Menopause alters temperature sensitivity of muscle force in humans.

Isometric maximum voluntary force (MVF) of the adductor pollicis and first dorsal interosseous muscles was measured in 11 pre- and 11 post-menopausal (Pre-M and Post-M) human subjects. The temperature of the hand varied in the range 18°-38°C by water immersion and skin temperature was recorded. MVF at each temperature was expressed relative to the value at skin temperature above 35°C to give MVF(REL). The form of the relation between MVF(REL) and temperature was different in the Pre-M and Post-M groups (p < 0.01). In the Pre-M group the maximum value of MVF(REL) occurred near 30°C and force fell at both higher and lower temperatures. In the Post-M group MVF(REL) showed an approximately linear decline with cooling across the whole temperature range. The maximum value of MVF(REL) for the Post-M group was near 35°C. The values of MVF(REL) for the Post-M group were significantly lower than for the Pre-M group at temperatures between 18° and 30°C.

Student views on the introduction of anatomy teaching packages into clinical attachments.

Following the implementation of the GMC document Tomorrow's Doctors in 1993 the amount of time dedicated to anatomy in undergraduate curricula has been reduced. This has resulted in considerable disquiet among physicians and surgeons with regard to the anatomical knowledge of newly qualified doctors, and also amongst students. This study aimed to assess the perceived student need for anatomical teaching packages to support clinical attachments in the later years of the undergraduate medical curriculum. The views of two groups of students were obtained: Group A were at the beginning of their clinical attachments, whereas Group B had completed all clinical attachments and had sat the final examination. The majority of students indicated that there was a need for the development of a teaching package for anatomy (and other basic sciences) in the later stages of the undergraduate medical curriculum. A high proportion stated that the completion of these packages should be in a self-directed manner with a staff member available. There was a difference between both groups in response to the best time to offer the packages, and in the clinical areas which might be prioritized in such a development. We conclude that the vertical integration of anatomy--perhaps through clinically focused teaching packages--would be welcomed by students as part of their clinical attachments.

Oestrogen status in relation to the early training responses in human thumb adductor muscles.

AIMS: The aims of this study were to identify the mechanisms for the early response to training in women of different oestrogen status and to determine whether any oestrogen and exercise effects on these would be additive. METHODS: We monitored training (ten 5-s contractions per day for 12 weeks)-induced changes in the size, strength, voluntary activation capacity and index of crossbridge force state (i.e. rapid stretch to isometric torque ratio), in the thumb adductor muscles of postmenopausal [eight who had never used, and 14 who were using, hormone replacement therapy (HRT)] and seven premenopausal eumenorrhoeic women. The contralateral untrained muscle was used as a control. RESULTS: There was a significant effect of oestrogen status on the magnitude of training-induced strength increment, with the non-HRT postmenopausal group exhibiting the greatest benefits (28 +/- 6%, P = 0.024) from training. There were no significant or commensurate changes in either cross-sectional area or voluntary activation capacity. The index of crossbridge force state improved most in the no-HRT group (19 +/- 7%, P < 0.05). CONCLUSIONS: Presence, rather than absence of oestrogen, is associated with relatively higher muscle function which limits the potential for any further training-induced increments in muscle performance, as would be expected if the muscle strengthening actions of training and oestrogen share a common, partially saturable physiological pathway. The mechanism that is involved in the early training-induced strength increment in the three differing oestrogen groups cannot be due to increased size or recruitment. It would appear instead that increased motor unit firing frequency is involved.

Heart rate and its variability change after the menopause.

Resting heart rate and heart rate variability of 33 postmenopausal women were compared with those of 50 premenopausal women of comparable activity level, none of whom had used hormone replacement therapy. Heart rate was measured as the mean of at least 600 consecutive R-R intervals obtained from electrocardiograph (ECG) records, and its variability as the standard deviation of these intervals. Activity levels were assessed by a scale modified from the Allied Dunbar National Fitness Survey (1992). There was a significant reduction in both mean R-R interval and the standard deviation in the postmenopausal women who had experienced their last menstrual period (LMP) 1 year or more prior to the observations being made, but no observable changes during the first year post menopause.

Hormone replacement therapy increases isometric muscle strength of adductor pollicis in post-menopausal women.

A randomized open trial of hormone replacement therapy was used to assess changes in adductor pollicis muscle strength during 6-12 months of treatment with Prempak C 0.625(R) in comparison with an untreated control group. Muscle strength (maximal voluntary force; MVF), muscle cross-sectional area and bone mineral density were measured. Women entering the trial had oestrogen levels below 150 pmol.l-1, confirming their post-menopausal hormonal status. In the treated group, MVF increased by 12.4+/-1.0% (mean+/-S.E.M.) of initial MVF over the duration of treatment, while it declined slightly (2.9+/-0.9%) in the control group. This increase in strength could not be explained by an increase in muscle bulk, there being no significant increase in cross-sectional area during the study. Those subjects who were weakest at enrolment showed the greatest increases in muscle strength after treatment. Bone mineral density in total hip, Ward's triangle and total spine increased in the treated group, in agreement with previous studies. There was no correlation between the individual increases in bone mineral density and those in MVF.

