Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.

Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic asthma, we analyzed a cohort of 5-year-old children (n = 45) according to the virus etiology of the first severe wheezing episode at the mean age of 13 months and to 5-year asthma outcome. The development of atopic asthma in children with early rhinovirus-induced wheezing was associated with DNA methylation changes at several genomic sites in chromosomal regions previously linked to asthma. The strongest changes in atopic asthma were detected in the promoter region of SMAD3 gene at chr 15q22.33 and introns of DDO/METTL24 genes at 6q21. These changes were validated to be present also at the average age of 8 years.

Plasma cell-free DNA methylation marks for episodic memory impairment: a pilot twin study.

Decline in episodic memory performance usually causes the first clinical symptoms of Alzheimer's disease. At present, Alzheimer's disease can only be diagnosed at a very late stage when neurodegeneration and cognitive impairment is already irreversible. New early disease markers are needed for earlier and more efficient Alzheimer's disease intervention. To identify early disease markers, we implemented a genome-wide bisulphite sequencing method for the analysis of plasma cell-free DNA methylation profiles and compared differences associated with episodic memory performance in Finnish twin pairs. A noticeable amount of cell-free DNA was present in plasma, however, the amounts as well as the genomic coverage of these fragments varied substantially between individuals. We found no significant markers associated with episodic memory performance in the twins' plasma cell-free DNA methylation profiles. Furthermore, our results indicate that due to the low genomic coverage of cell-free DNA fragments and the variety in these fragments between individuals, the implemented genome-wide bisulphite sequencing method is not optimal for comparing cell-free DNA methylation differences between large groups of individuals.

Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

CSF obtained for clinical purposes from newborn, children and adults has been analysed by high pressure liquid chromatography for hypoxanthine, xanthine, inosine, uridine and urate. Large rises in hypoxanthine and to a lesser extent xanthine occur for about 24 h after hypoxia. High concentrations were associated with later evidence of brain damage or subsequent death. Changes in CSF could be independent of those in plasma. Small or negligible rises were associated with localised and generalised infections including bacterial meningitis, fits, or both. Marked and rapid rises were found after death. These estimations may "predict" the extent of brain damage or brain death.

Effect of three different warm-up regimens on heat balance and oxygen consumption of thoroughbred horses.

Horses were exercised at 105% of their maximal O2 uptake until fatigued after three different warm-up regimens (no warm-up, a light warm-up, and a warm-up until the central venous temperature was > 39.5 degrees C) to assess the effect of the warm-up on the various avenues of heat loss. Approximately 12.79, 15.10, and 18.40 MJ of heat were generated in response to the warm-up and exercise after the three different warm-up regimens, respectively. Of the heat generated, 17.5, 17.2, and 17.4% remained as stored heat after 20 min of active recovery. Heat loss from the respiratory system was 63.6, 33.7, and 40.3% of the heat produced during and after the three warm-up intensities, respectively. The balance of the heat loss was assumed to be via the evaporation of sweat. On this basis, the heat loss by sweating was 14.9, 49.1, and 42.3% of the heat produced during and after the three warm-up intensities, which represented evaporation of 0.8, 3.1, and 3.0 liters of sweat, respectively. O2 consumption during exercise and heart rates 20 min postexercise, after two of the warm-up regimens, was significantly lower than that after no prior warm-up.

Nissen fundoplication prevents shortening of the sphincter during gastric distention.

