pH 6.9-7.0) did not affect steady state CSF:plasma or brain:plasma ratios for theophylline in neonatal or adult rats. In contrast, steady state CSF:plasma and brain:plasma ratios for L-glucose were increased by respiratory acidosis. 4. The lower steady state CSF:plasma, brain:plasma and erythrocyte:plasma ratios for theophylline in adult rats are likely to be due to a higher concentration of plasma proteins in adult blood compared with neonates, with a greater retention of protein-bound (non-exchangeable) theophylline in adult blood, and are unlikely to be due to p-glycoprotein-mediated efflux of theophylline at the adult blood-brain barrier.

Acidosis, Respiratory↗

Albumin transfer across the choroid plexus of South American opossum (Monodelphis domestica).

1. Blood-cerebrospinal fluid (CSF) transfer of various exogenous albumins has been investigated in developing Monodelphis domestica (South American grey short-tailed opossum) and compared with the steady-state CSF: plasma ratios for endogenous (Monodelphis) albumin. Ratios for Monodelphis albumin and human albumin were similar and were the highest at postnatal day 5 (P5) (48.2 +/- 4.4 and 40.6 +/- 4.5%, respectively). The ratio for bovine albumin was similar to the steady-state ratio for Monodelphis albumin at P7-8 but became consistently lower than the Monodelphis albumin ratio at all other ages until P32-36 when all albumins tested attained a similar low ratio. The CSF:plasma ratio of chemically modified (succinylated) bovine albumin was always significantly lower than that of other albumins, except at the oldest age examined (P32-36). 2. Immunocytochemistry showed that within the brain, albumin was confined to the lumen and endothelial cells of blood vessels. In the choroid plexus only a small proportion (0.2-1.7% of the total cell number) of epithelial cells was positive for albumin, both endogenous and exogenous, at all ages studied (except the 3rd ventricle where cells were only positive from P8). The CSF was strongly positive for all albumins. The peak proportion of positive cells and of albumin concentrations in CSF occurred at P8. These findings suggest that the primary route for penetration of albumin into CSF is directly across the choroid plexus rather than via the brain. 3. Double-labelling immunocytochemistry revealed that the same epithelial cells contained both endogenous (Monodelphis) and exogenous (human) albumin. In contrast, for succinylated albumin, at P7 only about 35% (lateral ventricle) and 50% (4th ventricle) of Monodelphis albumin-positive cells were also positive for succinylated albumin, but by P30 this proportion increased to 90% at both sites. 4. Thus the developing choroid plexus distinguishes between different albumins. Chemical modification of albumin (succinylation) disrupts this mechanism. It is proposed that in older animals (P32-36) all of the albumin in the CSF is derived from plasma by diffusion (as in adult animals). At earlier stages of development, a proportion of the albumin in CSF also appears to be transferred from the plasma by diffusion with an additional component transferred by a mechanism that can distinguish between different species of albumin. The main route of entry of albumin to CSF seems likely to be via the choroid plexus epithelial cells.

Albumins↗

Intercellular barriers to and transcellular transfer of albumin in the fetal sheep brain.

The nature of the barriers that keep proteins out of the developing brain has been studied in tissues obtained from fetal sheep in experiments conducted under controlled physiological conditions. In anaesthetised pregnant ewes, 60 day gestation fetuses (term is 150 days) were exposed to human albumin injected intravenously for periods up to 6 h. The immunocytochemical distribution of exogenous human albumin was compared with that of endogenous sheep albumin at both the light and electron-microscopical level. Immunogold labelling of ultracryosections suggests that a tubulocisternal endoplasmic reticulum system in immature choroid-plexus epithelial cells is the route by which albumin crosses from blood to cerebrospinal fluid (CSF) in the developing brain. The integrity of the blood-brain barrier, the blood-cerebrospinal fluid barrier and the cerebrospinal fluid-brain barrier to protein, was confirmed. In addition, at the outer surface of the developing brain there also appears to be a restriction on the passage of albumin from CSF into the brain. These observations support earlier proposals that the immature brain develops within an internal environment from which proteins in plasma and CSF are largely excluded.

