Localization of non–N-methyl-D-aspartate glutamate receptors in normal and Alzheimer hippocampal formation

The hippocampi and adjacent temporal cortices of 24 human brains were examined with antibodies to the GluR1, GluR2/3, and GluR4 subunits of the D ,L -α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–preferring glutamate receptor. GluR1 immunoreactivity was most dense in the dentate gyrus, with lower densities in other hippocampal and cortical regions. GluR2/3 immunoreactivity was the most intense of the three antibodies, with high levels throughout most hippocampal subfields, where it was localized to cell bodies, proximal axons, and dendrites. GluR4 immunoreactivity was very sparse in all regions. In Alzheimer's disease brains, the general pattern of staining was similar to that seen in control brains. GluR1 and GluR4 immunoreactivity was seen in some but not all neuritic plaques. All three antibodies recognized some neurons undergoing neurofibrillary degeneration.     

Ultrasonographic dating of pregnancy causes significant errors in Down syndrome risk assessment that may be minimized by use of biparietal diameter-based means.

OBJECTIVES: Gestational dates assessed by ultrasonographic measurement of fetal dimensions are usually quoted in terms of complete weeks because the uncertainty of ultrasonographic measurement is approximately +/- 7 days. This study examines the effect of ultrasonographic dating on Down syndrome risk assessment. STUDY DESIGN: The effect of small changes in measured biparietal diameter resulting in a change in estimated gestational week and the benefits of a more precise measure of fetal gestational age (raw biparietal diameter) are examined mathematically. RESULTS: If maternal serum alpha-fetoprotein and human chorionic gonadotropin are used to assess Down syndrome risk, risks assessed with ultrasonographically determined dates may be less than or equal to 45% too high for fetuses with biparietal diameter at the lowest end of the size band and less than or equal to 22% too low with biparietal diameter at the top of the size band. If the results for maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol are used, these figures become less than or equal to 150% and less than or equal to 60%, respectively. CONCLUSION: If ultrasonography is used to assess gestational age, the raw biparietal diameter and not the estimated week of gestation must be used to derive means for calculation of multiples of the mean.     

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

Vinyl chloride (VC) exposure is primarily via inhalation in the workplace. The primary target organ of VC toxicity is the liver and occupational exposure to VC leads to hepatic angiosarcoma. However, based on epidemiological studies, researchers have been unable to ascertain the effect of occupational VC exposure on embryo-fetal development or reproductive function. A limited number of animal studies available in the literature have examined the effect of VC on embryo-fetal development, however, there are no published studies on the effect of VC exposure on reproductive capability. The current study was designed to assess the potential maternal and/or embryo-fetal developmental and 2-generation reproductive toxicity of inhaled VC in CD(R) Sprague-Dawley rats at exposure levels of 0, 10, 100, and 1100 ppm. In the embryo-fetal/developmental toxicity study, the female rats were exposed to VC daily from gestation day (GD) 6 through 19. In the reproductive toxicity study, the F(0) generation male and female rats were exposed to VC for a 10-week premating and 3-week mating periods. The F(0) generation male rats were exposed to VC until terminal euthanasia. The F(0) generation female rats were exposed from GD 0 through GD 20 and lactation day (LD) 4 through LD 25. Our results indicate that up to 1100 ppm VC exposure did not adversely affect embryo-fetal developmental or reproductive capability over 2 generations in rats. The primary target organ of VC, the liver, was affected as evidenced by an increase in liver weight and/or histologically identified cellular alterations, such as centrilobular hypertrophy at 100 and 1000 ppm. Based on the results of these studies, the no observed adverse effect level (NOAEL) for embryo-fetal/development is 1100 ppm, and the NOAEL for reproduction is 1100 ppm. The results from the current studies, which are a more comprehensive embryo-fetal/developmental and reproduction study, may be incorporated into future risk assessments of occupational exposure to VC where concerns regarding the effects of VC exposure remain.     

