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Biomedical subjects

J B Andersen

Publications and source records attributed to J B Andersen.

At least 19 recordsLinked to original sources
PubMed2007

Effects of social isolation and restraint on adrenocortical responses and hypoalgesia in loose-housed dairy cows.

Effects of social isolation or restraint, applied outside the home pen, on adrenocortical and nociceptive responses were examined in 28 loose-housed dairy cows. Treatments lasted 15 min and consisted of social isolation in novel surroundings or restraint by the head in a test pen. A control treatment was applied in the test pen as well. Each cow was exposed to all treatments in a balanced order, with 3 to 4 d between treatments. Compared with the control treatment, social isolation in novel surroundings led to increased plasma concentration of cortisol (P < 0.001) as well as to indications of hypoalgesia [posttreatment lack of decrease in latency to respond toward nociceptive laser stimulation, a tendency for decreased frequency of kicking in the pauses between laser stimulations (P = 0.06), and an increased proportion of leg moving (least possible active response) after treatment (P = 0.04)]. Indications of hypoalgesia were also observed after restraint (reduced kicking in response to laser stimulation, P = 0.04); however, the indications were to a lesser extent than after social isolation, and restraint treatment did not lead to increased plasma concentration of cortisol. For control and restraint treatment, an initial increase (P < 0.02) in plasma concentration of cortisol was found, suggesting effects of pretreatment factors such as handling. No correlations between adrenocortical and nociceptive responses toward social isolation were found. The results confirm earlier reports stating that nociceptive changes induced by environmental challenges can be shown in dairy cows, even when they are kept in groups and removed from the home pen during the study of stress responses. However, testing outside the home pen seemed to affect the nociceptive and adrenocortical responses, thereby suggesting that care should be taken to avoid effects of pretreatment situational factors.

Animals↗
PubMed2006

Role of 2-5A-dependent RNase-L in senescence and longevity.

Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated beta-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P<0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L-/- mice.

Aging↗
PubMed2006

The interferon regulated ubiquitin-like protein, ISG15, in tumorigenesis: friend or foe?

The interferon-stimulated gene, 15 kDa (ISG15) is an interferon regulated gene that is induced as a primary response to diverse microbial and cell stress stimuli, and encodes the founding member of the ubiquitin-like protein family. ISG15 post-translationally modifies proteins via a pathway parallel to, and partially overlapping with, that of ubiquitin. In addition, ISG15 is released from cells to mediate extracellular cytokine-like activities. Although the biological activities of ISG15 have yet to be fully elucidated, it is clear that ISG15 has the capacity to modulate diverse cellular and physiologic functions. Consistent with this view, alterations in the ISG15 pathway have been identified in human tumors and in tumor cell lines. Here we review evidence of a role for ISG15 as an endogenous tumor suppressor that, when dysregulated in malignant cells, can be subverted to promote oncogenesis.

Amino Acid Sequence↗
PubMed2006

Stage-associated overexpression of the ubiquitin-like protein, ISG15, in bladder cancer.

Bladder cancer is among the most prevalent malignancies, and is characterised by frequent tumour recurrences and localised inflammation, which may promote tissue invasion and metastasis. Microarray analysis was used to compare gene expression in normal bladder urothelium with that in tumours at different stages of progression. The innate immune response gene, interferon-stimulated gene 15 kDa (ISG15, GIP2), was highly expressed at all stages of bladder cancer as compared to normal urothelium. Western blotting revealed a tumour-associated expression of ISG15 protein. ISG15 exhibited a stage-associated expression, with significantly (P<0.05) higher levels of ISG15 protein in muscle-invasive T2-T4 tumours, compared with normal urothelium. Although ISG15 is involved in the primary immune response, ISG15 expression did not correlate with bladder inflammation. However, immunohistochemical staining revealed expression of ISG15 protein in both cancer cells and stromal immune cells. Interestingly, a significant fraction of ISG15 protein was localised to the nuclei of tumour cells, whereas no nuclear ISG15 staining was observed in ISG15-positive stromal cells. Taken together, our findings identify ISG15 as a novel component of bladder cancer-associated gene expression.

