Benjamin H. Natelson

Spread and pathogenic characteristics of a G-deficient rabies virus recombinant: an in vitro and in vivo study.

Rabies virus (RV), a highly neurotropic enveloped virus, is known to spread within the CNS by means of axonal transport. Although the envelope spike glycoprotein (G) of cell-free virions is required for attachment to neuronal receptors and for virus entry, its necessity for transsynaptic spread remains controversial. In this work, a G gene-deficient recombinant RV (SAD delta G) complemented phenotypically with RV G protein (SAD delta G+G) has been used to demonstrate the absolute requirement for G in virus transfer from one neuron to another, both in vitro, in neuronal cell cultures (cell line and primary cultures), and in vivo, in murine animal models. By using a model of stereotaxic inoculation into the rat striatum, infection is shown to be restricted to initially infected cells and not transferred to secondary neurons. In mouse as in rat models of infection, the limited infection did not cause any detectable symptoms, suggesting that G-deficient RV recombinants might be valuable as non-pathogenic, single-round vectors for expression of foreign genes.

Plasma cortisol and corticosterone concentrations in the golden hamster, (Mesocricetus auratus).

Because some recent studies of hamster adrenocortical function have depended on older studies that may have been inadequate or misinterpreted, the present study re-examined plasma corticosterone and cortisol concentrations in hamsters under several conditions to determine which plasma glucocorticoid predominated in this animal. Sensitive radioimmunoassays were used to measure separately the two glucocorticoids in the basal condition, after adrenocorticotropin (ACTH) treatment, after acute stress, and after chronic stress. In the basal condition, corticosterone concentrations were 3-4 times higher than those of cortisol. After stimulation, this difference disappeared, but rarely were any hamsters cortisol levels higher than their corticosterone levels. Both ACTH and acute stress elevated plasma corticosterone and cortisol concentrations, but only plasma cortisol concentrations were elevated following chronic stress. The dissociation between cortisol and corticosterone concentrations after chronic stress suggests that the two glucocorticoid hormones in the hamster may be regulated independently. The data also indicate that both corticosterone and cortisol should be measured when assessing adrenocortical function in the hamster.

A clinical evaluation of rats dying in the activity-stress ulcer paradigm

Abstract Rats fed 1 hr daily and housed in running-wheel activity cages exhibited excessive running and developed stomach ulcers as compared to food control, body weight control and home cage control rats. In addition to the observed gastric disease, experimental animals had increased bilirubins, decreased glycogen and decreased serum proteins suggesting that hepatic disease played a role in the lethal consequence of exposing rats to the activity-stress procedure. The decreases in liver glycogen and serum glucose suggested that the terminal problem was related to incipient exhaustion of metabolic substrates.

Elevated plasma vasopressin in cardiomyopathic hamsters

Hamsters of the BIO 14.6 strain characteristically develop cardiomyopathy as they age, and hamsters of this strain have overt signs of heart failure by 11 months of age. Plasma levels of the posterior pituitary hormone arginine-vasopressin (AVP) were found to be elevated (approximately 2-fold) in 11 month old BIO 14.6 hamsters, compared to age-matched hamsters of a control strain. AVP appeared inappropriately elevated in these animals, since they were neither hyperosmotic nor markedly hypotensive. The elevated levels of AVP observed in these animals appears to contribute to vasomotor tone, since intravenous administration of a specific antagonist of the vasoconstrictor action of AVP [d(CH2)5Ome(TYR)AVP] elicited a fall in arterial pressure (9 +/- 2 mm Hg, n = 6, p less than 0.05). The AVP antagonist had no effect on arterial pressure in hamsters of a control strain, and vehicle administration had no effect on arterial pressure in either strain. These data indicate that inappropriately elevated levels of AVP contribute to the cardiovascular state of myopathic hamsters. Since elevated plasma AVP has been noted in human congestive heart failure, these results suggest that AVP may contribute to the cardiovascular status during congestive heart failure.

Summation of baroreflex and classically conditioned heart rate responses in dogs

Following instrumentation with pneumatic cuffs around the inferior vena cava and the descending aorta, dogs were studied either following differential classical conditioning or in a control state. The cuffs functioned to raise and lower blood pressure for the construction of baroreflex curves for heart rate. Conditioned dogs received 8 trials each day with each CS+ (tone paired with flank shock) and CS- (a different tone without shock). Curves were constructed from cuff inflations timed to coincide with the maximum conditioned heart rate response. These curves were constructed from data acquired during infusion of saline, methyl atropine, or propranolol. Comparison of these curves revealed that the CS+ shifted the curves toward higher heart rates while the CS- curve was shifted toward lower heart rates without a change in gain. The amount of shift was comparable to that of the conditioned heart rate response. This suggested that the responses were independent and additive. Neither propranolol nor atropine eliminated this separation between the curves induced by the conditioning. These observations lead us to conclude that classically conditioned stress and baroreceptor stimulation exert independent control over heart rate that are mediated by both sympathetic and parasympathetic influences.

