Association of GNB3 C825T polymorphism with peak oxygen consumption.

The C825T single nucleotide polymorphism (SNP) in the guanine nucleotide-binding protein, beta polypeptide 3 ( GNB3) gene gives rise to a splice variant, GNB3s that has enhanced G protein activation and signal transduction activity. This variant has been reported to be associated with cardiovascular disease, diabetes and obesity. We studied this SNP in 95 healthy 18 to 30 year-old African American university students to determine its association with aerobic capacity and cardiorespiratory fitness as measured by peak oxygen consumption (VO (2)peak). We also tested the effect of heart rate variability (HRV) as an independent predictor of VO (2)peak. We tested the association of the SNP and HRV with VO (2)peak in a multivariate regression analysis with appropriate adjustments of covariates, under dominant and recessive models. We found a significant independent association of the 825T allele with VO (2)peak under the dominant model (beta-coef.=-0.101, P=0.0442). We also observed that HRV marginally influenced VO (2)peak. This finding suggests that GNB3 C825T polymorphism is associated with VO (2)peak which is influenced by autonomic modulation of heart rate in African Americans.

Exercise training favourably affects autonomic and blood pressure responses during mental and physical stressors in African-American men.

Aerobic exercise is a powerful mechanism by which cardiovascular and autonomic parameters may be improved. We sought to quantify the extent of benefit that could be achieved by a short-term monitored exercise regimen on several autonomic parameters during recognized mental and physical stressors in young normotensive African-American men matched for a family history of hypertension, a group at high risk for the development of hypertension. Autonomic modulations were derived using spectral decomposition of the electrocardiogram and beat-to-beat blood pressures (BPs). Arterial compliance was obtained using contour analysis of the radial artery pulse wave. The analysis of variance revealed that compared with a matched sedentary control group, aerobic capacity of the trained group significantly increased by 16%. Autonomic modulations, arterial compliance and BP responses significantly improved during some of the stressors, whereas no such improvements were seen in the control group. Attenuated responses, mediated through a favourable shift in sympathovagal balance and enhanced arterial compliance, provide mechanistic evidence of how certain variables may be improved due to aerobic conditioning in a population at high risk for the development of hypertension.

Synergism between cocaine and atropine at the caudal ventrolateral medulla of cats.

We have previously reported that the anticholinergic properties of cocaine may be important in cocaine induced apneusis. We have studied the effects of the cholinergic muscarinic antagonist atropine (ATR) on cocaine induced apneusis at the caudal chemosensitive areas of the ventrolateral medulla oblongata (CVLM). Experiments were performed in urethane anesthetized and tracheotomized cats with the CVLM surgically exposed. Topical application of ATR (44 mM ) to the CVLM produced significant decrements in minute ventilation (V(E)) and mean arterial blood pressure (MABP) (P<0.05) but the effects on tidal volume (V(T)), respiratory frequency (f) and heart rate (HR) were not significant. Administration of cocaine (37 mM) to ATR pretreated animals increased the incidence of cocaine induced respiratory arrest to more than twofold greater than when cocaine was administered in the absence of pretreatment. The ATR pretreated animals that did not experience inspiratory arrest after cocaine were shown to exhibit significant decrements in f and V(E) as a consequence of prolonged inspiratory pauses. The reduction in MABP after cocaine in ATR pretreated animals was also significant. These results suggest that ATR enhances the central respiratory toxicity of cocaine by acting synergistically at CVLM chemosensitive sites.

Somatosensory evoked potential, neurological examination and magnetic resonance imaging for assessment of cervical spinal cord decompression.