Animals↗

Transthyretin distribution in the developing choroid plexus of the South American opossum (Monodelphis domestica).

The distributions of transthyretin and albumin in the choroid plexus during brain development have been compared. The South American opossum was chosen because the young are born around the time of choroid plexus formation. Previous work showed that in the adult opossum, transthyretin is expressed in the choroid plexus cells. However, systematic studies of transthyretin in the choroid plexus during development have not been carried out before. Transthyretin was present in 90-95% of the choroidal cells form birth to adulthood. In most cells, transthyretin immunoreactivity was concentrated in the apical region of the cytoplasm. Double labelling of choroid plexus sections with antibodies to albumin and transthyretin showed that 1-2% of cells were positive for both proteins. These findings suggest that from the very earliest stage of choroid plexus formation most epithelial cells both synthesize and contain transthyretin, and a few of these transthyretin-synthesizing cells also contain albumin that is probably being transferred form blood to the cerebrospinal fluid.

Age Factors↗

TGF-beta receptor type II and fetuin in the developing sheep neocortex.

Fetuin shows a characteristic pattern of distribution in the developing neocortex in many mammalian species. Its expression is confined to early-appearing cortical-plate and later subplate neurons. A short 19 amino-acid sequence of fetuin shows a degree of homology to an 18 amino-acid sequence of the TGF-beta type II receptor (TbetaR-II) and in vitro fetuin binds to members of the TGF-beta family of cytokines. It has been suggested that fetuin is the biologically significant antagonist of these cytokines. We have compared, using immunocytochemistry, the distribution pattern of TbetaR-II and fetuin in the developing neocortex of foetal sheep. TbetaR-II immunoreactivity first appears at around 40 days of gestation in the fetal sheep (E40, term in sheep is 150 days from conception), localised in two discreet bands: one just outside the cortical plate in the inner part of the marginal zone and one deep in the cortical plate in what becomes the transient subplate zone. By E70-E80, TbetaR-II is prominent in a population of subplate cells, whereas, by E120 only small patches of TbetaR-II-positive cells are visible, principally in pyramidal cells in layer VI. The developmental sequence of the staining pattern for TbetaR-II in the neocortex is complementary to that for fetuin, rather than overlapping with it. Double-labelling of fetuin and TbetaR-II shows some cellular co-localisation, especially at E60, but most fetuin-positive cells are not immunoreactive for TbetaR-II. Thus, fetuin's proposed role as an antagonist of TGF-beta cytokines and mimic of TbetaR-II is not consistent with the observed distribution of these two molecules in the developing neocortex of the foetal sheep.

Animals↗

"Low-dose" aprotinin modifies hemostasis but not proinflammatory cytokine release.

BACKGROUND: Cytokines are implicated in the pathogenesis of the "whole-body inflammatory response" that may complicate the period after cardiopulmonary bypass (CPB). Low-Dose aprotinin in the pump during CPB has been shown to improve postoperative hemostasis and platelet preservation. We tested the hypothesis that low-dose aprotinin influences the inflammatory reaction (in terms of cytokine release) after CPB. METHODS: In a prospective, randomized study, 36 patients undergoing elective coronary artery bypass grafting were investigated. Nineteen patients received low-dose aprotinin (2 x 10(6) KIU (280 mg] in the pump), and a control group of 19 did not. Complement activation, cytokine production, leukocyte elastase release. D-dimer level, full blood count, postoperative blood loss, and transfusion requirements were analyzed before, during, and after after CPB. RESULTS: Interleukin-1 beta was not detected in either group, whereas traces of tumor necrosis factor-alpha were infrequently observed. Plasma elastase, interleukin-6, interleukin-8, and neutrophil count increased (p < 0.001) during and after CPB compared with the baseline levels, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. Proinflammatory cytokine markers did not differ significantly (p > 0.1) between the groups throughout the study period. The C5b-9 level increased (p < 0.001) in both groups perioperatively, reaching its peak 15 minutes after protamine. Twenty-four-hour postoperative blood loss was significantly (p < 0.001) reduced in the aprotinin group in association with markedly reduced D-dimer levels (p < 0.001). Patients in the aprotinin group also received significantly less banked blood postoperatively than the control group (p < 0.01). CONCLUSIONS: Low-dose aprotinin fails to modify proinflammatory cytokine release, yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting.

