Multimodal Gamma Stimulation Improves Activity but not Memory in Aged Tgf344-AD Rats.

BACKGROUND: Multimodal sensory gamma stimulation is a treatment approach for Alzheimers disease that has been shown to improve pathology and memory in transgenic mouse models of Alzheimer's. Because rats are closer to humans in evolution, we tested the hypothesis that the transgenic rat line bearing human APP and PS1, line TgF344-AD, would be a good supplemental candidate to test the efficacy of this treatment. Current therapy approaches under investigation seek to utilize the immune response to minimize or degrade the accumulation of ß-amyloid plaque load in mouse models designed to overexpress Aß. However, many of these models lack some of the hallmarks of Alzheimer's disease, such as hyperphosphorylated tau and neuronal cell loss. The TgF344-AD transgenic rat model is a good candidate to bridge the gap between mouse models and clinical efficacy in humans. OBJECTIVE: The objective of this study was to use multimodal gamma stimulation at light and auditory modalities simultaneously to test whether this enhances memory performance as measured by the object location task and the spontaneous alternation task. METHODS: In our study, we designed and built a low-cost, easy-to-construct multimodal light and sound gamma stimulator. Our gamma stimulation device was built using an Arduino microcontroller, which drives lights and a speaker at the gamma frequency. We have included in this paper our device's parts, hardware design, and software architecture for easy reproducibility. We then performed an experiment to test the effect of multimodal gamma stimulation on the cognitive performance of fourteen-month-old TgF344-AD rats. Rats were randomly assigned to either an experimental group that received gamma stimulation or a control group that did not. Performance in a Novel Object Location (NOL) task and spontaneous alternation task was evaluated in both groups before and after the treatment. RESULTS: Multimodal gamma stimulation did not improve memory compared to unstimulated TgF344-AD rats. However, the gamma-stimulated rats did spend significantly more time exploring objects in the novel location task than the unstimulated rats. In the spontaneous alternation task, gamma-stimulated rats exhibited significantly greater exploratory activity than unstimulated controls. CONCLUSION: Multimodal gamma stimulation did not enhance memory performance in the object location task or the spontaneous alternation task. However, in both tasks, the treatment group had improved measures of exploratory activity relative to the untreated group. We conclude that several limitations could have contributed to this mixed effect, including aging complications, different animal models, or light cycle effects.

A Clot (Possibly); Due to Loss of TNF-α Supression.

INTRODUCTION: Inflammation and venous thrombosis enjoy a close Relationship. We present a patient who had multiple DVTs following the discontinuation of anti- TNF-α therapy. CASE: A 34 year old African American female with a history of multiple DVT's, miscarriages, and reported Crohn's disease presented with shortness of breath. In the Emergency Department, CTA showed bilateral pulmonary emboli. The patient had been off adalimumab for one year and reported abdominal pain with 6-7 non-bloody bowel movements daily. She had been prescribed lovenox for her unprovoked DVTs yet reported missing several doses prior to admission. Following admission, she developed severe abdominal pain prompting an emergent CT angiogram and she then developed a pulseless painful left lower extremity. CT revealed a partially occlusive thrombus in the infra-renal abdominal aorta, proximal left common iliac artery, and right renal artery with subsequent right renal infarction. Following emergent vascular surgery to restore blood flow to the left lower extremity, the patient received four days of plasma exchange and high dose steroids for potential catastrophic antiphospholipid syndrome. Serology for APLA was negative. The patient was discharged with lifelong anticoagulation. DISCUSSION: The endothelial surface is a complex organ that works in concert with the surrounding environment. Inflammation and thrombus formation is closely associated. TNF-α can increase the expression of adhesion molecules, specifically, tissue factor, on the surface endothelial cells and promote thrombosis. Suppression of TNF-α expression by low molecular weight heparin has been shown to inhibit the inflammatory cascade and reduce thrombus formation in animal models. Clinical data is less clear. Interruption of TNF blockers has been shown to increase the risk of DVT in patients with rheumatoid arthritis undergoing orthopedic surgery. For patients with Bechet's syndrome, anti-TNF agents appear help treat patients with pulmonary artery thrombosis. Further review of anti-TNF-α therapy in our general medicine patient population may disclose additional risks associated with discontinuation of these medications.

Neuronal correlates of signal detection in the posterior parietal cortex of rats performing a sustained attention task.

