RETARDATION OF PERIPHERAL NERVE MYELINATION IN MICE TREATED WITH INHIBITORS OF CHOLESTEROL BIOSYNTHESIS : A Quantitative Electron Microscopic Study

The effect of two inhibitors of cholesterol biosynthesis, triparanol and AY 9944, on peripheral nerve myelination, was studied. Suckling mice were intraperitoneally injected with both drugs on 3 consecutive days and were sacrificed 6 hr after the last injection; others were suckled by an injected mother and sacrificed at 2½ days of age. A single mouse which had been injected with both drugs at 1, 2, and 3 days of age was sacrificed 2 wk after the last injection. Membranous and crystalline intracytoplasmic inclusions were observed in the Schwann cells of the sciatic nerves of all the experimental animals. Both the number of unmyelinated single axons and the number of myelin lamellae around each myelinating axon in the sciatic nerves were recorded for treated mice and of mice suckled by treated mothers. The sciatic nerve of the experimental mice contained a larger proportion of unmyelinated single axons and smaller numbers of myelin lamellae around the myelinating axons, when compared with age-matched controls. The results suggest that a decrease of endogenous cholesterol in suckling mice may affect peripheral nerve myelination in two ways: by retarding the "triggering" of myelination in unmyelinated axons and by decreasing the rate of myelination already in progress.     

Evidence for a direct negative effect of estradiol at the level of the pituitary gland in sheep

The purpose of this experiment was to determine if pituitary stores of LH could be replenished by administration of GnRH when circulating concentrations of both progesterone and estradiol-17 beta (estradiol) were present at levels observed during late gestation. Ten ovariectomized (OVX) ewes were administered estradiol and progesterone via Silastic implants for 69 days. One group of 5 steroid-treated OVX ewes was given GnRH for an additional 42 days (250 ng once every 4 h). Steroid treatment alone reduced (p less than 0.01) the amount of LH in the anterior pituitary gland by 77%. Pulsatile administration of GnRH to steroid-treated ewes resulted in a further decrease (p less than 0.01) in pituitary content of LH. Compared to the OVX ewes, concentrations of mRNAs for alpha- and LH beta-subunits were depressed (p less than 0.01) in all steroid-treated ewes, whether or not they received GnRH. The ability of the dosage of GnRH used to induce release of LH was examined by collecting blood samples for analysis of LH at 15 days and 42 days after GnRH treatment was initiated. Two of 5 and 3 of 5 steroid-treated ewes that received pulses of GnRH responded with increased serum concentrations of LH after GnRH administration during the first and second bleedings, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity

The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic - cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1− Nx (n = 7); 2− Nx+NAC (n = 6); 3− Nx+Gd (n = 7); 4−Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (µg/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (µg/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.     

Aging alters properties of the circadian pacemaker controlling the locomotor activity rhythm in males of Drosophila nasuta

Effects of aging on the circadian rhythm of locomotor activity in males of Drosophila nasuta were investigated. The adult life of males was divided in 1-3 stages according to spontaneous changes in free-running period x in constant darkness (DD): stage 1, days 1-19; stage 2, days 20-36; stage 3, days 37-43. Stage 1 was characterized by a bimodal activity pattern with a short light-induced morning peak and a prolonged evening peak when the flies were entrained to light-dark cycles of 12 hours of light, 12 hours of darkness (LD 12:12). The morning peak had a phase angle difference Ψ_m (Ψ, the time from lights on in LD 12:12 cycles to the onset of morning peak) of about 0.1h, while Ψ_e (Ψ of evening peak) was about 9h at stage 1. The transient morning peak was curtailed at the end of stage 1. At stage 2, the Ψ_e was about 10h, and the activity end was delayed by an addition of about 3h of activity in the scotophase. The changes in W during DD free runs were determined in two groups of flies: flies reared in LD 12:12 and flies reared in DD. In both groups, W increased from about 23h at stage 1 to about 25h at stage 2. Stage 3 was characterized by arrhythmicity associated with highest mean activity level (total number of passes/fly/day) in the entrained and both free-running groups. The mean activity level increased significantly from stage 1 to stage 3 in all three groups of flies.     