Aged↗

Fetuin expression in the dorsal root ganglia and trigeminal ganglia of perinatal rats.

Fetuin, a fetal plasma glycoprotein, has been shown previously to be present in sub-populations of neurons in the developing central and peripheral nervous system. To gain a more complete description of the time course of the appearance of fetuin during neurogenesis we have examined fetuin immunoreactivity, and the presence of fetuin mRNA, in the developing rat trigeminal and dorsal root ganglia. Fetuin immunoreactivity and its mRNA were first seen at embryonic day 15 in the trigeminal ganglia, and at embryonic day 16 in dorsal root ganglia. In both trigeminal and dorsal root ganglion, fetuin appeared to be present up until around the time of birth, and then again between postnatal days 3 and 16. The results suggest that fetuin first appears at around the time that ganglion cell axons reach their central targets, which is also approximately when the cell-death period begins. The proportion of ganglion neurons that were fetuin immunoreactive at different ages was inversely related to the amount of cell death that is known to occur in these populations, thus it seems that fetuin is more likely to be associated not with dying cells, but with those that survive the cell-death period.

Animals↗

Ontogenetic development of diffusional restriction to protein at the pial surface of the rat brain: an electron microscopical study.

Blood-brain, blood-CSF and ventricular CSF-brain barriers to protein are present very early in brain development. In order to determine whether the outer pial surface of the brain also restricts free penetration of macromolecules, the dorso-lateral part of the sensorimotor cortex from rats at embryonic day 12 (E12), 14, 16, and 18, the day of birth (P0), and adult rat, was studied by electron microscopical techniques. Potassium ferrocyanide, Ruthenium Red and immunogold labelling of endogenous albumin were used to investigate junctional structures and the sites of restriction to albumin diffusion. At E12, large fenestrated sinusoids were present in the pia-arachnoid and the brain surface was formed by an incomplete layer of neuroepithelial and presumptive radial glial end feet, but capillaries in the pia-arachnoid showed no fenestrations at E14 or later. From E14, we observed the progressive appearance of distinct junctional structures between the glial end feet which, to our knowledge, have not been described before. Analysis of albumin distribution from E16 to P0 suggests that the junctions may contribute to restriction of diffusion between the subarachnoid space and the brain extracellular fluid. The restriction to the penetration of protein at both the pial and the ependymal surfaces may ensure the isolation of the neural environment during a critical phase in development of the nervous system. The changes in the structure of the junctions between E12 and P0 suggests a transitional series of embryonic junctional types, which eventually give way to the mature junctions of the adult. Parallels between the embryonic glial junctions and junctions described in adult invertebrate brain, suggest some interesting parallels in junctional development in phylogeny and ontogeny.

Albumins↗

The expression of fetuin in the development and maturation of the hemopoietic and immune systems.

The distribution and expression of fetuin, a fetal plasma protein that has been shown to have a wide-spread intracellular presence in many developing tissues including the central nervous system, has been studied in the developing immune and hemopoietic organs of fetal and adult sheep. The presence of fetuin was demonstrated using immuno-cytochemistry and expression of fetuin was studied using northern blot analysis and in situ hybridization. In the developing sheep fetus, fetuin was shown to be expressed first in the hemopoietic cells of the fetal liver and subsequently in the forming spleen. The very first stromal, bone marrow-forming cells, also expressed fetuin mRNA. These cells became more numerous during gestation and by embryonic day (E)115 (term is 150 days), fetuin-expressing cells were identified morphologically to be monocytes/macrophages. Fetuin protein, on the other hand, was present in all hemopoietic and immune organs from the earliest age studied (E30) but was confined initially to matrix, mesenchymal tissue. Fetuin-positive cells could be identified in the spleen at E60 as early hemopoietic cells, in the lymph nodes at E60 as stromal cells and macrophages, and at E115 in the thymus as macrophages and squamous cells. In the adult, fetuin mRNA was only detectable by northern blot in the liver and the bone marrow. Using in situ hybridization in adult tissue, fetuin mRNA-positive cells were identified in the bone marrow to be monocytes/macrophages. Additionally, in the spleen germinal centres, fetuin mRNA was identified in cells with the morphology of dendritic cells. Using three separate cellular markers: lysozyme, S-100, and alpha 1-antitrypsin, the cellular identification of fetuin-positive cells was confirmed to be in the monocyte/macrophage lineage.