Blotting, Western↗
PubMed2005

Effects of diet energy density and milking frequency in early lactation on tumor necrosis factor-alpha responsiveness in dairy cows.

A whole blood stimulation assay (WBA) with Escherichia coli lipopolysaccharide (LPS) and an enzyme-linked immunosorbent assay (ELISA) were established to measure the production of tumor necrosis factor-alpha (TNF-alpha) in bovine plasma. The assays were used to study the effect of time around parturition, and diet energy density, and milking frequency on TNF-alpha responsiveness of dairy cows in early lactation. Forty cows were included in a 2 x 2 factorial block design. One factor was high (H) versus low (L) diet energy density and the other factor was two versus three daily milkings. Blood samples were collected in weeks -3, -1, 2, 3, 5, 9, and 13 around parturition, and investigated for the TNF-alpha production ex vivo and CD14+ monocytes. The TNF-alpha response, CD14+ monocyte number, and CD14 expression level on monocytes were significantly increased in the weeks close to parturition. However, dips of varying sizes were observed for the measured parameters in week 3 after calving. Diet and milking frequency had no effect on the TNF-alpha response ex vivo or CD14 expression level on monocytes, but cows fed diet H had significantly higher numbers of CD14+ monocytes than cows fed diet L. The WBA with LPS was a fast reliable method for repeated measurements of TNF-alpha responsiveness in cattle. Previous findings of increased TNF-alpha responses in periparturient cows were confirmed, whereas diet energy concentration and milking frequency had no effect on the TNF-alpha responsiveness in early lactation.

Animal Feed↗
PubMed2005

Nonbioluminescent strains of Photobacterium phosphoreum produce the cell-to-cell communication signal N-(3-Hydroxyoctanoyl)homoserine lactone.

Bioluminescence is a common phenotype in marine bacteria, such as Vibrio and Photobacterium species, and can be quorum regulated by N-acylated homoserine lactones (AHLs). We extracted a molecule that induced a bacterial AHL monitor (Agrobacterium tumefaciens NT1 [pZLR4]) from packed cod fillets, which spoil due to growth of Photobacterium phosphoreum. Interestingly, AHLs were produced by 13 nonbioluminescent strains of P. phosphoreum isolated from the product. Of 177 strains of P. phosphoreum (including 18 isolates from this study), none of 74 bioluminescent strains elicited a reaction in the AHL monitor, whereas 48 of 103 nonbioluminescent strains did produce AHLs. AHLs were also detected in Aeromonas spp., but not in Shewanella strains. Thin-layer chromatographic profiles of cod extracts and P. phosphoreum culture supernatants identified a molecule similar in relative mobility (Rf value) and shape to N-(3-hydroxyoctanoyl)homoserine lactone, and the presence of this molecule in culture supernatants from a nonbioluminescent strain of P. phosphoreum was confirmed by high-performance liquid chromatography-positive electrospray high-resolution mass spectrometry. Bioluminescence (in a non-AHL-producing strain of P. phosphoreum) was strongly up-regulated during growth, whereas AHL production in a nonbioluminescent strain of P. phosphoreum appeared constitutive. AHLs apparently did not influence bioluminescence, as the addition of neither synthetic AHLs nor supernatants delayed or reduced this phenotype in luminescent strains of P. phosphoreum. The phenotypes of nonbioluminescent P. phosphoreum strains regulated by AHLs remains to be elucidated.

4-Butyrolactone↗
PubMed2005

Mammary cell turnover and enzyme activity in dairy cows: effects of milking frequency and diet energy density.