The present study was designed to determine the relationship between neurological testing, anatomical imaging, and electrophysiological monitoring for assessing outcome of cervical spinal cord decompression. We prospectively studied 28 consecutive patients (age 39-76 yr) who were subjected to presurgical-(1-3 wk) and postsurgical (3-4 mo) neurological examination and recording of the median nerve somatosensory evoked potential (SEP). In 13 patients, magnetic resonance imaging (MRI) was also performed. Changes in neurological function, SEP and MRI were evaluated and graded as (1) improvement,(2) no change or (3) deterioration. Neurological outcome (NO) was based on changes in motor grade strength, sensory, reflexes and gait. The SEP outcome was based on changes in latency and disappearance of SEP waveform components whereas MRI evaluation was based on changes in spinal cord and canal diameters. Significance of association between NO, SEP and MRI was determined by Pearson's Chi-Square statistic (P<.05). The SEP improved in 71% (20/28) and deteriorated in 28% (8/28) of the subjects. An association between SEP changes and NO was found in 82% (23/28) of the subjects (P = .0038). Decompression increased the spinal canal diameter in 92% (12/13), and the spinal cord diameter in 38% (5/13) of the subjects. An association between NO, or SEP and MRI was not detected. Changes in median nerve SEP latency appear to be predictive of the neurological status of patients subjected to cervical spinal cord decompression. Postoperative increments in SEP latency or disappearance of the SEP waves were indicative of poor outcome after surgical decompression of the cervical spinal cord.

Analgesic responses to intrathecal morphine in relation to CSF concentrations of morphine-3,beta-glucuronide and morphine-6,beta-glucuronide.

This study was performed to determine whether variations in analgesic responses to intrathecal morphine could be explained by cerebrospinal fluid (CSF) concentrations of morphine metabolites. Twenty-four CSF samples were collected at the beginning, middle and end of treatment periods in seven cancer patients with pain of malignant origin. CSF concentrations of morphine-3,beta-glucuronide (M3G) and morphine-6,beta-glucuronide (M6G) metabolites were measured by gas chromatography/mass spectrometry. Analgesic responses to morphine were estimated concurrent with CSF collection using a visual analog scale representing percentages of pain relief. Effective analgesia was defined as > or = 75% pain relief. CSF concentration of M3G and M6G in the 24 samples were 722 +/- 116 ng/ml and 699 +/- 158 ng/ml, respectively. CSF samples were categorized into two groups: (1) those collected during effective analgesia (N=14), and (2) those collected during ineffective analgesia (N=10). M6G levels detected in group 1 samples (effective analgesia) were significantly greater than those found in group 2 samples (ineffective analgesia) (978 +/- 243 ng/ml vs 309 +/- 68 ng/ml, P<0.05). Intergroup differences in CSF M3G concentrations and M3G/M6G ratios were not significant. It is concluded that CSF M6G may be indicative of effectiveness of analgesia in cancer patients subjected to intrathecal morphine.

Growth inhibition of subcutaneously transplanted hepatomas without cachexia by alteration of the dietary arginine-methionine balance.

Previous studies have shown that alteration of the dietary arginine-methionine balance by use of synthetic L-amino acids inhibits tumor growth of a subcutaneously transplanted Morris hepatoma at the expense of maintaining body weight. However, L-methionine is susceptible to degradation and, therefore, may contribute to a deficiency state. The present studies were performed to determine whether growth of subcutaneous hepatoma transplants is inhibited, and body growth maintained, when rats are fed diets containing L-methionine in replacement of N-acetyl-L-methionine (NALM) for 28 days. Tumor-free and tumor-bearing rats fed a control diet, with amino acids replacing protein, had gains in body weight: 31.3 +/- 1.0 and 19.1 +/- 0.5 g (12% and 7%), respectively. Rats fed six experimental diets, with varying L-arginine-NALM balances, had body weight gains ranging from 18.4 +/- 0.3 to 26.7 +/- 0.9 g (7-10%). Tumor weight of control rats was 10.65 +/- 0.24% of body weight. Diets supplemented with L-arginine in combination with normal and deficient NALM decreased tumor weights by 35% and 38%, respectively, It is concluded that dietary replacement of L-methionine with NALM and supplementation with L-arginine inhibits growth of a subcutaneously transplanted Morris hepatoma in the absence of cachexia.

Lower leg high-intensity resistance training and peripheral hemodynamic adaptations.

High-intensity resistance (HIR) training has been associated with muscle hypertrophy and decreased microvascular density that might produce a blood flow limitation. The effect of HIR training on lower leg maximal blood flow and minimum vascular resistance (Rmin) during reactive hyperemia were investigated in 7 healthy males. The gastrocnemius-soleus muscles of one leg were trained using maximal isokinetic concentric contractions for 4 weeks; the nontrained leg was the control. Lower leg blood flow was measured by venous occlusion plethysmography. Lower leg muscle volume was determined using magnetic resonance imaging. Peak isokinetic torque increased in both the trained (T) and nontrained (NT) legs (p < .05). Lower leg muscle volume increased by 2% in the T leg only (p < .05). In the T leg, maximal blood flow decreased and Rmin increased (p < .05); no hemodynamic change was detected in the NT leg. It is concluded that HIR training of the calf muscles is associated with a decrease in hyperemia-induced blood flow; thereby, indicating a blood flow limitation to the calf muscles.