Animals↗

Development of a clinical asthma score for use in hospitalized children between 1 and 5 years of age.

The objective of this study was to develop a clinical asthma score (CAS) for use in hospitalized children between 1 and 5 years of age. Formal approaches to item selection and reduction, reliability, discriminatory power, validity, and responsiveness were used. The final CAS consisted of five clinical characteristics: respiratory rate, wheezing, indrawing, observed dyspnea, and inspiratory-to-expiratory ratio. Interrater reliability was high (weighted kappa = 0.82), and the CAS was discriminatory (Ferguson's delta = 0.92). The CAS was valid, with a strong correlation with length of hospital stay (Spearman's correlation = 0.47, p < 0.05) and drug dosing interval (Spearman's correlation = -0.58, p < 0.01). The CAS was responsive, with a significant change in CAS from admission to discharge (Wilcoxon signed rank test, p < 0.01). This score, for use in hospitalized preschool children, is reliable, discriminatory, valid, and responsive.

Asthma↗

Synaptogenesis in the neocortical anlage and early developing neocortex of rat embryos.

The recent finding of synapses in Monodelphis domestica (South American grey short-tailed opossum) before the establishment of the cortical plate raises the question of whether this finding is species-specific. Therefore, the establishment of the first synapses in the developing neocortex has been studied in the sensorimotor cortex of rat fetuses with a gestational age ranging from embryonic day 12 (E12) to birth. At E14, we found well-defined synapses with postsynaptic thickening and containing several vesicles in the presynaptic element in the primordial plexiform layer, before the appearance of the cortical plate. The postsynaptic elements were probably dendrites of Cajal-Retzius cells in the primordial plexiform layer and/or differentiating dendrites of presumptive cortical plate neurons. At E16, in addition to the presence of axodendritic and very few axosomatic synapses in the marginal and the subplate zones, synapses of both types were present within the cortical plate. Thus, this paper provides evidence for the presence of synapses in the developing rat brain both at an earlier stage and with a wider distribution than previously reported.

Animals↗

Terbutaline improves efficiency of oxygenation after coronary artery bypass surgery.

OBJECTIVE: To assess the therapeutic role of the betareceptor agonist terbutaline in reducing postoperative pulmonary dysfunction following coronary artery bypass grafting (CABG). DESIGN: Prospective, randomized, open controlled study. SETTING: Cardiac surgical intensive care unit. PATIENTS. 22 consecutive patients undergoing elective CABG. INTERVENTIONS: 11 were randomized to receive terbutaline 0.5 mg subcutaneously 6 hourly for 48 hours following extubation (group T) while 11 controls did not (group C). MEASURES: FVC, FEV1 and PEFR measured pre-operatively and at 30 min, 12 hrs, 36 hrs and 5 days post-extubation. A-aDO2 calculated from arterial blood gas analysis during the first 24 hrs post-CABG. RESULTS: Terbutaline had no effect on spirometric variables which decreased by over 50% after extubation in both groups and increased in similar fashion over the next 5 days. A-aDO2 increased significantly (p<0.01) after extubation in both groups. Treatment with terbutaline eliminated this change in group T at 6 hrs after extubation. CONCLUSIONS: Terbutaline has little effect on the restrictive ventilatory deficit after CABG but does improve the efficiency of oxygenation in the early postoperative period.

Adrenergic beta-Agonists↗

Mitral valve replacement with the Carpentier-Edwards standard bioprosthesis: performance into the second decade.

