A study of the increased sensitivity of denervated and re-innervated muscle to depolarizing drugs

1. The response of re-innervated muscles to depolarizing blocking drugs was studied.

2. During the early stages of re-innervation the `new' neuromuscular junctions are more sensitive to decamethonium and suxamethonium. The recovery from the block and the repolarization of the end-plate are markedly slowed.

3. This increased sensitivity does not appear to be characteristic of all newly formed neuromuscular junctions. It was found that in new-born kittens the muscles are very insensitive to neuromuscular blocking drugs.

4. It is concluded that the increased sensitivity of re-innervated muscles to depolarizing blocking drugs and the slow repolarization are due to a persistence of changes which developed during denervation.

     

Changes in chemosensitivity of developing chick muscle fibres in relation to endplate formation

1. The sensitivity to acetylcholine (ACh) of the fast posterior latissimus dorsi (PLD) and slow anterior latissimus dorsi (ALD) during embryonic development was studied and compared. The sensitivities were expressed as a ratio of the maximal tetanic tension and tension developed in response to ACh. 2. Up to the 17th day of incubation both muscles are sensitive to ACh to a similar extent; at the 18th day the sensitivity of the PLD muscle decreases and continues to do so until hatching and thereafter. 3. Since the decrease in sensitivity of PLD muscles takes place a few days after innervation, it is suggested that this is caused by activity of the motor nerve. To test this curare (dTc) and hemicholinium (HC-3), drugs that interfere with neuromuscular transmission, were injected into the yolk sac of the embryos when nervemuscle connections are usually established. In the curare and HC-3 treated embryos the desensitization of the PLD muscles did not take place. 4. The distribution of endplates on PLD muscles from drug treated 20-21 day old embryos was compared to that of untreated controls. Whereas control PLD muscles have only one band of endplates, muscles from curarized embryos and HC-3 treated embryos have several bands of endplates, and many muscle fibres with multiple innervation were found. 5. It is suggested that nerve fibres which make connections with PLD muscle fibres bring about a decline in chemosensitivity by releasing more transmitter, and thereby prevent further nerve muscle connections from being made along the same muscle fibre.     

Two factors responsible for the development of denervation hypersensitivity

1. Innervated adult skeletal muscle is sensitive to acetylcholine at the end-plate region only. After denervation the entire muscle membrane becomes chemosensitive. The period of greatest increase in sensitivity in rat soleus muscles following section of the sciatic nerve in the thigh is between 48 and 72 hr post-operatively.2. Direct electrical stimulation was found to prevent the onset of the development of denervation hypersensitivity during the first 2-3 days after nerve section. Thereafter, electrical stimulation only reduced the sensitivity of denervated muscles to acetylcholine (ACh).3. The period of greatest increase in sensitivity follows loss of transmission and degeneration of the nerve terminals. Once this degeneration is under way, electrical stimulation is no longer as effective in preventing the development of denervation hypersensitivity.4. Hypersensitivity is also seen in muscles on which a small piece of thread or degenerating nerve has been placed. Hypersensitivity following these procedures declines within a few days, unlike denervation hypersensitivity which persists until innervation is restored.5. The present results suggest that activity alone cannot prevent the development of hypersensitivity in the presence of degenerating nerve fibres, or muscle damage. Activity does however counteract increased sensitivity. It is suggested that two factors interact to produce denervation hypersensitivity; the presence of degenerating nerve tissue and concomitant cellular changes bring about changes in the muscle fibre membrane causing it to become hypersensitive; and the loss of muscle activity, resulting in the persistence of hypersensitivity until innervation is restored.     

The importance of the motor nerve for the development of chemosensitivity at the neuromuscular junction

Experiments were performed on kittens to study the role of innervation on the development of the pharmacological responses of the neuromuscular junction. The importance of the nerve for the development of the differing properties of fast and slow muscles was also studied.It was confirmed that the different responses to depolarising drugs of the slow soleus and fast flexor hallucis longus muscles are not apparent during the first week of the animal's life.Even when the motor nerves to these muscles were crossed at this time the alien innervation did not affect the subsequent development of the different responses of fast and slow muscles to suxa- and decamethonium. This suggests that the different properties of the postsynaptic membrane are established very early in the animal's life and that they cannot be changed by altering the innervation.The neuromuscular junctions of these young animals are very insensitive to suxa- and decamethonium. When innervation is delayed, during the early postnatal period, the development of the high sensitivity of the neuromuscular junctions to the blocking and depolarising actions of these drugs was retarded. It is therefore concluded that the motor nerve induces the high chemosensitivity of the adult endplate region.     