Changes in isometric force of mouse soleus muscle during the oestrous cycle.

Muscles excised from young female mice at known phases of the oestrous cycle were studied in vitro to determine if there are variations in force analogous to those that occur in vivo during the menstrual cycle in women. Oestrous phase was determined from vaginal smears. The maximum isometric and eccentric forces of pairs of isolated soleus muscles were measured. The first muscle was studied immediately after dissection, the second after incubation in Ringer solution for up to 2 h. Normalised isometric muscle force in the first muscle of each pair depended on the oestrous phase, the force being greatest during dioestrus. There was a negative correlation between normalised force and the eccentric/isometric force ratio. Neither of these phenomena was found with the second muscle of each pair. These results show that in mouse soleus muscle cross-bridge function does vary according to the phase of the oestrous cycle. However, the rise in force does not follow the pattern of the rise in blood oestrogen levels as it does in humans, and in the mouse the effect on cross-bridge function washes out after a few hours in vitro.

A study of force and cross-sectional area of adductor pollicis muscle in female hip fracture patients.

OBJECTIVES: To determine the extent of muscle weakness in older female hip fracture patients compared with healthy older and young women; to determine the extent to which this weakness is caused by a decline of the force produced per unit area of muscle rather than by a decline in muscle bulk; and to investigate the mechanism of the decline in force per unit area. DESIGN: This was an open study of three groups of subjects, two age matched older groups and one young group. SETTING: University College London, Royal Free Hospital, and St. Thomas's Hospital, London. PARTICIPANTS: Twenty-nine older female hip fracture patients (mean age 85.6 +/- 0.9 SEM), 18 healthy older women (mean age 84.7 +/- 1.2 SEM), and 43 young women (mean age 28.9 +/- 1.2 SEM). MEASUREMENTS: Adductor pollicis muscle maximum voluntary force (MVF) during isometric and pliometric contractions and cross-sectional area (CSA), body weight, height, and demi-span. RESULTS: Isometric MVF was lowest in the hip fracture group. In both older groups, isometric MVF and CSA were lower than in the young women. Only part of this weakness in the older groups could be explained by the smaller CSAs. The isometric force per unit area (MVF/CSA) was also lower in both older groups, the hip fracture patients again having the lowest values. Analysis of variance showed a significant difference between groups. The age-related declines in pliometric force were much less than the declines in isometric force. This resulted in an increase in the pliometric/isometric force ratio both for the hip fracture patients and for the healthy older women compared with that for young women. CONCLUSION: In comparison with the results from young women, the adductor pollicis muscles of female hip fracture patients were even weaker than those of healthy older women when normalized for muscle size. This decline in isometric MVF/CSA accounted for at least half of the overall weakness in the hip fracture patients. Inasmuch as pliometric force is maintained in situations where weakness is caused by a decline in the force produced per muscle cross-bridge, this is the likely mechanism of the declines in isometric MVF/CSA observed in this study.

Interpreting the relation between force and cross-sectional area in human muscle.

The maximum force a muscle can produce depends on its cross-sectional area (CSA). However, the exact interpretation of this relationship has been a matter of controversy. Recently, the controversy has centered on whether the measurements are best correlated using regression analysis or ratio standards. Applying regression analysis to this problem implies that all the experimental error is in the measurement of force. Thus, confusion may arise by failure to take account of errors in the measurement of CSA. Using a statistical model, we show how regression analysis can be misleading as error is introduced into the measurement of CSA as well as that of force. Because neither the errors in force nor CSA can be quantified in the experimental situation, we conclude that ratio standards are less likely to mislead although the accuracy of the result depends on the degree of correlation between force and CSA in the muscle measured.

Changes in maximal voluntary force of human adductor pollicis muscle during the menstrual cycle.

1. Muscle strength of the adductor pollicis (AP) was studied throughout the menstrual cycle to determine whether any variation in force is similar to the known cyclical changes in ovarian hormones. Three groups of young women were studied: trained regularly menstruating athletes (trained), untrained regularly menstruating (untrained) and trained oral contraceptive pill users (OCU). In addition a group of untrained young men was studied as controls. 2. Maximum voluntary force (MVF) of AP was measured over a maximum period of 6 months. Ovulation was detected by luteinizing hormone measurements or change in basal body temperature. There was a significant increase in MVF (about 10%) during the follicular phase of the menstrual cycle when oestrogen levels are rising, in both the trained and untrained groups. This was followed by a similar in MVF around the time of ovulation. Neither the OCU nor the male subjects showed cyclical changes in MVF.