From March 1978, 196 Carpentier-Edwards standard bioprostheses (stCE) were implanted in 194 patients. There were 154 isolated mitral valve replacements (MVR) and 42 aortic plus mitral valve replacements (AVR/MVR) with a mean follow-up of 7.05 (range 0-15.2) years and 7.15 (range 0-13.8) years, respectively. Freedom from structural valve failure at 10 years was 70.8% +/- 4.9% (MVR) and 59.6% +/- 11.1% (AVR/MVR). The incidence of structural valve failure increased sharply after 7 years. Freedom from thromboembolism was 83.0% +/- 3.8% (MVR) and 89.0 +/- 6.0% (AVR/MVR). Thromboembolic events were related to the presence of atrial fibrillation in patients not receiving anticoagulation. Anticoagulant-related haemorrhage was rare. Freedom from mitral valve prosthetic endocarditis at 10 years was 90.9% +/- 3.1% (MVR) and 86.1% +/- 8.4% (AVR/MVR). Prosthetic valve endocarditis was associated with more than 60% mortality. The probability of event-free survival at 10 years follow-up was 43.6% +/- 4.6% (MVR) and 33.3% +/- 8.6% (AVR/MVR). The performance of the stCE in the mitral position shows a low rate of thromboembolic events and anticoagulant-related haemorrhage, but the long-term performance of the prosthesis is unsatisfactory due to a high rate of structural valve failure. This confirms earlier reports.

Adult↗

Results of pneumonectomy for cancer in patients with limited ventilatory function.

It is well established that patients with compromised pulmonary function have a greater incidence of morbidity and mortality following lung resection. The prognosis of 36 (9.7%) patients with poor respiratory function (forced expiratory volume in ls (FEV1) and FEV1/FVC (forced vital capacity) ratio were equal to or less than 50% of the predicted value) of a total of 369 patients who underwent pneumonectomy due to non-small cell lung carcinoma over 10 years were reviewed. All but three patients were male with a median age of 62.5 years. Right pneumonectomy was carried out in 12 (33%) and left in 24 (67%) patients. Median FEV1 and FEV1/FVC were 1.51 (46%) and 46.5% respectively. Three (8%) patients died within 30 days of surgery. The postoperative complication rate in patients with poor respiratory function was 44%. Nine (27%) of the hospital survivors died due to non-malignant causes (recurrent chest infection/respiratory failure) and 12 (36%) due to recurrent tumour. The cause of death in one patient was second primary lung tumour and it was unknown in three (9%) patients. Eight (24%) long-term surviving patients did not have severe respiratory symptoms; their FEV1 and FEV1/FVC were remeasured and revealed a median 1.05 l (38%) and 50%, respectively of the predicted value. Actuarial 5-year survival was 29%. Poor respiratory function is associated with postoperative complications and non-malignant deaths arising secondary to respiratory failure. The survival profile demonstrates that patients were successfully treated with pneumonectomy and suggests that surgery should not be withheld from those with limited lung function if detailed investigations predict adequate residual lung function.

Aged↗

Evaluation of short-course therapy with cefixime or rifampin for eradication of pharyngeally carried group A streptococci. The Ontario GAS Study Group.

Therapy to eradicate pharyngeally carried group A streptococci (GAS) has increasingly been used in the management of institutional outbreaks and is now recommended for household contacts of patients with streptococcal toxic shock syndrome. In this randomized, controlled trial, contacts of patients with GAS infections were screened for pharyngeal GAS colonization. Those whose cultures were positive were randomized to receive either cefixime (8 mg/[kg.d]; maximum 400 mg) or rifampin (20 mg/kg; maximum, 600 mg) once a day for 4 days. Two to five days following completion of therapy, repeated cultures were negative for 13 (38%) of 34 rifampin recipients and 71 (77%; 95% CI, 69%-85%) of 97 cefixime recipients. At 10-14 days after treatment, only 53% of cefixime recipients remained culture-negative. Rates of successful clearance improved with increasing age (P < .01); among 17 adults who received cefixime, the success rate was 94%. Four days of therapy with rifampin is not effective for eradication of pharyngeally carried GAS. Four days of therapy with cefixime may be effective for adults, but further studies are needed.

Adolescent↗