The posterior parietal cortex (PPC) plays an integral role in visuospatial attention. Evidence suggests that neuronal activity in the PPC predicts the allocation of attention to stimuli. The present experiment tested the hypothesis that in rats performing a sustained attention task, the detection of signals, as opposed to missed signals, is associated with increased PPC unit activity. Single unit activity was recorded from the PPC of rats and analyzed individually and as a population vector for each recording session. A population of single units (28/111) showed significant activation evoked by signals on trials resulting in correct performance (hits). A smaller population of neurons (three/111) was activated on trials in which signals were not detected by the animals (misses). Analysis of populations of simultaneously recorded neurons indicated increased activation predicting signal detection; no population of neurons was activated on trials in which the animal incorrectly pressed the hit lever following nonsignals. The increased, hit-predicting activity was not modulated by signal duration or the presence of a visual distractor, although the distractor reduced the number of trials in which hit-predicting activity and subsequent correct detection occurred. These findings indicate that attentional signal processing in the PPC integrates successful detection of signals.

Nasopharyngeal diseases in cats: a retrospective study of 53 cases (1991-1998).

The records of 53 cats with nasopharyngeal disease were examined. Of the cats with nasopharyngeal disease, 49% had lymphosarcoma and 28% had polyps. Clinical signs in these cats were compared to 24 cats with nasal disease alone. Cats with only nasal disease more commonly had historical nasal discharge and sneeze, whereas cats with nasopharyngeal disease more often had stertorous respiration, phonation change, and typically reported less nasal discharge or sneeze. It is important to include nasopharyngeal disease in the differential diagnosis for cats with nasal discharge, sneeze, stertor, or phonation change.

Electrocardiographic and radiographic changes in cats with hyperthyroidism: comparison of populations evaluated during 1992-1993 vs. 1979-1982.

Cardiovascular manifestations of feline hyperthyroidism were compared in two populations of cats diagnosed at The Animal Medical Center from 1992 to 1993 (n=202) and 1979 to 1982 (n = 131). The prevalence of sinus tachycardia and increased R-wave voltage in lead II were both lower in the 1993 population compared with the 1982 population (p less than 0.001). A low frequency of atrial and ventricular arrhythmias and intraventricular conduction abnormalities were recorded in both populations. No significant differences between populations were recorded in the number of cats with mild, moderate, and severe cardiomegaly seen on thoracic radiographs. The percentage of cats in which radiographs were deemed clinically necessary based upon history and clinical examination was 25% of the 1993 population, compared with 63% of the 1982 population. The number of cats with radiographic evidence of congestive heart failure was 8% in 1993 compared with 20% in 1982, although this difference was not statistically significant. In conclusion, the incidence and severity of certain thyrotoxic cardiovascular manifestations were reduced in cats diagnosed between 1992 and 1993 compared with those diagnosed between 1979 and 1982.

High environmental temperature and humidity decrease oocyte quality in Bos taurus but not in Bos indicus cows.

Two experiments were conducted to assess the effects of environmental temperature and humidity on the quality and developmental capabilities of bovine oocytes. In Experiment 1, Bos taurus (Holstein and crossbred Angus) cows were subjected to 5 weekly sessions of ultrasound-guided follicle aspiration from February 16 through March 23 (cool season) and 5 sessions from May 22 through June 20 (hot season). In Experiment 2, Bos taurus (Holstein) and Bos indicus (Brahman) cows were superstimulated (Super-Ov) during the months of August (hot season) or January (cool season), and each cow was subjected to a single oocyte aspiration session. In each experiment, oocytes were classified as normal or abnormal based on ooplasm morphology and cumulus cell layers. In Experiment 1, oocytes classified as normal were in vitro matured and fertilized (IVM/IVF), and the resulting embryos cultured for 8 d. All oocytes recovered from superstimulated cows in Experiment 2 were matured and fertilized in vitro and the subsequent embryos cultured for 8 d, regardless of their morphological appearance. In Experiment 1, Bos taurus cows produced a higher (P = 0.02) percentage of normal oocytes during the cool season (75.9 +/- 8.0) than during the hot season (41.0 +/- 9.5). The percentage of fertilized oocytes developing to the 2-cell (82.4), 8-cell (65.4) and morula (46.6) stages were also greater (P < or = 0.06) during the cool season than the hot season (45.0, 21.2, 6.0 for 2-cell, 8-cell and morula stages, respectively). In Experiment 2, Bos taurus cows (Holstein) had a lower (P = 0.01) percentage of normal oocytes in the hot season (24.5 vs 80.0) and a lower (P < or = 0.003) percentage of fertilized oocytes developing to the 8-cell, morula and blastocyst stages. No difference (P > or = 0.57) in the percentage of normal oocytes or in embryo development was detected between seasons in Bos indicus (Brahman) cows. In conclusion, high environmental temperature and humidity resulted in a marked decline in the quality of oocytes retrieved from Bos taurus cows and markedly decreased their in vitro developmental capabilities. In contrast, a high percentage of oocytes retrieved from Bos indicus cows exhibited normal morphology and yielded a high proportion of blastocysts, regardless of season.