Mutations of some critical amino acid residues in the hepatitis B virus surface antigen.

Amino acid substitutions at several positions in the surface antigen (HBsAg) of hepatitis B virus (HBV) in natural isolates and the products of recombinant DNA molecules have identified important residues for cross-reaction with specific antibodies (anti-HBs) and the induction of antibodies with certain serological specificities. In a further group of mutants described here, cysteine residues in a region believed to be significant of the a epitope have been changed to serines. Of the three adjacent cysteine residues at positions 137, 138 and 139, mutation of either of the flanking residues reduced cross-reactivity with polyclonal anti-HBs, while alteration of the central residue was relatively well-tolerated. Mutation of cysteine 149 to serine or of glycine 145 to arginine (imitating naturally occurring mutants), lysine, or glutamatic acid all led to loss of cross-reactivity with polyclonal antisera.

Messenger RNA levels of lung extracellular matrix proteins during ozone exposure.

Continuous exposure of rats to ozone has been shown to result in lung epithelial damage, inflammation, and subsequent increases in collagen content. The main goal of this study was to identify the earliest time point of altered extracellular matrix protein gene expression by utilizing Northern blot analyses of rat lungs continuously exposed to 1.0 ppm ozone for 14 days. An early increase of steady-state fibronectin mRNA levels was observed at 2 days of exposure, prior to the time point of increased type I collagen mRNA, which was seen at 4 days. This increased level of type I collagen mRNA preceded measurable changes in total lung collagen content, observed at 7 days. In addition, peak levels of the growth-related proto-oncogene c-myc mRNA could be correlated with maximal increases of lung DNA content, although the initial increase in c-myc mRNA preceded measurable changes of total lung DNA. The use of specific cDNA probes for measuring altered gene expression can be useful for defining the early cellular and molecular events in ozone-induced lung injury.

Muscle weakness in women occurs at an earlier age than in men, but strength is preserved by hormone replacement therapy.

1. The time-course of the age-related decline in specific muscle force (maximum voluntary force per cross-sectional area) in men and women was determined by measuring the maximum voluntary force and cross-sectional area of the adductor pollicis muscle in 273 subjects aged 17-90 years (176 men, 30 premenopausal women and 67 peri- or post-menopausal women who were not receiving hormone replacement therapy). 2. To determine whether the loss of specific muscle force is hormone-dependent in women, we studied a further 25 women, aged 42-72 years, who were receiving hormone replacement therapy. 3. There was no significant difference in specific force between young men and pre-menopausal women. Around the time of the menopause there was a dramatic decline in specific force in women which was prevented by the use of hormone replacement therapy. In men the weakness started later (around the age of 60 years) and the decline in specific force was more gradual, reaching the level seen in post-menopausal women after the age of 75 years. 4. The protective effect of hormone replacement therapy on muscle strength is likely to be an important contributory factor to its proven action in preventing osteoporotic fractures. The dramatic peri-menopausal decline in muscle strength is a likely explanation for the known increases in falls and Colles' fractures around the time of the menopause.

Gestation stage-specific frequency of adipogenic cells in Syrian hamster cell cultures.

High frequencies (up to 50%) of spontaneous adipocyte differentiation are observed in cultures of 9 day gestation Syrian hamster embryos (E9 cells) within six to eight population doublings after primary culture. This is in contrast to the absence of adipogenic cells in primary cultures derived from later gestation age Syrian hamster tissue. In addition, E9 primary cultures contain a transient subpopulation of presumptive mesenchymal stem or progenitor cells that lack density dependent inhibition of growth [contact-insensitive (CS-) cells]. Analysis of the temporal pattern of expression of the CS- and adipocyte phenotypes during the proliferative life span of E9 cells demonstrates that maximal expression of the CS- phenotype precedes maximal expression of adipocyte differentiation. In addition, lipid accumulation appears to occur primarily, if not exclusively, in the contact-sensitive (CS+) cells that are derived from CS- cells. These observations suggest that primary E9 cultures contain either adipoblasts or primordial mesenchymal cells that become determined to the adipocyte lineage early during the in vitro life span of the cultures, and that the CS- phenotype may be a marker for these earlier developmental cell stages.

Differential extracellular matrix gene expression by fibroblasts during their proliferative life span in vitro and at senescence.