Cardiorespiratory effects of cocaine and procaine at the ventral brainstem.

The caudal ventrolateral medulla (CVLM) is an area of the brainstem, in the vicinity of the hypoglossal nerve roots, where cholinergic and adrenergic neurons participate in respiratory and vasomotor control. Cardiorespiratory depression has been produced by topical application of cocaine to the CVLM. In the present studies, the effects of topical pretreatments of the CVLM with alpha-adrenergic blockers (prazosin 4.8 mM) and beta-adrenergic blockers (propranolol 11.3 mM) on the cardiorespiratory responses to topically administered cocaine (37 mM) were investigated in urethane anesthetized cats. Both prazosin and propranolol failed to produce ventilatory responses and to counteract cocaine-induced apneustic breathing. However, the cocaine-induced decrement in mean arterial blood pressure (MABP) following pretreatment of the CVLM with propranolol was found to be 11 +/- 5%, compared to the 18 +/- 5% decrement produced by cocaine alone. These differences were not statistically significant. Procaine (37 mM) in equimolar doses to cocaine, produced a small statistically significant decrement in MABP (P < 0.05) without ventilatory effects. Topical administration of procaine (73.3 mM), at approximately twice the equimolar dosage of cocaine, produced apneustic breathing that was indistinguishable from that produced by cocaine. The neurotoxic properties of cocaine that produce apneustic breathing appear to be similar to that produced by the anesthetic agent procaine, and the alpha- and beta-adrenoceptor blockers prazosin and propranolol do not appear to antagonize the vasomotor depression induced by cocaine at the CVLM.

Growth inhibition of subcutaneously transplanted hepatomas by alterations of the dietary arginine-methionine balance.

We hypothesized that alteration of the dietary arginine-methionine balance might inhibit tumor growth and suggest nutritional strategies for cancer therapy. The Morris hepatoma 3924A was subcutaneously transplanted in ACI rats. Control diets containing normal levels of arginine, methionine, and other amino acids in replacement of protein (24%), carbohydrates (59%), fat (10%), and fiber, vitamins, and minerals (7%) were fed for 28 days. Six experimental diets were adjusted to maintain amino acids at 23-25% and carbohydrates at 58-60%; these diets were 1%-2% deficient in arginine or supplemented with 1-2% arginine (expressed as percent amino acid content of diet) in combination with normal, deficient, and supplementary levels of methionine. Daily food intake was unaffected by the experimental diets. The control groups gained 26.4 +/- 2.8 g body weight, and small body weight decrements ranged from 3.5% to 8.4% in the groups fed the experimental diets. Tumor weight of controls was 8.5 +/- 1.5% of body weight. The experimental diets that produced significant tumor growth inhibition (TGI) were 1) the arginine-methionine-deficient diet, 2) the arginine-excess-methionine-deficient diet, 3) the arginine-deficient diet, and 4) the excess-arginine diet. Diets containing excess methionine failed to produce TGI. TGI resulted in tumor weights 41-46% of control values. TGI was associated with significantly lower blood urea nitrogen, plasma protein, and tumor spermidine-to-spermine ratio than in tumor-bearing controls. It is concluded that dietary alteration of a single amino acid, arginine, might be a potentially useful nutritional strategy for controlling tumor growth.

Monitoring of median nerve somatosensory evoked potentials during cervical spinal cord decompression.