The effect of lithium therapy on arginine vasopressin secretion and thirst in man

Lithium therapy is known to reduce the renal responsiveness to arginine vasopressin (AVP: the antidiuretic hormone in man) and a proportion of treated patients develop polyuria and polydipsia. In this study seven nonpolyuric female patients receiving lithium treatment for an affective disorder (lithium group) were age-matched with seven healthy females (control group). The mean response of plasma AVP to osmotic stimulation was significantly enhanced in the lithium group but the mean osmotic threshold for AVP release was unchanged. Thirst appreciation in the lithium group commenced and increased overall at an osmotic stimulus 5 mmol/kg less than the control group. It is suggested that primary thirst does play a role in the expression of lithium-induced polyuria.     

Complications of gastric catheters implanted in rhesus macaques (Macaca mulatta).

As part of a study addressing chronic alcohol consumption and simian immunodeficiency virus, 31 rhesus macaques (Macaca mulatta) were implanted with gastric catheters used to deliver alcohol or isocaloric sucrose (control). Once implanted, the animals wore jackets and were housed in specialized cages modified with swivels and tethers. During the course of the study, 3 animals developed clinical signs indicating possible instability of the implanted gastric catheter. All 3 animals were found to have a string foreign body wrapped around the distal end of the catheter, with 2 of the catheters perforating the intestinal wall. Gastroscopy was used to screen remaining animals to determine catheter position and the presence of a foreign body attached to the end of the catheter. Results of the screening revealed that of the 28 remaining animals, 9 had malpositioned catheters; string foreign bodies were associated with 3 of the 9 malpositioned catheters. We initially hypothesized that the peristaltic motion of the stomach, combined with the attachment of string, which was probably ingested by subjects after manipulating their jackets, led to eventual catheter displacement. We later concluded that the string may have played a secondary role but was not the primary cause of catheter instability, because several malpositioned catheters had no string attached at the time of diagnosis. Subsequent modifications were instituted, including modifying the surgical technique, altering the type of gastric catheter used, and increasing environmental enrichment for animals with known tendency to manipulate their jackets.     

Hyponatraemia in patients with head injury

Three patients with head injury are described to illustrate certain features of the development, treatment and recovery of hyponatraemia. The hyponatraemia is initially due to water retention but true sodium depletion may develop because of an associated urine sodium loss. The mechanism of the latter is discussed.     

Redox signalling to nuclear regulatory proteins by reactive oxygen species contributes to oestrogen-induced growth of breast cancer cells

Background:

17β-Oestradiol (E2)-induced reactive oxygen species (ROS) have been implicated in regulating the growth of breast cancer cells. However, the underlying mechanism of this is not clear. Here we show how ROS through a novel redox signalling pathway involving nuclear respiratory factor-1 (NRF-1) and p27 contribute to E2-induced growth of MCF-7 breast cancer cells.

Methods:

Chromatin immunoprecipitation, qPCR, mass spectrometry, redox western blot, colony formation, cell proliferation, ROS assay, and immunofluorescence microscopy were used to study the role of NRF-1.

Results:

The major novel finding of this study is the demonstration of oxidative modification of phosphatases PTEN and CDC25A by E2-generated ROS along with the subsequent activation of AKT and ERK pathways that culminated in the activation of NRF-1 leading to the upregulation of cell cycle genes. 17β-Oestradiol-induced ROS by influencing nuclear proteins p27 and Jab1 also contributed to the growth of MCF-7 cells.

Conclusions:

Taken together, our results present evidence in the support of E2-induced ROS-mediated AKT signalling leading to the activation of NRF-1-regulated cell cycle genes as well as the impairment of p27 activity, which is presumably necessary for the growth of MCF-7 cells. These observations are important because they provide a new paradigm by which oestrogen may contribute to the growth of breast cancer.     

The relationship between birth weight and maternal glycated haemoglobin (HbA1c) concentration in pregnancies complicated by Type 1 diabetes.

