Pathogenesis of Alzheimer's disease: Multiple interacting causes against which amyloid precursor protein protects.

Alzheimer's disease is the commonest form of senile dementia. It is characterised by neuronal cell death and amyloid deposition. Amyloid precursor protein (APP), which is highly conserved in evolution, is expressed in neurones in response to a wide range of damaging agents. The hypothesis proposed is that APP has a protective function to counter damage but if it fails and the neurone dies then breakdown products of APP miss-fold and lead to amyloid deposition. This fits with the evidence that amyloid deposition is a consequence rather than a cause of cell death. Germ line mutations in APP impair the protective role and lead to increased neuronal loss in response to damage. This leads to early onset and severe Alzheimer's disease. Inflammation, infection, hypoxia, trauma and pollution are damaging agents which interact to cause the disease. The bacteria which cause chronic periodontitis appear to have a significant role. Prevention needs to focus on avoiding trauma, reducing pollution and improving dental hygiene. Furthermore we should attempt to optimise the oral microbial flora by suppressing the growth of pathogenic bacteria that cause gum disease and the bacterial pathogens in the oropharynx that cause life threatening infections following viral upper respiratory infections. This leads to a key research question: does the regular consumption of natural live yoghurt reduce the carriage of periodontal and oropharyngeal bacterial pathogens? Theoretical considerations indicate it should and if so regular natural live yoghurt consumption could be an important preventive agent.

Sex-related differences in muscle size explained by amplitudes of higher-threshold motor unit action potentials and muscle fibre typing.

AIM: To investigate the relationships between motor unit action potential amplitudes (MUAPAMP ), muscle cross-sectional area (mCSA) and composition (mEI), per cent myosin heavy chain (%MHC) areas and sex in the vastus lateralis (VL). METHODS: Ten males and 10 females performed a submaximal isometric trapezoid muscle action that included a linearly increasing, steady torque at 40% maximal voluntary contraction, and linearly decreasing segments. Surface electromyographic decomposition techniques were utilized to determine MUAPAMPS in relation to recruitment thresholds (RT). Ultrasound images were taken to quantify muscle mCSA and mEI. Muscle biopsies were collected to calculate %MHC areas. Y-intercepts and slopes were calculated for the MUAPAMP vs RT relationships for each subject. Independent-samples t tests and ANOVA models examined sex-related differences in mCSA, mEI, slopes and y-intercepts for the MUAPAMP vs RT relationships and %MHC areas. Correlations were performed among type IIA and total type II %MHC area, mCSA and the slopes and y-intercepts for the MUAPAMP vs RT relationships. RESULTS: Males exhibited greater slopes for the MUAPAMP vs RT relationships (P = .003), mCSA (P < .001) and type IIA %MHC (P = .011), whereas females had greater type I %MHC area (P = .010) and mEI (P = .024). The mCSA, type IIA and total II %MHC area variables were correlated (P < .001-.015, r = .596-.836) with the slopes from the MUAPAMP vs RT relationships. CONCLUSION: Sex-related differences in mCSA and MUAPAMPS of the higher-threshold MUs were likely the result of larger muscle fibres expressing type II characteristics for males.

Moderate sedation in cardiac electrophysiology laboratory: a retrospective safety analysis.

OBJECTIVE: Cardiac electrophysiology (EP) procedures can be performed under moderate sedation without the direct involvement of an anaesthetist. However, concerns have been raised over the safety of this approach. This study examines the use of a standardised nurse-led physician-directed sedation protocol for EP procedures to determine the safety of moderate sedation administered by non-anaesthesia personnel who have been trained in sedation techniques. METHODS AND RESULTS: Consecutive EP procedures done under moderate sedation over 12 years at our institution were evaluated. Serious adverse events were defined as (i) procedural death related to sedation; (ii) intubation and ventilation; and (iii) hypotension requiring inotropic support. Reversal of sedation constituted a minor adverse event. Up to 7117 procedures were included. These comprised ablations (55%), devices (43%) and other procedures (2%). A majority of patients were men with a mean age of 61±10 years. 99.98% of procedures were completed successfully without sedation-related serious adverse events. Two patients (0.02%) required anaesthetic support for intubation. Sedation was reversed in 1.2% of procedures with less than 1% requiring reversal because of persistent drop in oxygen saturation, hypoventilation or markedly reduced level of consciousness. There was no significant difference in the patient characteristics, mean doses of sedative agents and procedure types in the group requiring reversal of sedation when compared with the whole cohort. CONCLUSIONS: Our study demonstrates that nurse-led, physician-directed moderate sedation is safe. Anaesthesia services are not required routinely for invasive cardiac EP procedures and should be available on a need basis.

Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation.

Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model.

Staphylococcus aureus and other bacteremias in hemodialysis patients: antibiotic therapy and surgical removal of access site.

BACKGROUND: Bacteremia is commonplace in patients undergoing hemodialysis since the vascular access site is a ready source of infection. Mortality is notably high. However, uncertainties exist with respect to therapy including indications for surgical removal of vascular access site and duration of therapy. We therefore conducted a large-scale collaborative study of bacteremia in hemodialysis patients in six US academic medical centers to define the epidemiology of such infections and to address issues of management. PATIENTS AND METHODS: We conducted a prospective observational study over 2 years. Severity of illness at onset of bacteremia was defined by objective criteria. Patients were followed for 90 days to assess late complications including endocarditis and mortality. Univariate and multivariate analyses were used to assess risk factors for mortality. RESULTS: Patients experiencing 127 consecutive episodes of bacteremia were enrolled. The most common cause of bacteremia was Staphylococcus aureus (31%), followed by aerobic gram-negative bacilli (28%) and coagulase-negative staphylococci (13%). Polymicrobial bacteremia occurred in 6% of patients. The most frequent focus of infection was the access site for hemodialysis, although urinary tract, gastrointestinal tract and lung were also implicated. Aerobic gram-negative bacilli and enterococci usually originated from the urinary tract. S. aureus was significantly more likely to cause infection of the access site than other bacteria (p = 0.0001). S. aureus endocarditis was diagnosed in two patients who were receiving antibiotic therapy for S. aureus bacteremia. Removal of the infected access site (shunt, fistula, catheter) was performed for 86% of the patients (95% of the intravenous catheters and 80% of the arteriovenous fistulas/shunts). Overall mortality was 33% at 90 days and was significantly associated with severity of illness at onset of antibiotic therapy and age >60 years. Mortality was not significantly different in patients undergoing surgical removal of infected access site versus those treated with antibiotics alone. CONCLUSION: When S. aureus was isolated from the blood, the access site was the most frequent source. Surgical removal of the access site did not have a notable impact on mortality. Until a randomized trial proves otherwise, it appears that surgical removal of the access site can be individualized. Selected patients who are less severely ill (based on objective criteria) can maintain their hemodialysis access site and be treated with 2 weeks of antibiotic therapy.

Pharmacy staff interventions in a medical center hematology-oncology service.

OBJECTIVES: Many pharmaceutical care efforts remain undocumented, resulting in underestimation of the importance of the pharmacy staff interventions and missed opportunities to find new directions for quality improvement. The purpose of this project was to document and analyze the pharmaceutical care interventions of the staff of a hematology-oncology pharmacy. DESIGN: Interventions were self-reported by pharmacy staff members. The data collection period was October 1, 1995, to May 31, 1996. Intervention analysis consisted to types of interventions performed, categories of personnel performing interventions, intervention acceptance rate by staff physicians, and medication cost avoidance. PARTICIPANTS: This project was performed by the Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed Army Medical Center, Washington, D.C. SETTING: Walter Reed Army Medical Center, Washington, DC, a 1,000-bed teaching and research institution of the U.S. Army Medical Department. RESULTS: Pharmacy staff reported 503 interventions. The leading categories of interventions were clinical consultations (167), correction of prescribing errors (85), and patient treatment procedures (65). The interventions were primarily initiated by oncology pharmacists and residents (68.8%) and oncology pharmacy technicians (30.6%). The intervention acceptance rate was 97%. Medication cost avoidance was $23,091. CONCLUSION: A significant amount of pharmaceutical care was documented by the hematology-oncology pharmacy staff, with both oncology pharmacists and oncology pharmacy technicians making key contributions. The pharmacy staff's interventions had a high rate of acceptance by the medical and nursing staffs, and resulted in significant medication cost avoidance.

Implant program effects on performance and carcass quality of steer calves finished for 212 days.