We evaluated the intraoperative utility of monitoring median nerve somatosensory evoked potentials (SEPs) in 31 consecutively hospitalized neurosurgical patients (mean age 55.3 +/- 2.1 years) who underwent spinal cord decompression for cervical herniated disc, spondylosis, or tumor. Pre- and postoperative standard neurological examinations included evaluation of motor function, sensory responses, gait, tone, and reflexes. Evoked potentials were recorded from clavicular Erb's (N9) and contralateral cortical (N20) points. Intraoperatively, SEP measurements were obtained after the onset of anesthesia (baseline control) and were repeated throughout the operative procedures. N20 and N9-N20 conduction latencies were measured for each SEP recording; disappearance of the SEP waveform was interpreted as a nonquantifiable increase in latency. Follow-up neurological examinations were made immediately after and up to 6 months following surgery. Postoperatively, the 31 study subjects were assigned to one of two groups based on neurological evaluation: 27 group I subjects had either no change or improvement (good outcome) whereas four group II subjects had postoperative neurological deterioration (poor outcome). Intraoperative N9-N20 interpeak latency was found to increase during cervical decompression in six of 27 group I and in two of four group II subjects. Only two of the Group I subjects exhibited increases > 10% (14 and 19%, respectively). Intraoperative communication to the surgeon of a marked increase of N9-N20 latency during positioning for cervical traction clearly obviated a poor outcome in one group I subject; Upon removal of traction, latency decreased and significant changes in neurological function were not detected postoperatively. The SEP waveform disappeared in two of the group II and in none of the group I subjects. In the two group II subjects exhibiting increases of N9-N20 latencies, increments were > 20%. These findings indicate that in patients undergoing cervical spinal cord decompression, disappearance of SEPs or increases > 20% in the N9-N20 interpeak latency are suggestive of operative conditions that place patients at risk for poor neurological outcome.

Effects of a stroma-free hemoglobin and perfluorochemical combination on ultrastructure and function of the isolated rat kidney.

Experimental perfusions of isolated rat kidneys were performed with flow rates adjusted to produce comparable glomerular filtration rates (GFR) in control and experimental groups. The experimental perfusate, consisting of Krebs-Ringer bicarbonate (KRB) containing 3.5% (uncrosslinked) stroma-free hemoglobin (SFH) plus 3.5% of the perfluorochemical (PFC) Fluosol-DA, was found to produce only 48% as much urine as the control perfusate consisting of KRB containing 7% dextran (without either SFH or PFC). Perfusion with the experimental SFH/PFC mixture was associated with mean fractional reabsorptions of sodium 3.3% greater and of potassium 5.1% lesser than perfusion with the control KRB (with dextran) solution (p < .05). The SFH/PFC mixture was localized histochemically to the capillaries and urinary spaces of glomeruli; and to the apical microvilli, basal laminae, and intracytoplasmic vacuoles of proximal renal tubular cells. Since the glomerular filtration rate was not a factor, decremental urine production appears to be associated with increased reabsorption of sodium, excretion of potassium, and proximal tubular uptake of the experimental SFH/PFC mixture by endocytosis.

Physical performance decrements in children with sickle cell anemia.

Prior studies have suggested that cardiorespiratory dysfunction might contribute to the inability of children with sickle cell anemia to exercise competitively with normal children. This article presents a study designed to detect differences in performance of routine physical activities between groups of children having homozygous hemoglobin of sickle cell anemia (HbSS) and those with normal hemoglobin (HbAA). Thirty 10-year-old girls were divided into two equal groups exhibiting no significant differences in height, weight, or body surface area. Each subject performed 20-yd swimming, 40-yd swimming, and 100-yd "potato" foot-racing activities. Results showed significant performance decrements in HbSS compared with HbAA children. Performance decrements on the 20-yd swimming were found to be significantly greater than in either the 40-yd swimming or the 100-yd "potato" races. Assessment of 20-yd swim time as a fraction of 40-yd swim time showed diminished capacity of HbSS children for "burst activity." It is concluded that distance might play a role in the capacity of HbSS children to compete with HbAA children in racing activities such as those encountered in school-based physical education programs. Parents and educators should consider that short distance racing might exaggerate the inability of children with sickle cell anemia to compete with normal children.

Acute beneficial effect of Fluosol-DA on urinary excretion of stroma-free hemoglobin in the isolated rat kidney.

In a timed study over 75 min, divided into 5 15-min periods, experimental perfusions of isolated rat kidneys using Krebs-Ringer bicarbonate (KRB) containing 3.5% (uncrosslinked) stroma-free hemoglobin (SFH) plus 3.5% of the perfluorochemical Fluosol-DA were found to excrete only 13% as much total hemoglobin (Hb) as control perfusions using KRB containing 7% SFH alone (controls). The glomerular filtration rate was the same for experimentals and controls in 3 periods, and slightly higher in the experimentals in 2 periods. However, urine flow was found to be significantly decreased in all 5 periods for the experimentals relative to the controls. These effects can be explained by reabsorption of glomerular filtrate containing Hb by endocytosis of renal tubular cells.