Effects of prostaglandin E2 on alveolar bone resorption during orthodontic tooth movement

Twenty Sprague-Dawley rats weighing 280-300 g were divided into two groups of ten animals each. They were treated by daily submucosal injections of 50 micrograms prostaglandin E2 (PGE2) per kilogram body weight into the region below the apex of the left first maxillary molar (experimental), or vehicle into the region below the apex of the right first molar (control), for a period of 5 days. The animals of the first group were sacrificed immediately following the treatment period, while those of the second group were sacrificed 5 days after the treatment period. Twenty-two hours prior to sacrifice, a piece of latex orthodontic elastic was secured to the adjacent area between the first and second maxillary molars of both sides of each rat by using two mosquito hemostats. The periodontal ligament (PDL) mesial to the mesiobuccal root of the first maxillary molar was assayed for changes in PDL cell factors. The results showed that immediately following the 5-day treatment period the left PDL had a significant decrease in the total number of fibroblasts and a significant increase in the total number of both osteoclasts and nuclei per osteoclast, while no significant changes in the osteoblasts when compared with those of the right control PDL. The left PDL of animals which were sacrificed 5 days after the treatment period revealed a significant decrease in the number of total fibroblasts and only a slight decrease in both numbers of total osteoclasts and total nuclei per osteoclast, but again no significant changes in osteoblasts when compared with those of the right control PDL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of light history on the rat retina: Timecourse of morphological adaptation and readaptation

Sprague Dawley rats were born and raised under either 5 or 800 lux cyclic light (12L:12D) and were sacrificed at 1, 2, 3, 6, 12, 16, and 28 weeks of age. At each time point outer nuclear layer (ONL) area and rod outer segment (ROS) length were measured. The former is an estimation of photoreceptor number, and the latter is an estimation of the photon-catching integrity of the retina, both of which are known to be dependent on the light environment. Regression analysis revealed an ONL area reduction with time of 0.003 mm²/wk for 5-lux-reared rats and 0.009 mm²/wk for 800-lux-reared rats. ROS length was relatively constant in the dim light group, but showed a decline in 800 lux rats of 0.5 m/wk. Rats moved from 800 to 5 lux at 9 and 21 wks of age showed no significant change in ONL area after 3 wks. ROS length in these rats increased at a prodigious rate, and in the 12-wk-olds (9 wks at 800 lux, followed by 3 wks at 5 lux), ROS length exceeded that of age-matched rats raised in 5 lux for life.Special issue dedicated to Dr. Frederick E. Samson     

Angiostrongylus cantonensis: apoptosis of inflammatory cells induced by treatment with mebendazole or/and interleukin 12 in mice

Angiostrongylus cantonensis is the major cause of human eosinophilic meningoencephalitis. ICR mice were infected orally with 35 infective larvae and sacrificed at 4-14 days, 25 days or 32 days post infection (dpi) for pathological and immunocytochemical examinations. In the non-treated group, no apoptosis signal was found in the meninges or parenchyma of the brains (4-14 dpi). Only a few apoptotic cells were noticed at 25 dpi (3%) and 32 dpi (10%). In the groups, the animals were given a single dose of mebendazole (20 mg/kg, per os at various times) or injections of interleukin 12 (IL-12) (10 ng/daily, intraperitoneally), all the animals were sacrificed at 14 dpi; the number of apoptotic cells was increased (17-21%). In the group that received a single dose of mebendazole (4 dpi) in combination with IL-12 injections (4-13 dpi), mild meningitis was observed, and most of the infiltrated inflammatory cells were in the apoptotic program (55%). Taken together, apoptosis of the inflammatory cells (most were eosinophils) could be induced when the infected mice were treated with mebendazole or/and IL-12.     

