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.

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.

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.

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.

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.

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.

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.

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.

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.

A new intraluminal antigastroesophageal reflux procedure in baboons.

BACKGROUND: A new endoscopic intraluminal procedure (valvuloplasty) was designed to provide a simple, easy approach to the cardia and to correct and augment any mechanical deficiencies present. The feasibility, durability, and efficacy of this procedure was tested in 13 baboons. METHODS: The valvuloplasty consisted of an intussusception of the gastroesophageal junction into the stomach to create a nipple-type valve. The configuration of the valve was maintained with eight staples and stability was aided by an intramural injection of sodium morrhuate. Gastrointestinal endoscopy and esophageal manometry were performed before and after the procedure. Competency was determined as the intragastric pressure (yield pressure) and volume (yield volume) needed to result in equalization of gastric and esophageal pressure while distending the stomach with water. Comparisons were made with a group of normal baboons (n = 10). RESULTS: All baboons had a normal eating pattern with none showing any evidence of vomiting or regurgitation. Endoscopic circumferential integrity of the valves was 86% at 6 months. The median lower esophageal sphincter length in the valvuloplasty group was significantly (p < 0.01) increased after the procedure from 21 mm to 30 mm. The median yield pressure (22.1 mm Hg) and yield volume (1,525 ml) of the valvuloplasty group was significantly (p < 0.01) greater than the controls (14 mm Hg and 859 ml). CONCLUSIONS: The valvuloplasty is simple, safe, and durable. It augments mechanical function of the cardia and improves competency.

Laparoscopic Nissen fundoplication: where do we stand?

Laparoscopic Nissen fundoplication was first performed in 1991. With the increasing number of these procedures being performed it is appropriate to review the published short-term results. A retrospective review of reports on this subject was performed. There were a total of 2453 patients available for review. Twenty-five of 2453 (1.0%) patients had an esophageal or gastric perforation and 28 of 2453 (1.1%) patients required transfusion for bleeding. Forty-nine of 2453 (2%) patients developed a pneumothorax. Two of 2453 (0.1%) patients required a splenectomy. Conversion to the open procedure was necessary in 5.8% (143 of 2453) of patients. The laparoscopic approach is associated with minimal postoperative morbidity. Four of 2453 (0.2%) needed further early surgery for persistent bleeding, 11 of 2453 (0.4%) for a missed perforation, 22 of 2453 (0.9%) for crural disruption, paraesophageal herniation, or gastric volvulus. Four of 2453 (0.2%) patients died of either a missed duodenal perforation, a missed esophageal perforation, ischemic bowel with mesenteric thrombosis, or myocardial infarction. Early postoperative dysphagia occurred in 500 of 2453 (20.3%) patients. Late postoperative dysphagia occurred in 114 of 2068 (5.5%), with the need for dilatation in 72 of 2068 (3.5%). Endoscopy was required for food impaction in 11 of 2068 (0.5%) and re-operation for dysphagia occurred in 18 of 2068 (0.9%). Fifty-seven of 1658 (3.4%) patients developed reflux symptoms and 11 of 1658 (0.7%) required revisional surgery. Satisfaction rates ranged from 87 to 100%. In the short term, laparoscopic fundoplication can be performed with less morbidity and mortality than the open procedure. It is superior to medical therapy. Long-term follow-up is awaited.

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.

An assessment of pain and return to normal activity. Laparoscopic herniorrhaphy vs open tension-free Lichtenstein repair.

BACKGROUND: Laparoscopic herniorrhaphy is controversial and deserves critical evaluation. METHODS: In a randomized prospective study transabdominal preperitoneal laparoscopic herniorrhaphy (n = 24) was compared in patients to the tension-free Lichtenstein repair (n = 29) utilizing validated and reliable pain and activity assessment tools. The Sickness Impact Profile (SIP) was used to compare preoperative normal activity to postoperative activity. A Pain-O-Meter (visual analogue scale plus affective and sensory pain descriptors) assessed intensity of pain. The total pain assessment score and SIP were compared across time (postoperative day 1-42). Analgesic medication was used as a covariate. RESULTS: The total pain score was less for laparoscopic herniorrhaphy but this did not reach statistical significance. Similarly, the SIP showed modest improvement for laparoscopic herniorrhaphy. No differences between groups were noted for morphine equivalents of administered analgesics or length of hospitalization. CONCLUSION: Further investigation of laparoscopic herniorrhaphy is warranted.

Integrative model for predicting thermal balance in exercising horses.

A theoretical integrative model was developed to determine the heat balance of horses working in a given environment. This model included the following parameters: metabolic heat gain, solar heat gain, evaporative heat loss due to sweating, respiratory tract heat loss, radiation from the body and heat gain or loss due to convection and conduction. The model developed in this study includes an unique approach for estimating heat loss via evaporation of sweat from the animal's skin surface. Previous studies modelling evaporative heat dissipation were based on the volume of sweat loss. While it is known that the ambient conditions affect evaporation rate, these effects have not been adequately described. The present model assumes the horse's skin surface is adequately represented by a body of water and it describes the interaction of that water body with the atmosphere. It is assumed that sweat has thermodynamic characteristics equivalent to distilled water. Sweat, however, has high electrolyte and protein concentrations and anecdotal evidence has shown that the thermodynamic characteristics may be significantly affected. Further research is, therefore, required to confirm these characteristics for equine sweat. The model describes all factors known to affect the thermal balance of the horse working in a given environment. The relative significance of the various variables on the whole integrative model has been illustrated. The effect of ambient temperature and humidity on the evaporative heat loss, the most significant and critical avenue of heat dissipation, is defined and quantified. The model illustrates clearly how increasing relative humidity limits evaporative heat loss, which can be further compromised when horses exercise on treadmills with no air movement.

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.

Laparoscopic fundoplication: the alternative to long-term medical therapy for severe gastroesophageal reflux disease.

UNLABELLED: Gastroesophageal reflux disease is common. Fundoplication is very effective for those patients who fail medical therapy, particularly those with an incompetent lower esophageal sphincter. Open surgery is reported to achieve cure rates in excess of 90 percent. Laparoscopic fundoplication has been performed since 1991. The early experience with this procedure is reviewed. RESULTS: 1992 cases were reported in the literature. The mortality rate was 0.1 percent. Operative complications occurred as follows: 0.9 percent esophagogastric perforation rate; 0.6 percent bleeding rate (requiring transfusion); and 0.6 percent pneumothorax rate. No splenectomies were reported. 4.8 percent of patients required conversion to the open procedure. As experience with the procedure is gained this conversion rate decreases. Recurrent reflux postoperatively is 3.4 percent, but follow-up is short (range: 0 to 36 months; mean: two years). Dysphagia requiring dilatation occurs in 3.5 percent of patients. Gas bloat occurs in 0 to 24 percent of patients. These results compare favorably with the published results of medical therapy and the open fundoplication. CONCLUSIONS: The early experience with laparoscopic fundoplication appears promising and provides an attractive alternative to long-term medical therapy and to open surgery in appropriate patients. Long-term follow-up is awaited.

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.