The aim of the study was to investigate the effects of diet energy density and milking frequency on mammary cell turnover and synthetic capacity in dairy cows. Experiment 1 used 20 dairy cows. From d 4 to wk 16 postpartum, the cows were fed either a low-energy density or a high-energy density diet. From d 4 through wk 8, half of the cows in each group were milked 3 times (3x) or 2 times (2x) daily. From wk 9 to 16, all cows were milked 2 times daily. Mammary biopsies were obtained at wk 8 and 16 postpartum. In experiment 2, udders of 18 individual cows were milked diagonally 2x and 4x, and biopsies were obtained after 7 d. In experiment 1, cows on the low-energy density diet yielded 17 and 24% less milk during wk 3 to 8 and wk 11 to 16 postpartum, respectively. Furthermore, at 8 wk postpartum, mammary enzyme activities tended to be lower and mammary cell proliferation was lower in cows on the low-energy density diet. Three times daily milking during the first 8 wk postpartum resulted in 11% higher milk yield. Mammary cell turnover or enzyme activities were not significantly affected at 8 wk. The 3x milking for 8 wk resulted only in a transient carryover effect on milk yield and neither cell turnover nor enzyme activities were significantly affected at 16 wk postpartum. In experiment 2, mammary cell turnover and enzyme activity were unaffected after 7 d of 4x milking although milk yield increased by 18%. We conclude that nutrient restriction affects mammary cell turnover and possible enzyme activity, and that tuning of negative feedback loops in response to filling of the gland may be the dominating effects of changes in milking frequency.

Acetyl-CoA Carboxylase↗
PubMed2005

The effects of dry period versus continuous lactation on metabolic status and performance in periparturient cows.

It has been argued that dairy cows with a high genetic milk production potential can maintain high milk production even with total omission of the dry period. Further, when omitting the dry period, cows are believed to experience fewer metabolic changes during the transition from late gestation to early lactation compared with cows having a traditional dry period. The performance and metabolic response to omission of the dry period for cows with an expected peak milk yield higher than 45 kg/d were studied in 28 Holstein dairy cows. The cows were followed in late gestation and in the subsequent 5 wk of early lactation. Fourteen cows were milked through late gestation (CM) and another 14 dairy cows underwent a 7-wk dry period (DRY). In the early lactation period, the cows had the same dry matter (DM) intake but cows in the CM group had a 22% reduction in milk yield compared with the cows in the DRY group. At calving, the experimental groups had the same average body weight and body condition score and there were no significant differences in body weight and body condition score changes in early lactation. However, the cows in the CM group compared with the cows in the DRY group had a higher plasma concentration of glucose and insulin and a lower plasma concentration of nonesterified fatty acids and beta-hydroxybutyrate in the following 5 wk of early lactation. Furthermore, the cows in the CM group had lower liver triacylglycerol concentration and higher liver glycogen concentration in the following early lactation. It is concluded that, even in dairy cows with an expected peak milk yield above 45 kg/d, omission of the dry period results in a relatively high reduction in milk yield in the following early lactation. Furthermore, these cows are in less metabolic imbalance in the following early lactation.

3-Hydroxybutyric Acid↗
PubMed2004

Characterisation of the quadriceps stretch reflex during the transition from swing to stance phase of human walking.

The main objective of this study was to characterize the stretch reflex response of the human thigh muscles to an unexpected knee flexion at the transition from stance to swing during walking. Eleven healthy subjects walked on a treadmill at their preferred speed. Reliable and constant knee flexions (6-12 degrees amplitude, 230-350 degrees /s velocity, 220 ms duration) were applied during the late swing and early stance phase of human walking by rotating the knee joint with a specifically designed portable stretch apparatus affixed to the left knee. Responses from rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM), biceps femoris (BF), medial hamstrings (MH) and medial gastrocnemius (GM) were recorded via bipolar surface electromyograms (EMG). The onset of the response in the RF, VL and VM, remained stable and independent of the time in the step cycle when the stretch was applied. Across all subjects the response onset (mean +/- SD) occurred at 23+/-1, 24+/-1 and 23+/-1 ms for RF, VL and VM, respectively. The duration of the initial response was 90-110 ms, at which time the EMG signal returned towards baseline levels. Three reflex response windows, labelled the short latency reflex (SLR), the medium latency reflex (MLR) and the late latency reflex response (LLR), were analysed. The medium and late reflex responses of all knee extensors increased significantly ( p=0.008) as the gait cycle progressed from swing to stance. This was not related to the background EMG activity. In contrast, during standing at extensor EMG levels similar to those attained during walking the reflex responses were dependent on background EMG. During walking, LLR amplitudes expressed as a function of the background activity were on average two to three times greater than SLR and MLR reflex amplitudes. Distinct differences in SLR and LLR amplitude were observed for RF, VL and VM but not in the MLR amplitude. This may be related to the different pathways mediating the SLR, MLR and LLR components of the stretch response. As for the knee extensor antagonists, they exhibited a response to the stretch of the quadriceps at latencies short enough to be monosynaptic. This is in agreement with the suggestion by Eccles and Lundberg (1958) that there may be functional excitatory connections between the knee extensors and flexors in mammals.