Effect of unilateral ovariectomy and subsequent ovum implantation in mice.

Unilateral ovariectomy (ULO) was done on any stage of the cycle and the animals were mated within day 1 to day 21 to observe the acute and long term effect of ULO on ovum implantation. Implantation reduced in proportion to single ovary if the animals were mated within 24 hr of ULO. Increase in ovarian weight along with an increase in implantation number continued in mated mice and reached at peak on day 19-21 of ULO (sacrificed after 6 days i.e., 25-27 days of ULO). After ULO the remaining ovary compensated within day 5-6 of ULO even during pregnancy. Ovarian histology showed stimulation of small antral follicles in mice mated on day 3 of ULO (sacrificed after 6 days i.e., day 9 of ULO) along with a decrease of large antral follicles and pre-antral follicles. Preantral follicles were at peak on day 12-14. Large antral follicles attained a peak on day 4 which slowly decreased. The occurrence of implantation in such ULO conditions are discussed.     

The high-resolution crystal structure of a parallel intermolecular DNA G-4 quadruplex/drug complex employing syn glycosyl linkages

We have determined the X-ray structure of the complex between the DNA quadruplex d(5′-GGGG-3′)₄ and daunomycin, as a potential model for studying drug–telomere interactions. The structure was solved at 1.08 Å by direct methods in space group I4. The asymmetric unit comprises a linear arrangement of one d(GGGG) strand, four daunomycin molecules, a second d(GGGG) strand facing in the opposite direction to the first, and Na and Mg cations. The crystallographic 4-fold axis generates the biological unit, which is a 12-layered structure comprising two sets of four guanine layers, with four layers each of four daunomycins stacked between the 5′ faces of the two quadruplexes. The daunomycin layers fall into two groups which are novel in their mode of self assembly. The only contacts between daunomycin molecules within any one of these layers are van der Waals interactions, however there is substantial π–π stacking between successive daunomycin layers and also with adjacent guanine layers. The structure differs significantly from all other parallel d(TGGGGT)₄ quadruplexes in that the 5′ guanine adopts the unusual syn glycosyl linkage, refuting the widespread belief that such conformations should all be anti. In contrast to the related d(TGGGGT)/daunomycin complex, there are no ligand–quadruplex groove insertion interactions.     

A novel measuring system for the determination of paramagnetic particle labels for use in magneto-immunoassays

Coated micrometer-sized paramagnetic particles (PMPs) are readily available and widely used in immunoassays, mainly for separation and as a solid phase. We have described in a separate paper a model sandwich assay in which ≈1×10⁵ to 1×10⁶ PMPs (2.8 μm diameter) are immobilised on a plastic strip at the end of the assay. In this paper, we describe the design of an instrument that is capable of determining the number of PMPs on the plastic strip. The paper also describes a method of making standard plastic strips with known numbers of PMPs on them. A strip, when placed in a coil of wire in parallel with a capacitor, causes the resonant frequency of the coil to decrease because of the presence of the PMPs. The decrease in frequency relates directly to the number of PMPs on the strip. A circuit based on a voltage-controlled oscillator and a phase-locked loop is used to accurately measure the resonant frequency of the coil. The instrument is capable of detecting at least 1×10⁵ PMPs immobilised on a plastic strip and has a linear response (r=0.99) for up to at least 3.33×10⁶ PMPs. In terms of the iron content of the PMPs, the detection limit is ≈1.2 μg Fe in the paramagnetic particles and the sensitivity is ≈3 Hz per μg of Fe. The instrument is small and compact and together with a suitable magneto-immunoassay will have many applications, including near-patient monitoring.     