We compared the effects of seven implant treatments combining use of Ralgro (RAL), Synovex-S (SYN), and Revalor-S (REV) on performance and beef quality traits of crossbred steer calves (n = 560) finished for 212 d. A randomized complete block design was used to compare treatments consisting of 1) non-implanted control (CON); 2) RAL on d 0, SYN on d 60, and REV on d 130 (RALSYNREV); 3) RAL on d 0, REV on d 60, and REV on d 130 (RALREVREV); 4) SYN on d 30 and REV on d 130 (SYNREV); 5) REV on d 30 and REV on d 130 (REVREV); 6) REV on d 0, REV on d 75, and REV on d 150, 12.5% crude protein diet (REV3X-12.5); and 7) REV on d 0, REV on d 75, and REV on d 150, 14.5% crude protein diet (REV3X-14.5). All implant groups had higher ADG and gained more efficiently (ADG: feed intake) than the CON group. No distinct performance advantages were noted for particular implant schemes. Implant treatments did not (P > .05) affect dressing percentage, carcass weight, or KPH fat percentage. Fat thickness did not differ (P > .05) for implanted vs CON steers; however, REVREV, SYNREV, and RALREVREV steers produced fatter carcasses than did REV3X-12.5 and RALSYNREV steers. The REV3X-12.5 and REV3X-14.5 treatments increased longissimus muscle area compared with CON; longissimus muscle areas for all other treatments did not differ (P > .05) from CON. No reduction in percentage of Choice and Prime carcasses occurred with use of SYNREV or REVREV; however, all treatments receiving three successive implants had lower (P < .05) percentages of Choice and Prime carcasses than the CON group. Increasing dietary crude protein seemed to lessen the detrimental effect of three successive REV implants on percentages of Choice and Prime carcasses. Loin steaks from REVREV, REV3X-12.5, and REV3X-14.5 steers had higher (P < .05) shear force values than steaks from CON steers.

Effects of dietary virginiamycin on performance and liver abscess incidence in feedlot cattle.

The effects of dietary virginiamycin level on performance and liver abscesses in feedlot cattle were evaluated in seven dose-response studies. Steers and heifers were fed finishing diets ranging in energy content from 1.34 to 1.51 Mcal of NEg/kg of DM. In all studies, virginiamycin added to the diet improved average daily gain and(or) feed conversion, with no substantial effect on dry matter intake. Pooled analyses of four studies providing virginiamycin at 11.0, 19.3, and 27.6 mg/kg of DM in the complete diet indicated that growth and feed conversion were linearly improved (P < .05); feeding 19.3 mg/kg improved these measurements by 3.0 and 3.8%, respectively. Overall incidence (score 0 vs score 1, 2, and 3) and severity (score 0, 1, and 2 vs score 3) of liver abscesses were reduced (P < .01) by feeding virginiamycin at either 19.3 or 27.6 mg/kg. Linear plateau modeling indicated that the effective dose range for virginiamycin in feedlot diets (DM basis) was 19.3 to 27.3 mg/kg for increasing average daily gain, 13.2 to 19.3 mg/kg for improving feed conversion, and 16.5 to 19.3 mg/kg for reducing liver abscess incidence.

Efficacy of laidlomycin propionate for increasing rate and efficiency of gain by feedlot cattle.

One thousand twenty steers and heifers were used in six feeding trials to examine the influence of laidlomycin propionate on feedlot performance and to determine the most efficacious dietary concentrations of that ionophore. Cattle were fed diets ranging in energy content from 1.08 to 1.49 Mcal NEg/kg of DM. Laidlomycin propionate improved rate of gain and feed conversion in both steers and heifers. Improvements in performance were not evident when laidlomycin propionate was fed at only 3 mg/kg. However, both average daily gain and feed conversion were improved by laidlomycin propionate within the range of 6 to 12 mg/kg of DM (P less than .001). Feed consumption was not substantially affected by inclusion of laidlomycin propionate in the diet. Improvements in ADG and feed conversion were greater on lower-energy diets than on higher-energy diets, but both these performance characteristics were improved regardless of the type of diet fed. Average daily gain was maximized with laidlomycin propionate at 6 mg/kg, whereas improvements in feed conversion were sustained through 12 mg/kg. Carcasses of cattle fed diets containing 6 to 12 mg/kg of laidlomycin propionate weighed 7.3 kg more (P less than .001) than carcasses of cattle fed the control diets. Yield grade and quality grade were not affected by laidlomycin propionate (P greater than .05).

Effect of monensin on the performance of cattle on pasture or fed harvested forages in confinement.