Effects of dexamethasone administration to diestrus cows on systemic progesterone, estrogen and uterine cyclooxygenase production.

Parenteral administration of dexamethasone to diestrus cattle can extend the length of the natural estrous cycle. In mice, dexamethasone has been shown to inhibit production of the second isozyme of the cyclooxygenase (COX) enzyme (a rate limiting enzyme in prostaglandin formation). Therefore, the purpose of this study was to determine the effect of dexamethasone on estrous cycle length and COX-1 and -2 production by the uterine endometrium of cyclic cattle. Nine crossbred beef cows that exhibited two previous normal estrous cycles were randomly assigned to two treatments; a control group administered intramuscular injections of vehicle, and a dexamethasone group administered 8 mg of dexamethasone (Azium, Schering Corp., Kenilworth, NJ). Both groups received twice daily injections on day 13-22 of the treatment cycle. Uterine endometrial biopsies were collected on days 16, 19 and 22 of the treatment cycle. Blood samples were collected daily on day 13-22 of the treatment cycle for plasma progesterone and estradiol concentrations.

Effect of unilateral ovariectomy, gonadotropin stimulation and immunization against a synthetic peptide of the inhibin alpha-subunit on follicular development and oocyte recovery in cattle.

Nulliparous Holstein cows were randomly distributed among 4 treatment groups to test the effects of treatments, including unilateral ovariectomy, anti-inhibin immunization and gonadotropin stimulation on ovarian follicle population and oocyte recovery. The Control treatment consisted of intact cows (I-Control). Unilaterally ovariectomized cows were included in the 3 remaining treatments consisting of ovariectomy alone (U-Control), cows immunized against a synthetic peptide of the alpha(c)-subunit of bovine inhibin (alpha(c)I; U-IH), and cows stimulated with FSH (Super-Ov; 75 units/female/week) and also immunized with alpha(c)I as in the previous treatment (U-IH/FSH). Oocytes were collected by transvaginal ultrasound-guided aspiration on a weekly basis from cows in each treatment for 5 consecutive weeks. Intact Control cows had a greater (P<0.05) number of follicles > or = 3 mm per female (4.7) than the U-Control and U-IH cows (2.6 and 2.9, respectively), and had a similar number of follicles as the U-IH/FSH treatment group (3.5). The numbers of follicles aspirated (2.7 to 3.6) and oocytes recovered/cow (1.6 to 2.6) were similar for cows in the I-Control, U-IH and U-IH/FSH treatment groups. Cows in the U-Control treatment group had a lower (P<0.05) number of aspirated follicles (2.0) and recovered oocytes (1.1) than the I-Control cows. Cows in the U-IH/FSH and U-IH treatments had follicles with larger (P<0.01) diameters (8.7 and 8.2 mm, respectively) than cows in the I-Control (6.6 mm) and U-Control (5.7 mm) treatments. In conclusion, unilateral ovariectomy did not result in compensatory increase of follicle number or size in the intact ovary; cows in the U-IH/FSH treatment group had a greater number of follicles aspirated than the U-Control cows. In addition, the anti-alpha(c)I immunization may have played a role in increasing the number and diameter of the follicles. None of the treatments evaluated in this study improved oocyte retrieval over that of the intact, nontreated cows.

[Anti-thyroid autoantibodies in hepatitis C. Thyroid function after interferon therapy in 4 patients]. / Auto-anticorps anti-thyroïdiens au cours de l'hépatite C. Evolution de la fonction thyroïdienne sous traitement par interféron chez 4 malades.

Four female patients had chronic hepatitis C associated with antithyroid autoantibodies. Hepatitis C virus infection was evidenced by liver biopsy and a positive-four-antigen recombinant immunoblot assay. All four patients were euthyroid before interferon therapy. Recombinant interferon alpha was given at a dose of 3 millions units three times a week for 6 months. At the end of the treatment, serum aminotransferase levels were within the normal range. Two patients progressed to hypothyroidism and 2 patients remained euthyroid. One year after the end of the treatment, only one patient had hypothyroidism and another had normal serum aminotransferase levels. These case-reports suggest that interferon administration may induce thyroid dysfunction in patients with antithyroid autoantibodies at the beginning of treatment. Thyroid dysfunction may be reversed when cytokine is withdrawn.

Effect of media substitutes on bovine granulosa cell function and proliferation during in vitro culture.