OBJECTIVE: To determine the dynamic effects of a Nissen fundoplication on a volume-stressed lower esophageal sphincter (LES). DESIGN: Before and after experimental study in 10 baboons. SETTING: University animal research unit. INTERVENTIONS: Continuous manometric evaluation of the esophagus, cardia, and stomach during distention of the stomach with water. Slow motorized pull-through of the LES after each successive intragastric increment of 50 mL of water. Tests were performed again after a Nissen fundoplication. MAIN OUTCOME MEASURES: Lower esophageal sphincter length and frequency of common cavity episodes after each volume increment. The pressure and intragastric volume at the yield point are defined as the point of permanent loss of the gastroesophageal pressure gradient. RESULTS: Gastric distention of the stomach with water resulted in a progressive decrease in LES length and competency. The median +/- interquartile range LES length decreased by 1.5 +/- 0.3 mm for every 1-mm Hg increase in gastric pressure before fundoplication and by 0.2 +/- 0.1 mm after fundoplication (P < .02). With gastric distention there was an indirect correlation between the degree of LES length and the frequency of reflux episodes (r = -0.70). This correlation was abolished by a Nissen fundoplication (r = -0.31). The median +/- interquartile range frequency of common cavity episodes (2.19 +/- 2.05 episodes per minute) before fundoplication decreased significantly (P < .001) to 0 +/- 0.59 episodes per minute after fundoplication. The median +/- interquartile range yield pressure (13 +/- 9 mm Hg) and yield volume (825 +/- 855 mL) were significantly (P < .01) improved after Nissen fundoplication to 39 +/- 36 mm Hg and 1250 +/- 750 mL, respectively. CONCLUSION: By preventing sphincter shortening, a Nissen fundoplication improves competency of the LES to progressive degrees of gastric distention.

Apoptosis is inhibited early in the dysplasia-carcinoma sequence of Barrett esophagus.

OBJECTIVE: To evaluate the alteration of apoptosis in the esophageal epithelium during the esophagitis-Barrett esophagus-adenocarcinoma sequence. DESIGN: Archival tissue samples of 85 lesions in 58 cases were used. The lesions represented 7 groups: normal esophagus (n = 10), reflux esophagitis (n = 12), Barrett metaplasia (n = 21), Barrett low-grade dysplasia (n = 17), Barrett high-grade dysplasia (n = 5), well- or moderately differentiated adenocarcinoma (n = 10), and poorly differentiated adenocarcinoma (n = 10). Apoptotic cells with fragmented DNA were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) method. Monoclonal antibodies against bcl-2 protein were applied using the avidin-biotin complex immunoperoxidase method. RESULTS: The esophagitis group showed many apoptotic cells on the epithelial surface; in the other groups, few apoptotic cells were seen. Weak bcl-2 expression was seen in the basal cells in normal subjects and those with esophagitis. There was overexpression of bcl-2 in 72% of Barrett metaplasia, 100% of Barrett low-grade dysplasia, 25% of Barrett high-grade dysplasia, 40% of well- or moderately differentiated adenocarcinoma, and 20% of poorly differentiated adenocarcinoma. CONCLUSIONS: Increased apoptosis in reflux esophagitis may be a protective mechanism counteracting increased proliferation. Inhibition of apoptosis by overexpression of bcl-2 protein occurs early in the dysplasia-carcinoma sequence of Barrett esophagus. The resulting prolongation of cell survival may promote neoplastic progression. Despite the absence of apoptosis, bcl-2 was not widely overexpressed in Barrett high-grade dysplasia and adenocarcinoma, suggesting that cells acquire other ways of avoiding apoptosis as malignancy appears.

Laparoscopic Toupet fundoplication for gastroesophageal reflux disease with poor esophageal body motility.

Impaired esophageal body motility is a complication of chronic gastroesophageal reflux disease (GERD). In patients with this disease, a 360-degree fundoplication may result in severe postoperative dysphagia. Forty-six patients with GERD who had a weak lower esophageal sphincter pressure and a positive acid reflux score associated with impaired esophageal body peristalsis in the distal esophagus (amplitude <30 mm Hg and >10% simultaneous or interrupted waves) were selected to undergo laparoscopic Toupet fundoplication. They were compared with 16 similar patients with poor esophageal body function who underwent Nissen fundoplication. The patients who underwent Toupet fundoplication had less dysphagia than those who had the Nissen procedure (9% vs.44%; P=0.0041). Twenty-four-hour ambulatory pH monitoring and esophageal manometry were repeated in 31 Toupet patients 6 months after surgery. Percentage of time of esophageal exposure to pH <4.0, DeMeester reflux score, lower esophageal pressure, intra-abdominal length, vector volume, and distal esophageal amplitude all improved significantly after surgery. Ninety-one percent of patients were free of reflux symptoms. The laparoscopic Toupet fundoplication provides an effective antireflux barrier according to manometric, pH, and symptom criteria. It avoids potential postoperative dysphagia in patients with weak esophageal peristalsis and results in improved esophageal body function 6 months after surgery.