Three series of trials were conducted to evaluate the effect of monensin on the growth performance of cattle. Twenty-four trials were conducted to evaluate the addition of monensin at 200 mg/d to limited quantities of supplemental concentrate for growing cattle grazing pastures. The pastures ranged from dormant end-of-the-season grasses and crop residues to lush green pastures, and were located in several different states. Pasture plus supplement supported gains of control cattle (without monensin) of .24 to .96 kg, with an average of .56 kg/d. The addition of 200 mg monensin to the supplement increased daily gain in all 24 trials by an average of .09 kg daily (+16.3%). Eleven trials were conducted with monensin and energy supplements fed at .907 kg.- head-1 X d-1 to growing cattle grazing growing, nondormant pastures for an average period of 117 d. Each trial was designed to compare the performance of unsupplemented cattle, cattle fed a supplement and cattle fed a supplement with monensin. Cattle on pasture gained .50 kg daily. Supplement feeding increased average daily gain by .09 kg and the addition of monensin to the supplement further increased gain by .09 kg, for a total increase of .18 kg (34.2%). The efficiencies with which supplemental feed was converted to extra gain (kg supplement/kg gain) for the supplement-only and the monensin treatment groups were 10.1:1 and 5.0:1, respectively. In a series of 12 trials, monensin was added at a level of 33 mg/kg air-dry diet to limited quantities of supplemental feed for cattle fed harvested forages in confinement. All trials compared monensin feeding with a nonmedicated control treatment. Hay was fed in 8 of the 12 trials, fresh-cut green-chop in two trials and ensiled corn stover and ensiled milo stover in one trial each. Monensin reduced feed intake by -3.1%, improved average daily gain by .09 kg (+14.4%) and improved feed efficiency by 15.3%.

Administration of monensin in self-fed (salt limiting) dry supplements or on an alternate-day feeding schedule.

Two series of trials were conducted to evaluate alternative methods of administering monensin to pasture cattle. In a series of five trials, monensin was incorporated into supplements at 440 mg/kg to provide an average intake of 200 mg X head-1 X d-1 for growing cattle on pasture. Comparisons were made between daily and alternate-day feeding of the supplements. A control treatment consisting of unmedicated supplement fed daily also was included. Monensin at 200 mg/d and 400 mg on alternate days increased gain by .077 (P less than .01) and .082 (P less than .01) kg/d above control-cattle gains (.54 kg daily). Nine pasture trials were conducted to compare the effectiveness of monensin in increasing the daily gain of growing cattle when hand-fed daily in a supplement or self-fed in supplements that contained salt to regulate supplement intake. Desired supplement intakes were approximately .454 kg X head-1 X d-1 in six trials, .68 kg/d in one trial and 1.81 kg/d in two trials. Monensin produced gain increases of .09 kg daily (P less than .01) with both feeding systems. The daily gains of cattle that were hand-fed and self-fed were equal (P greater than .10). Self-fed treatments containing monensin required fewer changes in salt level than self-fed treatments not containing monensin, and the salt levels required to limit intake were generally 25 to 50% lower when monensin was in the supplement.

Effect of monensin and tylosin on average daily gain, feed efficiency and liver abscess incidence in feedlot cattle.

Fourteen trials were conducted to evaluate the effects of feeding monensin at 33 ppm alone, tylosin at 11 ppm alone and the two feed additives in combination on the average daily gain, average daily feed intake, feed:gain ratio and the incidence of liver abscesses in feedlot cattle. Monensin reduced feed intake and improved feed efficiency (P less than .05), and had no effect on average daily gain. Tylosin improved average daily gain (P less than .05) and had no effect on daily feed intake. The effect of tylosin on feed efficiency approached significance. The interaction of monensin and tylosin was nonsignificant for daily gain, daily feed intake and feed:gain ratio. Monensin had no effect on liver abscess incidence, while tylosin reduced abscess incidence from 27 to 9%.

Relationship of head posture and the rest position of the mandible.

Eight subjects were evaluated to assess the relationship between VDR and head posture. Photographic evaluation of head position and VDR was performed initially to quantify a baseline recording. All subjects were then given 4 weeks of physical therapy to improve head posture. Photographs were remade after 2 and 4 weeks of therapy. An increase in the VDR and in the angle of the head to the cervical vertebra was noted in all patients. Although further study is indicated to confirm the findings of this pilot study, it appears that the VDR is influenced by head position. This finding should be considered when prosthodontic problems are treated.

Therapist agreement for palpation and observation of iliac crest heights.

Ten subjects were assessed by 11 examiners (three physical therapy students, three physical therapists experienced in rehabilitation, and five physical therapists experienced in orthopedics) to determine intrarater and interrater agreement for an assessment procedure involving palpation and observation of iliac crest heights. The results of two separate trials in a single session showed that both groups of experienced physical therapists had slightly higher intrarater and interrater agreement than student physical therapists. Findings suggest that a need exists to improve the reliability of this commonly used physical therapy assessment procedure.

Effect of forearm abduction on the ulnar collateral ligament.

Seven fresh cadaveric elbows from one woman and three men were studied to determine if the forearm abduction mobilization commonly used to restore the last 20 degrees of elbow extension produced an increase in the length of the anterior band of the ulnar collateral ligament. Initial ligament length and maximum length during mobilization were measured with a dial caliper and recorded on videocassette. Results indicated no significant difference between ligament lengths at rest and during the mobilization. The mechanism by which the forearm abduction mobilization restores elbow extension remains unknown.