Adult↗
PubMed2004

Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice.

INTRODUCTION: Antibiotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of biofilms opens up new ways to control certain bacterial infections. Furanone compounds capable of inhibiting bacterial quorum-sensing systems have been isolated from the marine macro alga Delisea pulchra. OBJECTIVES: Two synthetic furanones were tested for their ability to attenuate bacterial virulence in the mouse models of chronic lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth. METHODS: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test the interference of furanones with quorum-sensing. Study II. Mice with lung infection by Pseudomonas aeruginosa PAO1 [dsred, lasR-PlasB-gfp(ASV)] were injected intravenously with furanones to evaluate their inhibiting effects on quorum-sensing. Study III. Mice with P. aeruginosa PAO1 lung infection were treated with different doses of furanones to evaluate the therapeutic effects of furanones on the lung infection. RESULTS: Furanones successfully interfered with N-acyl homoserine lactone and suppressed bacterial quorum-sensing in lungs, which resulted in decreases in expression of green fluorescent protein. Furanones accelerated lung bacterial clearance, and reduced the severity of lung pathology. In a lethal P. aeruginosa lung infection, treatment with furanone significantly prolonged the survival time of the mice. CONCLUSION: Synthetic furanone compounds inhibited bacterial quorum-sensing in P. aeruginosa and exhibited favourable therapeutic effects on P. aeruginosa lung infection.

Alginates↗
PubMed2004

Combined ACTH and glucocorticoid treatment improves survival and organ maturation in premature newborn calves.

Glucocorticoids play an important role in prenatal organ maturation in many species. In humans, maternal treatment with synthetic glucocorticoids improves neonatal adaptation of prematurely born infants. In cows, pre-term calf survival is improved following a single maternal glucocorticoid administration. We hypothesized that stimulation of endogenous cortisol secretion by adrenocorticotropin (ACTH) treatment combined with maternal dexamethasone treatment, would be even more efficient in stimulating organ maturation in the prematurely delivered calf. Three groups of premature calves were delivered by caesarian section at 90% of gestation length from dams which were either untreated or injected with dexamethasone before delivery, combined with either prenatal or postnatal ACTH treatment to the calf. During the first 24h after birth, thermoregulation, blood chemistry, liver values and organ weights were recorded. In the untreated calves, survival was significantly correlated with blood oxygenation, sodium and calcium levels at the moment of birth. There were marked maturational effects of the treatments on body temperature regulation, blood acid-base status, oxygenation, glucose, insulin, IGF-1 levels, weight of the heart, liver, gastrointestinal tract and thymus weight. For many of the measured metabolic, endocrine and organ weight parameters, the intrauterine ACTH treatment was associated with improved values relative to the postnatal ACTH treatment, which appeared to have no immediate effect on calf viability. In conclusion, the premature calf delivered by caesarian section at 90% of gestation length showed blood chemistry, metabolic, endocrine and organ growth characteristics that indicated severe prematurity. However, the maturation of organ function in newborn premature calves following maternal glucocorticoid injections was further enhanced if is was preceded by intra-fetal injections of ACTH.