Effects of cholinomimetics on cocaine-induced hypotension and apneusis at a ventral brainstem cardiorespiratory control site.

The current study was undertaken to evaluate the effects of cholinomimetic drugs on cocaine-induced central cardiorespiratory depression. Cats anesthetized by urethane (2.0 g/kg) were subjected to topical application at the caudal ventrolateral medullary surface (cVMS) of cocaine and two cholinomimetic pretreatment drugs. The following drug regimens were tested: 37 mM cocaine 1) given alone; 2) given 5 min after 2.7 mM carbachol pretreatment; and 3) given 5 min after 3.6 mM physostigmine pretreatment. In 7 of 11 cats, pretreatment with physostigmine decreased the incidence of cocaine-induced apneusis and hypoventilation significantly (p < 0.05); these animals showed no significant change in the mean arterial blood pressure during the 5-min pretreatment before administration of cocaine. In 4 of 11 cats, the physostigmine pretreatment produced a significant decrease in mean arterial blood pressure followed by lethal cardiorespiratory arrest when cocaine was administered. Pretreatment with carbachol resulted in cardiorespiratory responses which were not significantly different from those produced by cocaine alone. In anesthetized cats not exhibiting hypotensive responses to physostigmine, pretreatment may ameliorate cocaine-induced respiratory failure by ventral brainstem control mechanisms.

Cocaine and ventral brainstem neurotoxicity

One of the complications of cocaine abuse is central cardiorespiratory failure. However, the site and mechanism of cocaine are unknown. The present study evaluates the effect of cocaine applied topically to the caudal and intermediate areas on the ventrolateral surface of the brainstem. These areas are known to be involved in the CO2 /pH chemosensory drive to respiration and in vasomotor control. Cats were anesthetized with urethane (2.0 g/kg), the trachea cannulated and the ventro-lateral surface of medulla oblongata (VMS) exposed. Cocaine prepared in mock CSF pH 7.4 was applied bilaterally to chemosensitive zones using pledgets. The effect of procaine was also tested. Tidal volume (Vt), respiratory frequency (f), arterial blood pressure (BP) and heart rate (HR) were monitored. Cocaine (62.5 ug/site) produced a significant decrease in minute ventilation (Ve) and blood pressure (BP) (p<0.05); the cuadal area was more sentive. In equimolar doses to cocaine, procaine (50 ug/site) produced small but significant effects on BP with no changes in Ve however, twice the equimolar dose(100 ug/site), produced respiratory responses similar to that of cocaine. Alpha and beta adrenoceptor antagonists prazosin (10 ug.site) and propranolol (16.7 ug/site) respectively, failed to alter the hypotensive or respiratory depressant effect of cocaine. Only animals that were hypotensive before or during physostigmine pretreatment (5 ug.site) experienced cardiorespiratory failure upon administration of cocaine. Carbachol (2.5 ug/site) had no effect on the cocaine induced cardiorespiratory responses. The present data suggest that (1) central cocaine neurotoxicity may result from interaction of cocaine with VMS sites; (2) the mechanism of action of cocaine at these sites is similar to that of procaine and does not appear to involve adrenergic receptors; and (3) pretreatment with the involve adrenergic receptors; and (3) pretreatment with the cholinomimetic physostigmine was effective in protecting animals from cocaine induced respiratory failure, its efficacy being limited to those animals that were not hypotensive during pretreatment. (AU)

Central cocaine neurotoxicity at brainstem cardiorespiratory control sites.

Cocaine hydrochloride was applied topically to the ventrolateral medullary surface (VMS) where chemosensitive respiratory and vasomotor control sites are colocalized. Cats (n = 16) were anesthetized with urethane (2.0 g/kg, 80 percent of dose titrated over 60 min). The trachea of each animal was cannulated and the VMS was surgically exposed. Tidal volume (VT), frequency of breathing (f), systolic and diastolic blood pressure (SBP and DBP, respectively), and heart rate (HR) were measured. Cocaine (62.5 micrograms per site) administered at the VMS control sites decreased f, SBP, and DBP significantly (p < 0.05), without changing HR or VT values. This cocaine-induced hypoventilation was associated with brief intervals of inspiratory cramp (apneusis). Central cocaine neurotoxicity may result from interaction of cocaine with VMS sites, producing increased inspiratory drive and decreased vasomotor tone.