Sleep and Fibromyalgia

Fibromyalgia (FM) is a medically unexplained illness characterized by four quadrant pain lasting at least 3 months and accompanied by multiple areas of tenderness on palpation of the body using 4 kg force. FM occurs more often in women than men but is quite common in both sexes, occurring in approximately 3% of the population. Although sleep difficulties are not part of standard diagnostic criteria, insomnia complaints of poor and nonrestorative sleep are common and have been associated with intense of pain, fatigue, sleepiness, and cognitive difficulties in FM. FM frequently occurs in conjunction with chronic fatigue syndrome (CFS). CFS is a medically unexplained condition characterized by persistent or relapsing fatigue lasting at least 6 months, which substantially reduces normal activity. In addition to severe fatigue, one of the eight symptoms used for diagnosing CFS is “unrefreshing sleep”, and this sleeprelated problem is the most common complaint among CFS patients. Although, FM and CFS often have similar symptoms, including sleep-related complaints, differences between FM and CFS exist. In this chapter, we will review studies on sleep in FM and CFS patients in order to better understand differences between them. Polysomnographic studies have shown sleep problems in FM by using simple descriptive statistics, for instance, increased non-rapid eye movement (non-REM) Stage 1 sleep, reduced slow-wave (Stages 3 and 4) sleep, more arousals, prolonged sleep onset, reduced sleep efficiency, etc. Sleep problems in CFS shown by polysomnographic studies are quite similar to those in FM. However, we have shown that dynamic aspects of sleep, a new way of assessing sleep, are different between patients with CFS alone compared to those with CFS+FM. The probability of transition from rapid eye movement (REM) sleep to waking in CFS is greater than in healthy controls. Probabilities of transitions from waking, Stage 1 sleep, and REM sleep to Stage 2 and those from slow-wave sleep to waking and Stage 1 sleep are greater in FM+CFS than in healthy controls. Over the course of the many decades, sleep researchers have used simple descriptive statistics to characterize and summarize sleep architecture. While this methodology has

Metabolic Abnormalities and Differential Responses to Stress Associated with Hamster Cardiomyopathy

Abstract Metabolic differences between cardiomyopathic hamsters (CMHs), as they progress through various physiologic phases before reaching end-stage heart failure (HF), and healthy hamsters (HHs) are often difficult to demonstrate. We suggest that metabolic differences, magnified by application of chronic stress (S: cold immobilization 2 hr/day for 5 days) followed by acute stress (AS: 55 min global ischemia /30 min reperfusion), can be used to characterize different stages in this cardiomyopathic process. High performance liquid chromatography (HPLC) and 31P NMR methods were used to monitor the effects of acute stress applied to nonstressed (NS) and previously stressed CMHs (NS-2.5-month NS-5-month; S-2.5-month, S-5-month) and HHs (NS-HH, S-HH). Cardiac tissue extracts from nonstressed and stressed hamsters were analyzed for ATP and PCr at baseline and after completion of ischemia/reperfusion (AS) using HPLC. In nonstressed hamsters, ATP and PCr were 12% lower in CMHs (both NS-2.5-and NS-5-month) than in NS-HHs. After exposure to stress, ATP was 26% lower in CMHs (S-2.5-and S-5-month) compared to S-HHs, whereas there were minimal differences in PCr between the groups. 31P NMR monitoring of metabolism in the perfused beating heart during application of acute stress produced similar changes (%) in ATP and PCr in all groups (NS and S), whereas P, increase was less in NS-5-month (118%) compared to NS-2.5-month (179%) and NS-HHs (306.8%), P < 0.05; and in S-5-month (148%) compared to S-2.5-month (216%) and S-HHs (222%). The changes in myocardial pH were inversely related to changes in Pi: NS-5-month (-13.5%); NS-2.5-month (-9.7%); NS-HH (-17.7%). pH changes in stressed cardiomyopathic hamsters were similar to those of S-HHs. The postischemic recovery of ATP and Pi return closer to baseline values in cardiomyopathic hamsters (both NS and S) compared to healthy hamsters. The data suggest that cardiomyopathic hamsters have baseline metabolic abnormalities, and their responses to chronic cold immobilization stress, acute ischemia, and chronic cold immobilization stress plus acute ischemia are different from those in HHs. These responses may help to characterize specific stages of disease.