Adrenocorticotropic Hormone↗
PubMed2004

Effect of energy density in the diet and milking frequency on plasma metabolites and hormones in early lactation dairy cows.

The effects of energy density in the diet [low = 0.86 SFU/kg dry matter (DM) or high = 1.06 SFU/kg DM] and daily milking frequency (two or three times) in early lactation on plasma concentrations of metabolites and hormones were evaluated in 40 Holstein dairy cows arranged in a 2 x 2 factorial block design. The four treatment combinations were L2, L3, H2 and H3, and the experimental period comprised the first 8 weeks of lactation. Plasma glucose, insulin and insulin-like growth factor (IGF)-I concentrations were on average 8 (3.43 versus 3.19 mmol/l), 114 (41.6 versus 19.4 pmol/l) and 60% (91.9 versus 57.4 ng/ml) higher, whereas beta-hydroxybutyrate (BOHB), plasma urea nitrogen (PUN) and growth hormone (GH) concentrations were on average 18 (0.73 versus 0.89 mmol/l), 14 (7.18 versus 8.35 mmol/l), and 63% (1.0 versus 2.6 ng/ml) lower for cows fed diet H than for cows fed diet L. Cows milked three times daily had a 6% (3.20 versus 3.42 mmol/l) lower plasma glucose concentration and a 19% (0.88 versus 0.74 mmol/l) higher plasma concentration of BOHB compared with cows milked two times daily. Plasma non-esterified fatty acid (NEFA) concentration was not affected by either treatment. Overall, it is concluded that increasing the daily milking frequency creates a higher metabolic imbalance in early lactation. Cows in early lactation will benefit from receiving a high energy density diet and thereby avoid a too high metabolic imbalance when mobilizing body tissue in support of milk production.

3-Hydroxybutyric Acid↗
PubMed2002

Effect of energy density in the diet and milking frequency on hepatic long chain fatty acid oxidation in early lactating dairy cows.

The objective of this study was to examine the effects of diet energy density (high versus low) and increased milk yield, induced by increased milking frequency (two versus three times daily), on the hepatic status of triacylglycerol (TAG) and glycogen content and hepatic long chain fatty acid (LCFA) oxidation capacity in early lactation in a 2 x 2 factorial design. Forty multiparous Danish-Holstein dairy cows were used from 8 weeks before to 8 weeks after calving. Liver biopsies and blood samples were taken in weeks -2, 2, and 7 from calving. The cows fed the high energy density diet, compared with the cows fed the low energy density diet, had an 18 and 28% higher milk production and net energy intake, respectively. Milk yield was increased by 10% when the cows were milked three times compared with twice daily. Complete (CO2 production) and incomplete (ketone body production) LCFA oxidation capacity in the liver were 35 and 32% higher, respectively, and liver TAG content was 48% lower for the cows fed the high energy density diet compared with the low energy density diet. Overall there was no effect of milking frequency on liver parameters. However, a significant interaction between diet and milking frequency showed that the cows milked three times daily and fed the low energy density diet had the lowest liver LCFA oxidation (CO2 and ketone body) capacity. Furthermore, these cows had the numerically highest liver TAG content. The results for liver LCFA metabolism are discussed in relation to the plasma concentration of metabolites and insulin. In conclusion, cows in early lactation given a high energy density diet will, in general, have a lower risk of high TAG infiltration in the liver.

Animals↗
PubMed2002

Effects of hyperinsulinaemia under euglycaemic condition on liver fat metabolism in dairy cows in early and mid-lactation.