The hypertensive lower esophageal sphincter.

BACKGROUND: This study defines the entity of the hypertensive lower esophageal sphincter (HLES) and its treatment, including surgical implications. METHODS: Esophageal manometry was performed on 1,300 patients. Of these, 53 (4%) had HLES with resting pressure > 26.5 mm Hg, defined as the upper limit of normal resting LES pressure. Thirty-two of these patients had 24-hour esophageal pH studies. The response to treatment was assessed. RESULTS: Fourteen patients (26%) with HLES had achalasia. Of the remaining 39 (74%), 25 had an isolated HLES with normal esophageal body motility, 5 had a nonspecific esophageal motility disorders (NEMD), 4 were post-Nissen fundoplication, 3 had a nutcracker esophagus, and 2 had diffuse esophageal spasm (DES). Nineteen percent of HLES patients had gastroesophageal reflux on pH studies. Eighty-two percent of HLES patients responded well to symptom-directed medical therapy. Two patients with esophageal body dysmotility responded well to an esophageal myotomy with a partial fundoplication. CONCLUSIONS: Patients with the HLES form a heterogeneous group. Gastroesophageal reflux in HLES patients is not uncommon. Patients with HLES respond well to medical therapy. Carefully selected patients require surgery.

Esophageal manometry and 24-hour pH testing in the management of gastroesophageal reflux patients.

BACKGROUND: With rising interest in gastroesophageal reflux disease, an evaluation of the importance of manometry (M) and 24-hour pH testing (pH) for decisions regarding these patients is appropriate. METHODS: Two gastroenterologists and two surgeons were presented with history and physical examination, endoscopy, histology, and esophagram data ("DATA") from 100 patients and asked to make a treatment decision. After some time, either pH or M was added to DATA, and a further decision requested. Finally, DATA plus pH plus M was presented, and a decision was requested. Decisions were evaluated for changes in medical therapy, changes between medical and surgical therapy, and changes in type of surgery offered. RESULTS: Overall, 43% (173 of 400) of decisions were altered by the addition of both M and pH to DATA, with 28.5% (114 of 400) of decisions changed from medical therapy to surgery or vice versa by the addition of both tests to DATA. The addition of M alone changed decisions more often than pH alone especially with regard to the type of surgery offered (P <0.05). CONCLUSIONS: Together, M and pH alter clinical decisions and often alter the decision regarding surgery. Both tests appear important, but M more frequently alters overall management decisions and the type of surgery offered. Despite the need for cost containment, these clinical tools are essential to important decisions regarding the care of patients with gastroesophageal reflux disease.

The effect of the anastomotic size on gastric emptying after hemigastrectomy with Billroth II reconstruction.

OBJECTIVE: To determine if the size of the gastrojejunal anastomosis after Billroth II reconstruction was the rate-limiting factor in gastric emptying in the postoperative period. METHODS: Twelve mongrel dogs were randomized to have either 1.5 cm or 5 cm gastrojejunal anastomoses prior to Billroth II hemigastrectomy. Each dog had three solid and three liquid radiolabelled emptying studies pre- and postoperatively. Data were collected using a gamma camera. For liquid studies, images were obtained at 0 min, 2 min, 4 min, 6 min, 8 min, 10 min, 20 min, 30 min, 40 min, 50 min and 60 min. For solid studies, images were obtained at 0 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min and 120 min. Means were compared by analysis of variance using the repeated measures option. RESULTS: Postoperative liquid emptying was significantly faster in the first 10 min with both 1.5 cm and 5 cm anastomoses compared with preoperative scans in the same animals (45% versus 20% and 48% versus 29%, respectively). On the other hand, solid gastric emptying was much slower postoperatively with the 1.5 cm anastomosis compared with preoperative scans (29% versus 65%) as well as compared with postoperative 5 cm anastomosis (29% versus 62%) at the end of 120 min. CONCLUSIONS: Our model suggests that the gastric emptying of solids is affected by the size of the gastrojejunal anastomosis and not by the diameter of the efferent limb of the small intestine following Billroth II reconstruction.