Cholinergic-opioid interactions at brainstem respiratory chemosensitive areas in cats.

Central respiratory chemosensitivity has been ascribed to CO2-sensitive neurons located on the ventral brainstem surface. The effects of cholinergic mechanisms on CO2-sensitive neuronal activity recorded extracellularly at the brainstem respiratory chemosensitive area at the caudal ventral medullary surface (cVMS) were investigated in cats (n = 14) anesthetized with chloralose-urethane. The neurons increased their firing rate from 10.4 +/- 1.6 Hz to 33.9 +/- 5.2 Hz when the mock cerebrospinal fluid (mCSF) superfusing buffer solution was changed from pH 7.4 (control) to pH 7.0 (acidic). Atropine (ATR) applied topically to the cVMS depressed the H(+)-ion-induced increase in neuronal frequency from 32.8 +/- 4.8 Hz to 13.4 +/- 2.2 Hz. ATR also depressed the inspired-CO2-induced increase in neuronal activity from 33.2 +/- 8.3 Hz to 18.9 +/- 4.9 Hz, suggesting the possibility of a muscarinic cholinergic involvement in cVMS neuronal responses to changes in PCO2 and mCSF-pH. Acetylcholine (ACh) increased the activity of cVMS CO2-sensitive neurons by 237.5% +/- 34.9%, and naloxone applied topically to the cVMS augmented the ACh responsiveness to 338.6% +/- 52.7%. Physostigmine (PHY) increased neuronal activity by 254.3% +/- 42.9%, and this increase was augmented to 435.4% +/- 61.2% by naloxone. Although responses of the CO2-sensitive neurons to PHY were biphasic, the depressant phase failed to appear whenever the cVMS was pretreated with naloxone. Naloxone also augmented the responsiveness of cVMS neurons to increased H+ ion superfusion. These findings suggest that the endogenous opiates may be involved in the central regulation of respiration by interaction with CO2-sensitive cholinergic structures at the cVMS.(ABSTRACT TRUNCATED AT 250 WORDS)

Amelioration of nephrotoxicity associated with synthetic oxygen transport media.

Use of synthetic oxygen transport media offers the potential advantages of reducing requirements for coadministration of blood products and oxygen at the scene of mass casualty situations. Previous studies have shown perfusions of isolated kidneys with stroma-free hemoglobin (SFH) to be physiological while those with Fluosol-DA (20% FDA) have been associated with low glomerular filtration rate, urinary flow rate, and fractional reabsorption of sodium and potassium (FrNa+ and FrK+). In the present studies, perfusions with SFH/FDA mixtures showed normal glomerular filtration rate, a 50% lower urinary flow rate, and FrNa+ values 3% to 5% higher than SFH controls. Compared with 20% FDA perfusions, nephrotoxic effects of SFH/FDA combinations were moderate. Compared with SFH/FDA mixtures, perfusion with 20% FDA showed lower urinary flow and glomerular filtration rates. Ultrastructural assessment of glomerular filter revealed that FDA emulsion particles were adherent to epithelial podocytes. We conclude that resuscitation with a mixture of SFH and FDA may ameliorate the previously reported nephrotoxicity associated with the use of FDA alone.

Naloxone application to the ventrolateral medulla enhances the respiratory response to inspired carbon dioxide.

Previous studies have shown that systemic administration of the opiate antagonist naloxone potentiates the ventilatory response to inspired carbon dioxide. The present study was designed to localize the site of action of naloxone for increasing the respiratory chemosensitivity to inhaled carbon dioxide (CO2) in cats. Naloxone applied topically to the caudal chemosensitive area on the ventral medullary surface (VMS) during hypercapnic breathing produced a 75% greater increase in minute ventilation than hypercapnic breathing alone. Furthermore, hypercapnic breathing produced a 200% increase in neuronal activity of VMS chemosensitive cells; this was further increased 120% by naloxone. It is concluded that naloxone increases the sensitivity of neurons in the caudal respiratory chemosensitive area of cats to hypercapnia, and that endogenous opiates may act as modulators at VMS chemosensitive sites during hypercapnic breathing.