The objective was to examine the effects of insulin under euglycaemic conditions on liver long chain fatty acids (LCFA) metabolism with special focus on the aetiology of hepatic lipidosis in early lactation. A 4-day hyperinsulinaemic-euglycaemic clamp (clamp) was conducted on four dairy cows starting in weeks 4 and 17 postpartum. Insulin was infused continuously (1 microg/kg BW per h) and a 50% glucose solution was infused to maintain euglycaemia. Liver biopsies were taken 6 days before, the last day of, and 5 days after the clamp, and blood samples were taken in the same period. In the liver tissue, the relative triglyceride content decreased (P < 0.01) and the glycogen content increased (P < 0.0001) in response to the clamp. Hepatic in vitro palmitate oxidation capacity was lowest during the clamp period and could be explained by a significant decrease in incomplete oxidation (ketogenesis) (P < 0.04) and a tendency to a decreased complete oxidation of palmitate (P < 0.10). Plasma non-esterified fatty acids concentration was decreased during the clamp in early lactation (P < 0.05) but there was no effect on the mid-lactation clamp. The present study shows that increased insulin under euglycaemic conditions seems to depress hepatic LCFA oxidation capacity. However, in terms of preventing hepatic lipidosis, the anti-lipolytic effect of insulin on adipose tissue, which results in decreased mobilization of and hence hepatic load with LCFA, appears more important.

Animals↗
PubMed2002

Antibiotic and biosurfactant properties of cyclic lipopeptides produced by fluorescent Pseudomonas spp. from the sugar beet rhizosphere.

Cyclic lipopeptides (CLPs) with antibiotic and biosurfactant properties are produced by a number of soil bacteria, including fluorescent Pseudomonas spp. To provide new and efficient strains for the biological control of root-pathogenic fungi in agricultural crops, we isolated approximately 600 fluorescent Pseudomonas spp. from two different agricultural soils by using three different growth media. CLP production was observed in a large proportion of the strains (approximately 60%) inhabiting the sandy soil, compared to a low proportion (approximately 6%) in the loamy soil. Chemical structure analysis revealed that all CLPs could be clustered into two major groups, each consisting of four subgroups. The two major groups varied primarily in the number of amino acids in the cyclic peptide moiety, while each of the subgroups could be differentiated by substitutions of specific amino acids in the peptide moiety. Production of specific CLPs could be affiliated with Pseudomonas fluorescens strain groups belonging to biotype I, V, or VI. In vitro analysis using both purified CLPs and whole-cell P. fluorescens preparations demonstrated that all CLPs exhibited strong biosurfactant properties and that some also had antibiotic properties towards root-pathogenic microfungi. The CLP-producing P. fluorescens strains provide a useful resource for selection of biological control agents, whether a single strain or a consortium of strains was used to maximize the synergistic effect of multiple antagonistic traits in the inoculum.

Agriculture↗
PubMed2001

Group II muscle afferents probably contribute to the medium latency soleus stretch reflex during walking in humans.

1. The objective of this study was to determine which afferents contribute to the medium latency response of the soleus stretch reflex resulting from an unexpected perturbation during human walking. 2. Fourteen healthy subjects walked on a treadmill at approximately 3.5 km h(-1) with the left ankle attached to a portable stretching device. The soleus stretch reflex was elicited by applying small amplitude (approximately 8 deg) dorsiflexion perturbations 200 ms after heel contact. 3. Short and medium latency responses were observed with latencies of 55 +/- 5 and 78 +/- 6 ms, respectively. The short latency response was velocity sensitive (P < 0.001), while the medium latency response was not (P = 0.725). 4. Nerve cooling increased the delay of the medium latency component to a greater extent than that of the short latency component (P < 0.005). 5. Ischaemia strongly decreased the short latency component (P = 0.004), whereas the medium latency component was unchanged (P = 0.437). 6. Two hours after the ingestion of tizanidine, an alpha(2)-adrenergic receptor agonist known to selectively depress the transmission in the group II afferent pathway, the medium latency reflex was strongly depressed (P = 0.007), whereas the short latency component was unchanged (P = 0.653). 7. An ankle block with lidocaine hydrochloride was performed to suppress the cutaneous afferents of the foot and ankle. Neither the short (P = 0.453) nor medium (P = 0.310) latency reflexes were changed. 8. Our results support the hypothesis that, during walking the medium latency component of the stretch reflex resulting from an unexpected perturbation is contributed to by group II muscle afferents.

Adrenergic alpha-Agonists↗