Water and electrolyte intake and output in conditioned Thoroughbred horses transported by road.

The objectives of this trial were to measure the water and electrolyte intake and loss, of horses during road transportation in relatively hot environmental conditions. Six mature, Thoroughbred horses in full training were used in a balanced crossover design. The horses were conditioned on a treadmill for 6 weeks before the start of the trial in order to simulate the type of horse that is transported most often over long distances in South Africa. The horses were assigned randomly to one of 2 treatment groups. On a particular day 3 horses were transported, while the other horses served as controls. One month was allowed before the crossover. Horses in the 'transport group' were transported by tarred road in a circular route over 600 km. This allowed the standardisation of measurements and use of the same instruments in both groups. Data were collected in each treatment group during transportation that lasted for 8 h (transport phase) and for 6 h after travelling (recovery phase). The following data were collected or calculated: Water and electrolyte (sodium, potassium and chloride) intake and output, changes in bodyweight and feed consumption. Although water was always available, the transport group failed to drink during transit. Based on bodyweight, the transported horses were 3% dehydrated at the end of transit. This bodyweight loss was corrected within one hour after their return due to a significantly higher water intake compared to control horses. The feed intake in the transported horses was unaffected during travelling, but was decreased for 6 h following transportation. Urinary water loss was similar in the 2 treatment groups during and following transportation. The faecal water loss decreased in the transported horses and remained lower than the control group for 6 h following transit. Total sodium and chloride intake were unaffected, while the potassium intake was decreased during transportation. Sodium and potassium loss via the faeces and urine during the transport period were similar in the 2 treatment groups, whereas potassium output in the transport group was significantly decreased during the recovery period of the study. It was concluded that transportation by road affected the water and electrolyte balance of conditioned horses for a period up to 6 h after travelling.

Surgical treatment of spastic conditions of the esophagus.

Primary esophageal motility disorders include achalasia, diffuse and segmental esophageal spasm, nutcracker esophagus and hypertensive lower esophageal sphincter. Failed medical therapy frequently precedes the presentation of these patients for surgical intervention. Both laparoscopic and thoracoscopic techniques have been developed to successfully treat these spastic disorders of the esophagus. Laparoscopic and thoracoscopic operative techniques are described.

Extrapulmonary tuberculosis in patients with end stage renal disease--two case reports and a brief review.

Chronic renal failure is a risk factor for tuberculosis. In the past five years we have identified two cases of tuberculosis in our dialysis population. The first patient, showed chronic failure to thrive on hemodialysis. An enlarged cervical lymph node was biopsied and, although no acid fast bacilli (AFB) were seen, a culture grew Mycobacterium tuberculosum (TB). Her chest X-ray did not show evidence of past tuberculosis. The second patient was a long time smoker who presented with an enlarged cervical node, which was biopsied. AFB were not seen on her biopsy, but her culture grew TB. Extrapulmonary TB is common in patients with ESRD, and lymph node involvement is the most common extrapulmonary presentation. Screening with the purified protein derivative (PPD) is not helpful in ESRD patients, since defects in cell mediated immunity are common. A high index of suspicion for TB is warranted in patients with ESRD.

An unusual cause of back pain in a patient with an abdominal aortic aneurysm. A case report.