Effect of different durations of exercise on transferrin-bound iron uptake by rat erythroblast

This study evaluated effects of different durations of exercise on transferrin receptor (TfR) expression on the membrane of rat erythroblasts. Female rats were assigned to six groups: 3, 6 and 12 months of strenuous exercise (swimming 2 h/day, 5 days/wk) groups and their corresponding controls. At the end of experiments, the erythroblasts were isolated for Tf binding assay and transferrin-bound iron (Tf-Fe) uptake. Tissue non-heme iron and hematological iron indices were also measured. The TfR number on the cells was about 603,189 plus minus 107,562, 890,150 plus minus 164,849 and 384,695 plus minus 46,295 molecules/cell in three control groups (3, 6, 12 months) respectively. Exercise groups had significantly higher levels of TfR than those of the control groups, being 1,374,137 plus minus 243,677, 2,175,360 plus minus 462,737 and 1,012,759 plus minus 249,423 molecules/cell in 3, 6 and 12 months of exercise groups respectively (p < 0.05). After 30 min of incubation, cellular Tf approached to levels of 8.28 plus minus 1.94, 10.73 plus minus 3.30 and 6.60 plus minus 0.93 fmole/10(6) cells in 3, 6 and 12 months of exercise groups, while the corresponding control values were 3.09 plus minus 0.36, 5.03 plus minus 1.01 and 2.51 plus minus 0.88 fmole/10(6) cells respectively (all P < 0.05). The rates of cellular iron accumulation were 7.07 (3), 8.79 (6) and 5.96 (12 month) fmole/10(6) cells/min in the exercised rats and 2.91, 3.85, and 2.03 fmole/10(6) cells/min in their corresponding controls (all p < 0.05). However, no significant difference was observed in the ratios (Exercise/Corresponding control) of the increased TfR expression, Tf-Fe uptake and Tf endocytosis as well as of the decreased plasma iron and tissue non-heme iron levels induced by different periods of exercise. Furthermore, the increase in the length of exercise (6 or 12 month) did not induce a remarkable decrease in plasma hemoglobin and hematocrit. These results indicate that a true iron deficiency or 'sport anemia' can not develop even if under longer periods (6 or 12 month) of strenuous exercise.     

Retention of nickel oxide (green) aerosol in rat lungs by long-term inhalation

Wistar male rats were exposed to green nickel oxide [NiO(G)] aerosols (mass median aerodynamic diameter, 0.6 μm) for 7 h/d, 5 d/wk for up to 12 mo. The average exposure concentration was controlled at 0.3 mg/m³ and 1.2 mg/m³ during the exposure period. Some rats were sacrificed just after the 3- and 6-mo exposures, and others were sacrificed after the termination of the 12-mo exposure. There were no differences in body weight gain between NiO(G) exposure groups and controls. The lung weights in the exposed rats were heavier than those in the control ones. Nickel concentrations in lungs of exposure groups were much higher than those of controls. The nickel concentrations in liver, kidney, spleen, and blood slightly increased with the passing of the exposure time. The nickel content in rat lungs during the 12-mo exposure was estimated theoretically. The estimated values agreed with the experimental data. This result shows that the clearance rate increases with the decreasing of the particle diameter.     

Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice

Background

Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice.

Methods

Balb/c mice received single-dose urethane (1 g/kg at day 0) and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12), tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96), or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter). In addition, interleukin (IL)-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment.

Results

Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis.

Conclusions

Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.     

Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease

The effect of angiotensin-converting enzyme inhibition on function and structure of the aorta was studied in the Lewis polycystic kidney (LPK) rat model of cystic renal disease and Lewis controls. Pulse-wave velocity (PWV) was recorded under urethane anesthesia (1.3 g/kg ip) in mixed-sex animals aged 6 and 12 wk and in 12-wk-old animals treated with perindopril (3 mg·kg(-1)·day(-1) po) from age 6-12 wk. Tail-cuff systolic pressures were recorded over the treatment period. After PWV measurements, animals were euthanized and the aorta was removed for histomorphological and calcium analysis. Hypertension in LPK at 6 and 12 wk was associated with a shift of the PWV curve upward and to the right, indicating a decrease in aortic compliance, which was significantly reduced by perindopril. LPK demonstrated greater aortic calcification (6 wk: 123 ± 19 vs. 65 ± 7 and 12 wk: 406 ± 6 vs. 67 ± 6 μmol/g, P < 0.001, LPK vs. Lewis, respectively). This was reduced by treatment with perindopril (172 ± 48 μmol/g, 12 wk LPK P < 0.001). Medial cross-sectional area and elastic modulus/wall stress of the aorta were greater in LPK vs. Lewis control animals at 6 and 12 wk of age and showed an age-related increase that was prevented by treatment with perindopril (P < 0.001). Perindopril also ameliorated the degradation of elastin, increase in collagen content, and medial elastocalcinosis seen in 12-wk LPK. Overall, perindopril improved the structural and functional indices of aortic stiffness in the LPK rats, demonstrating a capacity for angiotensin-converting enzyme inhibition to limit vascular remodeling in chronic kidney disease.     

MSCs transplantation with application of G-CSF reduces apoptosis or increases VEGF in rabbit model of myocardial infarction

The purpose of this study was to test whether mesenchymal stem cells (MSCs) transplantation with application of granulocyte colony-stimulating factor (G-CSF) would have beneficial effects on damaged heart in a rabbit model of myocardial infarction (MI). MI was created by ligation of the left anterior descending coronary artery. After induction of MI, 40 New Zealand white rabbits were randomly divided into 8 groups: (1) MSCs injection at 3 days after MI; (2) G-CSF injection at 3 days after MI; (3) MSCs + G-CSF (20 u/kg/day) injection at 3 days after MI; (4) PBS injection at 3 days after MI; (5) MSCs injection at 7 days after MI; (6) G-CSF injection at 7 days after MI; (7) MSCs + G-CSF (20 u/kg/day) injection 7 days after MI; and (8) PBS injection 7 days after MI. TUNEL analysis showed that the apoptotic cells were distributed in the marginal area of MI. In both 3 and 7 days after MI groups, there were less apoptotic cells in the MSCs and MSCs + G-CSF groups as compared with the PBS group (P < 0.05). However, no decrease in apoptosis was observed in the G-CSF only group (P > 0.05). Immunohistochemistry analysis demonstrated that the expression level of vascular endothelial growth factor was higher in the MSCs, MSCs + G-CSF and G-CSF groups as compared with the PBS group. The present study demonstrated a beneficial effect of MSCs transplantation with application of G-CSF in the treatment of rabbit MI.     

Comparison of the effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men

We examined the extent to which supraphysiological doses of androgen can modify body composition and strength in normally virilized men. In doubly blind tests, 30 healthy young men received testosterone enanthate (TE) or 19-nortestosterone decanoate (ND), at 100 mg/wk or 300 mg/wk for 6 weeks. The TE-100 mg/wk group served as replacement dose comparison, maintaining pretreatment serum testosterone levels, while keeping all subjects blinded to treatment, particularly through reduction in testicular volumes. Isokinetic strength measurements were made for the biceps brachii and quadriceps femoris muscle groups before treatment and 2–3 days after the 6th injection. Small improvements were noted in all groups but the changes were highly variable; a trend to greater and more consistent strength gain occured in the TE-300 mg/wk group. There was no change in weight for TE-100 mg/wk but an average gain of 3 kg in each of the other groups. No changes in 4 skinfold thickness or in estimated percent body fat were observed. Of 15 circumferences, significant increases were observed only for men receiving TE-300 mg/wk (shoulders) and ND-300 mg/wk (shoulders and chest). The data suggest that high dose androgens increase body mass and may increase strength in normal men but, except for a consistent weight gain with greater than replacement doses, the detectable changes were highly variable and relatively small, especially in comparison to the significant alterations which were observed for other markers of androgen action.     