Increasing evidence supports the idea that the finite proliferative life span of normal fibroblasts is a differentiation-like phenomenon. If this were correct, an ordered sequence of differential gene expression should be associated with the in vitro progression of cells from low passage to high passage (senescence). To define the pattern of expression of fibroblast differentiation-associated genes during this in vitro progression, we have determined the temporal pattern of expression of extracellular matrix (ECM) genes in Syrian hamster dermal fibroblasts as a function of passage level and percentage of proliferative life span in vitro. Steady-state mRNA levels were determined by Northern and dot blot analyses of total cellular RNA hybridized with cDNA probes specific for fibronectin, procollagen alpha 1III, and procollagen alpha 1I. Cells were analyzed at 24 hr postconfluence to minimize the presence of actively proliferating cells, and because maximal levels of fibronectin, alpha 1III, and alpha 1I mRNAs were observed 24 hr postconfluence. Unique, multiphasic patterns of expression of each of these ECM components were observed as the cells progressed from low passage to high passage. As the cells reached midhigh passage, fibronectin mRNA levels increased. This midpassage increase in fibronectin was followed by an increase in the level of alpha 1III mRNA as the cells reached the end of their in vitro proliferative life span, and then alpha 1I when the cells entered the postmitotic senescent phase, at which time the level of fibronectin mRNA also declined. A similar overlapping cascade pattern of up-regulation of these genes is seen during development and wound repair. This suggests that as cultured fibroblasts reach the end of their proliferative life span, they reinitiate a gene expression program used in tissue development and repair.

The weakness of old age is not due to failure of muscle activation.

Maximum voluntary force and cross-sectional area (MVF and CSA) of the human adductor pollicis muscle were compared in groups of young (19-55 years, mean = 28, n = 53) and elderly (74-90 years, mean = 80, n = 39) subjects, of both sexes. Despite the elderly subjects being in good health and active outdoors, they were considerably weaker than the young subjects, their MVF/CSA being 26 +/- 3% (mean +/- SEM) lower. It was found that both young and elderly subjects could fully activate their muscles. Therefore the muscle weakness of old age does not appear to be due to reduced activation and must be caused by another mechanism, possibly biochemical in nature.

The successful medical management of gastric outflow obstruction associated with the use of non-steroidal anti-inflammatory drugs in the elderly.

One hundred and nineteen consecutive elderly patients with endoscopically diagnosed peptic ulceration were reviewed. Associated gastric outflow obstruction was present in 10.1%. The presenting clinical features differed significantly from typical younger patients and most (11/12) were taking non-steroidal anti-inflammatory drugs, suggesting a possible role for these agents in the pathogenesis of gastric outflow obstruction. These elderly patients have been successfully managed by medical therapy alone.

NMR studies of intracellular water at 300 MHz: T2-specific relaxation mechanisms in synchronized or EGF-stimulated cells.

Responses specific to the spin-spin relaxation time (T2) have been observed in two time-dependent studies of the intracellular water in normal and transformed Syrian hamster fetal fibroblasts. At 300-MHz (7.0 T), the spin-lattice relaxation time (T1) was insensitive to several aspects of cellular physiology that produced changes in the T2 and the apparent self-diffusion coefficient (Dapp) of intracellular water. In normal cells stimulated with epidermal growth factor (EGF), T1 was insensitive to time-dependent changes detected by T2 and Dapp. In synchronized tumor cells, T1 was insensitive to cell-cycle-dependent changes detected by T2. The strongly coupled behavior of T2 and Dapp that was observed as a function of time in EGF-stimulated cells indicates that the diffusion of intracellular water through inhomogeneous local magnetic field gradients produced effects observable in T2. Conformational changes in large intracellular macromolecular assemblies such as chromatin or the cytoskeleton may alter the magnitude and inhomogeneity of local field gradients, producing responses in T2 and Dapp only.

Age-related differences in promoter-induced extension of in vitro proliferative life span of Syrian hamster fibroblasts.

The proliferative capacity of Syrian hamster dermal fibroblasts has been previously shown to be inversely related to the age of the donor (Mech. Ageing and Dev., 34 (1986) 151). The present study demonstrates an inverse correlation between in vivo age and the in vitro morphological and proliferative response of Syrian hamster dermal fibroblasts to the tumor promoter phorbol-12,13-didecanoate. Treatment of fetal fibroblasts with promoter increased the proliferative life span of the cultures by approximately 2-fold, but did not increase the frequency of conversion to established cell lines. Neonatal and young adult fibroblasts exhibited intermediate responses to promoter treatment, showing 54.9% and 33.1% extension, respectively. In contrast, promoter treatment had no significant effect on aged adult fibroblasts. Maximal extension required continual treatment beginning in primary culture or at passage 1. Promoter-induced extension of proliferative life span appears to be mediated through the prolonged maintenance of small, highly proliferative cells that are present in primary cultures of these cells.