A case of a 50-year-old man with chronic back pain, an abdominal aortic aneurysm and bony erosion of the lumbar spine due to a chondrosarcoma is reported. This report shows that the lumbar erosion seen in association with an aneurysm is unlikely to be a result of pressure erosion of the spine by the aneurysm, and that an extensive metastatic and septic work-up is required in such patients.

Measurement of maximal oxygen consumption of thoroughbred horses at an altitude of 1250m using open-circuit flow-through calorimetry.

This study determined the maximal O2 uptake (VO2max) of Thoroughbred horses acclimatised to mild hypobaric conditions using a standard exercise test on a treadmill inclined at a 7% slope. The O2 uptake (VO2) versus speed relationship was linear below the exercise intensity required to attain VO2max. The VO2max of individual horses ranged from 143.5 to 172.6 ml/kg/min. The proportion of total variance for the VO2 versus speed relationship was greater than 0.992, and the coefficients of variation in repeated tests in individual horses ranged between 0.07 and 1.54%. The VO2 versus speed relationship attained a plateau at speeds above the VO2max, which ranged from 9.3 to 12.0 m/s. When work intensity was increased above that of the VO2max, there was no further increase in VO2, thus showing that a maximum had been attained.

Survey of selected design and ventilation characteristics of racehorse stables in the Pretoria, Witwatersrand, Vereeniging area of South Africa.

Stables housing more than 20 horses in training were surveyed in the Pretoria, Witwatersrand, Vereeniging area of South Africa. Most racehorses were kept in loose boxes, bedded on straw or sawdust and remained indoors while the stables were cleaned. The average floor area was 13 m2 and airspace was 55 m3 per animal. The average predicted minimum air change rate by natural convection in calm winds was 7.0 air changes per hour, which was reduced to 2.2 when the doors and shutters were closed. The survey showed that many of the stables had been built without due consideration to factors that might have adverse effects on the occupants.

Thermoregulation. Base mechanisms and hyperthermia.

Metabolic HP is extremely high during exercise in horses. Thermoregulation in horses is primarily dependent on evaporative heat loss from sweating in particular. Under thermoneutral conditions, these mechanisms are sufficient to allow horses to perform high-intensity exercise for long periods. Under thermally stressful conditions, particularly in high ambient humidity, the efficiency of evaporative heat loss mechanisms is compromised and may result in horses developing hyperthermia. Early recognition and vigorous treatment are essential to limit the consequences of heat stress in horses. Meticulous planning and management of equestrian events that are held under thermally stressful conditions are essential to ensure the welfare of competing horses and their riders. The conditioning program of horses expected to compete under thermally stressful conditions must also make adequate provision for acclimatization to the hot, humid conditions.

Cholelithiasis in a preterm infant.

A case of cholelithiasis in a preterm infant is described. The baby survived for 105 days, during which time she received multiple blood transfusions. Three pigment stones were found in the gallbladder at necropsy. It is suggested that they were a consequence of an excessive bilirubin load, the result of maintaining the hemoglobin above physiological levels.

Rhabdomyolysis and acute renal failure after changing statin-fibrate combinations.

Statin-fibrate combinations are commonly used to treat hyperlipidemia. These drugs have been previously reported to cause rhabdomyolysis with acute renal failure. Whether different statin-fibrate combinations have different risks for rhabdomyolysis is not known. We report a patient who developed rhabdomyolysis with acute renal failure promptly after switching from the combination of pravastatin and fenofibrate to simvastatin and gemfibrozil.

Prophylaxis against gonococcal ophthalmia neonatorum. A prospective study.

The incidence of gonococcal ophthalmia neonatorum (GON) in the area served by the Peninsula Maternity and Neonatal Services in Cape Town is 273/100,000 live births. Two prophylactic agents, 1% silver nitrate ophthalmic solution and 0.5% erythromycin ophthalmic ointment, were introduced in routine eye care of the newborn in the main academic obstetric units. These agents resulted in a significant decrease in the incidence of GON to 34/100,000 live births. The alternative forms of prophylaxis against GON are discussed and the need for reinstitution of prophylaxis is emphasised.