The development of a serum-free culture system for bovine granulosa cells that would allow for cellular proliferation without induction of steroidogenesis would provide researchers with an important in vitro tool for determining differentiation mechanisms during folliculogenesis. The objective of the present study was to determine the effect of a commercially prepared serum substitute and a medium supplement on proliferation and progesterone production by bovine granulosa cells. Granulosa cells were obtained by aspirating the follicular fluid of follicles 2 to 8 mm in diameter. For each experiment, growth curves to determine the proliferative and steroidogenic response of granulosa cells to several different medium additions were constructed. Cells were counted on d 1, 2, 4, 6, and 8 of culture to determine cell concentration and the media harvested to determine progesterone content. In Exp. 1, granulosa cells were seeded at an initial rate of 5.0 x 10(5) for 48 h in serum-supplemented medium then allotted to one of five treatments including medium alone or medium containing fetal bovine serum (FBS; 1%), Gibco BRL media supplement-x (GMS-X; 1%), fatty acid-free bovine serum albumin (FAF-BSA; 4 mg/mL), or SerXtend (5%). For Exp. 2 and 3, granulosa cells were plated in serum-supplemented medium for either 48 or 24 h and seeded at either 5.0 x 10(5) or 2.5 x 10(5) cells/flask, respectively, and cultured in different concentrations of SerXtend. All treatment media supported granulosa cell proliferation to some extent; the SerXtend treatment provided the highest proliferation rate at all concentrations above .3125%. Also, during the proliferative stage of the growth curve, cells in the SerXtend treatment produced lower amounts of progesterone compared with cells in the other treatments. In summary, granulosa cells may be propagated in vitro in a serum-free environment without inducing progesterone production.

Insulin therapy.

Insulin therapy is the most important treatment aspect of diabetes mellitus. Since the discovery of insulin in 1921, a variety of insulin formulations have been developed. The purpose of this article is to describe the current sources, formulations, and types of insulins available for therapy of diabetes mellitus in small animals and to provide the veterinarian with guidelines for insulin therapy in dogs and cats.

Transvaginal aspiration of oocytes from hormone-treated pregnant beef cattle for in vitro fertilization.

The ability to produce oocytes from genetically valuable, pregnant donors in a safe, repeatable manner would broaden the application of in vitro fertilization (IVF) procedures for beef and dairy cattle. The objectives of this study were to evaluate two gonadotropin treatment schedules for follicle stimulation of pregnant donor cattle and to determine the efficacy and safety of the repeated oocyte aspiration procedure from pregnant cattle. In Exp. 1, pregnant donors at 60 to 90 d of gestation were randomly allotted to three treatment groups. Cows in Treatment A received a total dose of 40 mg of FSH. Cows in Treatment B were administered a total of 20 mg of FSH, and females in Treatment C served as pregnant vehicle-treated controls. A group of luteal phase cows received a total of 40 mg of FSH and served as nonpregnant controls (Treatment D). Ultrasound-guided transvaginal oocyte aspiration was performed 12 h following the last FSH or saline injection. Following follicle aspiration, oocytes were matured for 24 h and then entered a standard bovine IVF procedure. Experiment 2 was conducted to determine the repeatability of this procedure on first trimester cows. Cows in Exp. 2 were selected (after a 20-d recovery period) from each of the three pregnant treatment groups in Exp. 1 and each given 40 mg of FSH before a second oocyte aspiration procedure. The number of follicles aspirated per cow in treatment groups receiving the high FSH dose treatment (40 mg of FSH total dose) was not different (Treatment A, Treatment D, and cows in Exp. 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased serum D-lactate associated with diabetic ketoacidosis.

We hypothesized that serum D-lactate may be increased in vivo in diabetes mellitus as a result of increased glucose flux through the glyoxalase pathway and/or via hepatic ketone metabolism. Levels of D-lactate and related metabolic intermediates were measured in 30 cats with spontaneous diabetes mellitus and in one ketoacidotic nondiabetic cat. Serum D-lactate was significantly (P = .0051) elevated in cats with ketoacidosis (337.2 +/- 70.2 mumol/L) as compared with nonketoacidotic diabetic (140.3 +/- 58.8) and control (25.0 + 6.5) cats. Two nonketoacidotic cats also had high levels of D-lactate. There was a significant linear correlation (r = .684, P = .0001) between D-lactate and beta-hydroxybutyrate concentrations. Serum D-lactate did not correlate with serum glucose (r = .078, P = .6825), and in vitro erythrocyte D-lactate formation did not increase in the presence of hyperglycemia. These data suggest that hepatic ketone metabolism, rather than hyperglycemia, may be a major source of serum D-lactate in diabetics.