Maternal cigarette smoke exposure contributes to glucose intolerance and decreased brain insulin action in mice offspring independent of maternal diet

Background

Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.

Method

Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.

Results

Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.

Conclusion

While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.     

Iron supplementation improves endurance after training in iron-depleted, nonanemic women.

Our objective was to investigate the effects of iron depletion on adaptation to aerobic exercise, assessed by time to complete a 15-km cycle ergometer test. Forty-two iron-depleted (serum ferritin <16 microg/l), nonanemic (Hb >12 g/dl) women (18-33 yr old) received 100 mg of ferrous sulfate (S) or placebo (P) per day for 6 wk in a randomized, double-blind trial. Subjects trained for 30 min/day, 5 days/wk at 75-85% of maximum heart rate for the final 4 wk of the study. There were no group differences in baseline iron status or in 15-km time. Iron supplementation increased serum ferritin and decreased transferrin receptors in the S compared with the P group. The S and P groups decreased 15-km time and respiratory exchange ratio and increased work rate during the 15-km time trial after training. The decrease in 15-km time was greater in the S than in the P group (P = 0.04) and could be partially attributed to increases in serum ferritin and Hb. These results indicate that iron deficiency without anemia impairs favorable adaptation to aerobic exercise.     

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.     

Hyperglycemia compensates for diet-induced insulin resistance in liver and skeletal muscle of rats

High-fat and high-sucrose diets increase the contribution of gluconeogenesis to glucose appearance (glc R(a)) under basal conditions. They also reduce insulin suppression of glc R(a) and insulin-stimulated muscle glycogen synthesis under euglycemic, hyperinsulinemic conditions. The purpose of the present study was to determine whether these impairments influence liver and muscle glycogen synthesis under hyperglycemic, hyperinsulinemic conditions. Male rats were fed a high-sucrose, high-fat, or low-fat, starch control diet for either 1 (n = 5-7/group) or 5 wk (n = 5-6/group). Studies involved two 90-min periods. During the first, a basal period (BP), [6-3H]glucose was infused. In the second, a hyperglycemic period (HP), [6-3H]glucose, [6-14C]glucose, and unlabeled glucose were infused. Plasma glucose (BP: 111.2 +/- 1.5 mg/dl; HP: 172.3 +/- 1.5 mg/dl), insulin (BP: 2.5 +/- 0.2 ng/ml; HP: 4.9 +/- 0.3 ng/ml), and glucagon (BP: 81.8 +/- 1.6 ng/l; HP: 74.0 +/- 1.3 ng/l) concentrations were not significantly different among diet groups or with respect to time on diet. There were no significant differences among groups in the glucose infusion rate (mg x kg(-1) x min(-1)) necessary to maintain arterial glucose concentrations at approximately 170 mg/dl (pooled average: 6.4 +/- 0.8 at 1 wk; 6.4 +/- 0.7 at 5 wk), percent suppression of glc R(a) (44.4 +/- 7.8% at 1 wk; 63.2 +/- 4.3% at 5 wk), tracer-estimated net liver glycogen synthesis (7.8 +/- 1.3 microg x g liver(-1) x min(-1) at 1 wk; 10.5 +/- 2.2 microg x g liver(-1) x min(-1) at 5 wk), indirect pathway glycogen synthesis (3.7 +/- 0.9 microg x g liver(-1) x min(-1) at 1 wk; 3.4 +/- 0.9 microg x g liver(-1) x min(-1) at 5 wk), or tracer-estimated net muscle glycogenesis (1.0 +/- 0.3 microg x g muscle(-1) x min(-1) at 1 wk; 1.6 +/- 0.3 microg x g muscle(-1) x min(-1) at 5 wk). These data suggest that hyperglycemia compensates for diet-induced insulin resistance in both liver and skeletal muscle.