Temporal analysis of acute myocardial infarction in Ontario, Canada

BACKGROUND: Acute myocardial infarction (AMI) is a substantial cause of morbidity and mortality in Canada. Evidence suggests that the incidence and mortality of AMI increase in the winter. Determining the strength and nature of seasonality patterns in relation to age and sex may be helpful in health care planning. OBJECTIVES: To examine the seasonal patterns of AMI hospital admissions by age and sex, to assess the strength of the seasonal patterns and to examine the overall trends in admissions. METHODS: A retrospective population-based study was conducted to assess temporal patterns in 14 years of hospital admissions for AMI (from April 1, 1988, to March 31, 2002) in Ontario. Seasonality was assessed using the autoregression coefficient (R2Autoreg), and Fisher's Kappa and Bartlett's Kolmogorov-Smirnov tests. RESULTS: There were 271,321 people in the cohort, of whom 63% (n = 171,546) were male and 37% (n = 99,775) were female. There was an increase in AMI admissions since 1988 that reached a plateau in 1992, which was attributable mostly to the increased rate in the oldest age groups (70 years and older), where admission rates more than doubled. An association between seasonality and AMI admissions was found in most age and sex groups, with men consistently exhibiting a stronger seasonality pattern. The greatest difference in the cohort, 2.5 per 100,000 per month (134 admissions), occurred between December and September (13.64 per 100,000 in September versus 16.14 per 100,000 in December). CONCLUSIONS: AMI admissions show seasonality patterns, which are more pronounced in men. Although statistically significant, the seasonal differences are small in terms of absolute numbers, and are likely irrelevant in health care planning.     

Liver injury associated with the use of selective androgen receptor modulators and post-cycle therapy: Two case reports and literature review

BACKGROUNDMuscle growth promoters are being developed for the treatment of disease-induced loss of muscle mass. Ligandrol and ostarine are selective androgen receptor modulators (SARMs) with a non-steroidal structure and a presumably more favorable side effect profile. In recent years, these substances with or without “post-cycle therapy” (PCT) are often misused by amateur athletes aiming to promote muscle growth. At the same time, reports on their toxic effects on organ systems are emerging.CASE SUMMARYWe report two cases of liver injury in young men who used ligandrol and/or ostarine for a few weeks followed by the use of substances for PCT. Acute liver injury occurred in both cases after stopping SARMs while on PCT. The clinical picture was dominated by jaundice and fatigue. The biochemical pattern showed a mixed type of injury with normal alkaline phosphatase and high concentrations of bilirubin and serum bile acids. Histological evidence showed predominantly cholestatic injury with canalicular bile plugs, ductopenia, and mild hepatocellular damage without significant fibrosis. The patients recovered from the condition after 3 mo. The off target effects of SARMs were likely idiosyncratic, but our report highlights the yet unrecognized effects of other toxic substances used for PCT, supra-therapeutic doses, and the complete absence of monitoring for adverse effects.CONCLUSIONAmong muscle-building amateur athletes, SARMs (ligandrol or ostarine) and/or substances in PCT may cause cholestatic liver injury with prolonged recovery.     

The effect of neonatal nerve injury on the expression of heat shock proteins in developing rat motoneurones

The expression of the heat shock proteins hsp27 and hsp70 was examined in the spinal cord and sciatic nerves of developing rats. Using immunohistochemistry, we found that hsp27 is present in many motoneurones at birth. With development, the intensity of staining increases, reaching adult levels by 21 days, when all sciatic motoneurones express hsp27. In the sciatic nerve, hsp27 is strongly expressed throughout postnatal development. In contrast, hsp70 immunoreactivity in motoneurones and the sciatic nerve is weak at birth and does not change with development. The expression of heat shock proteins has been shown to increase in cells under conditions of stress, where they have beneficial effects on cell survival. The effect of neonatal nerve injury on hsp27 and hsp70 expression was also examined in this study. Four days after injury, staining for hsp27 increases in motoneurones, whereas hsp70 does not change. However, there is a significant increase in hsp70 staining in glial cells surrounding the injured motor pool, predominantly in astrocytes. Since neonatal nerve injury induces apoptotic motoneurone death, we also studied the co-expression of hsp27 with markers of apoptosis. No hsp27-positive motoneurones were found to be apoptotic, as assessed by both TUNEL and caspase-3 immunoreactivity. Therefore, it is possible that the upregulation of hsp27 observed in injured motoneurones may play a role in protecting motoneurones from apoptotic cell death following nerve injury.     

Localization of angiotensin II (AT1)-receptor-immunoreactive fibres in the hypothalamus of rats: angiotensin II-sensitive tanycytes in the ependyma of the third ventricle?

Scanning the hypothalamus of rats for receptor binding sites of the octapeptide hormone angiotensin II (ANG II), we observed ANG II-sensitive fibres in the ventrolateral hypothalamus. The ANG II (AT(1))-receptor-immunoreactive processes originate from cells-probably tanycytes-embedded in the base and the ventrolateral walls of the third ventricle and reach into the retrochiasmatic area, the ventrolateral hypothalamus and the median eminence.