AIM: To examine the relationships between maternal HbA1c concentration at different time points and birth weight in pregnancies complicated by pre-existing Type 1 diabetes. METHODS: A comprehensive audit dataset was collected prospectively on all deliveries in Scotland to women with pre-existing Type 1 diabetes occurring between 1 April 1998 and 31 March 1999. Data items included HbA1c concentrations prior to conception and in each of the three trimesters of pregnancy, and birth weight. Relationships between standardized birth weight and HbA1c concentrations at each of the four time points were examined using correlation analysis. RESULTS: Standardized birth weight (Z scores) could be calculated for 203 of 208 singleton liveborn infants. HbA1c concentrations, standardized to correct for assay differences among hospitals, at different time points were available for between 134 (pre-pregnancy) and 192 (third trimester) cases. Standardized birth weight, relative to a reference population, showed a unimodal distribution, shifted to the right (mean, +1.57 sd). There was a significant negative correlation between pre-pregnancy HbA1c and birth weight (Spearman's R, -0.208; P = 0.016). There were no statistically significant correlations for other time points. CONCLUSIONS: Standardized birth weight scores of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic status and birth weight, but there appears to be a paradoxical inverse relationship between pre-pregnancy glycaemic control and standardized birth weight.     

Value of notching and slurring of the resting QRS complex in the detection of ischemic heart disease

The resting 12-lead ECG has long been known to be an insensitive marker of underlying ischemic heart disease (IHD). The purpose of this study was to determine if QRS complex notching and slurring is of significant value as a diagnostic discriminator in the detection of IHD. The data from 205 consecutive patients coming to cardiac catheterization for evaluation of probable IHD were initially analyzed. Eighty-three patients were excluded based upon ventricular hypertrophy, bundle-branch block, lack of data, and pacemaker rhythm. The balance, 122 patients (mean age 61.7 years), were evaluated for angiographic evidence of IHD, ECG findings of QRS notching or slurring, and abnormal Q waves. The data revealed a high prevalence of QRS notching or slurring; 62.2% in those patients with IHD, double the prevalence of significant Q waves (33.3%). The two markers had an approximately equal prevalence (QRS notching or slurring 61.7% vs. Q waves 53.2%) in patients with angiographic evidence of infarction; however, in patients with less than infarct criteria for IHD, the prevalence of QRS notching or slurring was 62.8%, while only 11.6% showed abnormal Q waves. Analysis indicated that QRS notching or slurring has a sensitivity of 62.2% and a specificity of 93.8% for the detection of IHD. The study demonstrates that QRS notching or slurring is a moderately sensitive and a very specific marker of ischemic heart disease in selected patients when using the resting ECG, and is of greatest value in those patients with lesser degrees of ischemic myocardial injury where the prevalence of Q waves is low.     

Electrophysiology of Disopyramide in Man*

Summary: The electrophysiological effects of an intravenous dose of disopyramide phosphate (2 mg per kg body weight) were studied in 17 patients. Studies were performed with the patients fasting, unpremedicated, and off all medication for three days. Blood samples for estimation of serum levels of disopyramide were collected in 15 of these patients. The effects of intravenous disopyramide were maximal at five minutes, less marked at 20 minutes, and largely gone by 30 minutes after administration of the drug. Sinus cycle length and corrected sinus node recovery time were shortened significantly. No index of atrioventricular nodal function was significantly changed. Both atrial and ventricular effective refractory periods were significantly prolonged. Further impairment of intraventricular conduction occurred in six patients with bundle branch block on electrocardiogram or prolonged HV interval. In one of two patients with Wolff-Parkinson- White syndrome, the bypass effective refractory period was prolonged. These electrophysiological changes are similar to quinidine and quinidine like drugs. It is recommended that disopyramide should be used cautiously in patients with evidence of His Purkinje system disease since it may lead to higher degrees of intraventricular block.