Acute renutrition by cyclic enteral nutrition in elderly and younger patients.

OBJECTIVE: To evaluate the efficacy and tolerance of cyclic enteral nutrition (CyEN) in elderly compared with younger patients. DESIGN: Prospective case series. SETTING: University hospital nutritional support unit. PATIENTS: A total of 51 patients younger than 65 years (mean age, 45 years) and 46 patients 65 years of age and older (mean age, 77 years) referred for refeeding after having lost at least 20% of their body weight or at least 10% in 3 months. All patients were severely undernourished but were ambulatory. INTERVENTION: Cyclic enteral nutrition was administered via a nasogastric tube during the night; in the daytime patients were allowed to eat normally. MEASUREMENTS: Ten biological and anthropometric nutritional parameters and a global nutritional deficiency (GND) were measured at day 0, at day 15, and at the end of CyEN. RESULTS: Total energy intakes were 288% and 282% of resting energy expenditure in groups 1 and 2, respectively, and duration of CyEN was a mean of 27 days in both groups. Tolerance was generally good, although one patient in each group discontinued refeeding because of aspiration pneumonia. In both groups, seven nutritional parameters and the GND improved significantly; six parameters improved significantly more in younger than in elderly patients: body weight, serum albumin, serum prealbumin, serum transferrin, 24-hour urinary creatinine, and the GND (44.7% vs 35.4%; P = .006). After 1 year, the probability to be alive without relapse was 62% in the elderly and 76% in the younger patients (P = .18). CONCLUSIONS: Cyclic enteral nutrition appears to be a well-tolerated and effective treatment of undernutrition in older malnourished ambulatory patients, although their response to CyEN was somewhat less than in younger patients.

Heinz body formation associated with ketoacidosis in diabetic cats.

Oxidative damage plays an important role in the pathophysiology of diabetes and diabetic complications. Feline hemoglobin is uniquely susceptible to oxidative denaturation; therefore, Heinz body formation is a highly sensitive indicator of in vivo oxidative stress in this species. Heinz bodies also contribute to anemia. We investigated hematological and clinical biochemical changes in 30 cats with spontaneous diabetes mellitus (as compared to 15 healthy control cats) and evaluated the relationship of these changes to erythrocyte oxidative damage. Cats were categorized as ketoacidotic or nonketoacidotic based on their clinical presentation and the presence of urine ketones. Ketoacidotic cats had significantly (P = .0009) more Heinz bodies (28.3% +/- 9.1%) than nonketotic diabetic cats (6.5% +/- 1.60%) and healthy control cats (0.6% +/- 0.2%). Percent Heinz bodies in diabetic cats directly correlated with plasma beta-hydroxy-butyrate concentration (r = .622; P = .0002), as well as with serum chloride concentration (r = -0.576; P = 0.0009) and the number of monocytes (r = .536; P = .0023). Percent Heinz bodies were negatively correlated with erythrocyte glutathione concentrations. Erythrocyte membrane lipid peroxidation was slightly but not significantly increased in diabetic cats. There were no significant associations between percent Heinz bodies and degree of anemia, hyperglycemia, or glycohemoglobin. These data indicate that ketones are associated with oxidative hemoglobin damage in cats, and suggest that ketone metabolism, ie by cytochrome P450 2E1, may be a potential source of in vivo oxygen radical generation in animals with ketosis.

Established cell lines and their conditioned media support bovine embryo development during in-vitro culture.

These experiments were conducted to evaluate the ability of different somatic-cell monolayers or conditioned medium from somatic cells for supporting bovine embryo development in vitro. In the first experiment, bovine embryos (2- to 4-cells) were allocated randomly to a control (medium 199 with 10% fetal bovine serum and antibiotics) group or co-cultured with bovine oviduct epithelial (BOEC), buffalo rat liver (BRL), Madin Darby bovine kidney (MDBK) or African green monkey kidney (Vero) cells. In the second experiment, bovine embryos (1-cell) were allocated randomly to the following groups: control medium or conditioned medium from BOEC, BRL, MDBK and Vero monolayers. In both experiments, development to the blastocyst stage was assessed after 8 days of incubation at 39 degrees C and 5% CO2. In Experiment 1, coculture improved development to the blastocyst stage compared with control medium alone, and the highest development was observed after co-culture with BOEC. In Experiment 2, conditioned medium enhanced development to morulae and blastocysts compared with the control medium; however, no differences were detected among different cell supports. These results indicate that both co-culture and conditioned medium from different cell monolayers supported development to the blastocyst stage at a higher efficiency than control medium alone.