PR Group Research Articles

Ability of ram introduction to induce LH secretion, estrus and ovulation in fall-born ewe lambs during anestrus

The ability of ram introduction (RI) and progesterone pre-treatment to induce increases in LH secretion and ovulation, and the ability of progesterone pre-treatment with or without estrogen to induce estrus and ovulation in fall-born ewe lambs during seasonal anestrus was investigated. In early July, lambs of mixed breeds (41.8±0.6 kg and 250.7±1.3 days of age) were assigned to receive no treatment (C, n=7), to be introduced to rams (7:1 ewe:ram ratio; R, n=7), to be treated with progesterone (a used CIDR device) for 5 days (P, n=5), to be treated with progesterone and introduced to rams at CIDR removal (PR, n=11), or to receive the latter treatment plus an injection of estradiol benzoate (25 μg, E 2β i.m.) 24 h after CIDR withdrawal/RI (PER, n=11). Blood samples were collected from all lambs every 4 h for 60 h beginning at RI/CIDR withdrawal (0 h), to characterize the LH surge profile and in groups R and C every 15 min for 8 h between 12 and 20 h for determination of LH pulse frequencies. Ultrasonographic examinations of the ovaries were conducted at 0, 36 and 60 h. In ram-exposed groups lambs were also observed for raddle marks every 4 h from 0 to 60 h. The LH pulse frequency (pulses/8 h) was higher in group R ( P<0.01; 7.7±0.5) than group C lambs (2.7±0.8). More lambs in groups exposed to rams than in the C or P groups showed an LH surge ( P<0.05; 0, 100, 0, 72.7 and 100%, for C, R, P, PR and PER groups, respectively). Time from RI/CIDR removal to initiation of the LH surge was greater in lambs in the PR (43.5±3.8 h) than in the R (32.6±4.6 h; P=0.08) or PER (33±1.2 h; P<0.01). Diameter of the largest follicle at 0 h (3.2±0.2 mm) was not different among groups. Growth rate of the largest follicle between 0 and 36 h was greater ( P<0.05) in RI than in C or P groups. Diameter of the largest follicle at 36 h was larger ( P<0.05) in lambs in R (5.6±0.2 mm) and PR (5.1±0.5 mm) than C (4.0±0.6 mm) or P (3.8±0.4 mm) groups, and in R than PER (4.3±0.4 mm) treatment groups. Only lambs in the RI groups ovulated. Among RI groups the percentage of lambs ovulating was greater in the R ( P<0.05; 85.7%) than PR (33.3%) groups with an intermediate response observed in lambs in treatment group PER (71.4%). The estrous response in progesterone pre-treated groups was greater ( P<0.05) in lambs also treated with estrogen (PER; 81.8%), than in lambs introduced to rams alone (PR; 45.5%). In conclusion, ram introduction by itself, but not progesterone treatment alone, induces increases in LH pulse frequency, follicular development, and ovulation in fall-born ewe lambs during seasonal anestrus, further, P 4 pre-treatment and RI when combined with E 2 results in a high estrous response.

The mandibular catch-up growth controversy in Pierre Robin sequence.

The purpose of this retrospective longitudinal cephalometric study was to investigate differences in craniofacial and especially mandibular morphology between patients with Pierre Robin sequence and isolated cleft palates. The experimental group comprised 96 patients (54 males and 42 females) with a history of Pierre Robin sequence. This group was compared cephalometrically with a control group of 50 patients (25 males and 25 females) with a history of isolated clefting of the palate. All 96 patients in the PR group had a lateral cephalogram at a mean age of 5.5 years. Thirty-eight of those patients had additional cephalograms at the mean ages of 10.3 years and 16.8 years. All patients in the cleft palate group had 3 corresponding cephalograms at the following mean ages: 5.7 years, 10.6 years, and 17.0 years. Twenty-nine cephalometric measurements were performed on each cephalogram with the use of computerized cephalometric software. Significant differences were identified between the 2 groups, particularly in the size and sagittal position of the mandible, which was consistently shorter in the Pierre Robin group at all 3 ages. Less severe differences were noted in the inclination of the palatal plane, the facial height proportions, and the midface depth. We conclude that patients with Pierre Robin sequence have a significantly smaller mandible as compared with patients with isolated cleft palate, and the difference does not change after the age of 5 years.

Pre-parturition profile of steroids and prostaglandin in cows with or without foetal membrane retention

Retained foetal membranes in cattle is one of the most common complications associated to the reduction in milk yield and impaired fertility in dairy cattle. In order to determine some endocrine mechanisms controlling parturition and delivery of foetal membranes, plasma concentrations of steroids and prostanoids were determined in 20 healthy Holstein cows. Samples were taken within the interval of 5 days pre-parturition to 12 h after calving. Progesterone (P 4) levels were similar in cows with (PR) and without (NPR) placental retention. While the estradiol-17β (E 2) peak at parturition was lower in PR than in NPR cows, cortisol levels were greater in PR cows 12 and 24 h pre-parturition. The Prostaglandin F 2α metabolite (PGFM) levels were higher at parturition in NPR compared with the PR group, but 12 h later, these levels in the PR group increased so that concentrations were greater as compared with NPR cows. The Prostaglandin E 2 metabolite (PGEM), 24, 48 and 72 h pre-parturition, were higher in PR cows. However, the PGFM:PGEM ratio was greater in cows up NPR at all time when included, indicating the importance of higher levels of Prostaglandin F 2α (PGF 2α) than Prostaglandin E 2 (PGE 2) for normal placental delivery. In conclusion, placental retention was related to both estrogen and PGF 2α deficiency, which may be a consequence of metabolic stress leading to PGE 2 and maternal cortisol synthesis before parturition.

99mTc-MIBI SPECT in small cell lung cancer patients before chemotherapy and after unresponsive chemotherapy.

We evaluated the accumulation of 99mTc-MIBI in small cell lung cancer patients before chemotherapy and after unresponsive chemotherapy. The pre-chemotherapeutic group included 22 newly diagnosed patients. These patients underwent a 99mTc-MIBI SPECT study before starting chemotherapy. After chemotherapy, based on changes in tumor size, three different patterns of response (complete remission: CR, partial remission: PR and no change: NC) were defined. The post-chemotherapeutic group included 11 patients after chemotherapy who did not respond to chemotherapy. These patients underwent a 99mTc-MIBI SPECT study after completion of chemotherapy. SPECT images were acquired 15 min (early) and 2 hr (delayed) after injection of 99mTc-MIBI. With a region of interest technique, the early ratio, delayed ratio and retention index were calculated. Early and delayed ratios in pre-chemotherapeutic patients were significantly higher than those in post-chemotherapeutic patients. There were no significant differences between the pre-chemotherapeutic and post-chemotherapeutic patients in the retention index. In the pre-chemotherapeutic patients, early and delayed ratios for the CR and PR groups were significantly higher than those for the NC group. There were no significant differences in the retention index with respect to the tumor response. 99mTc-MIBI might be useful for evaluating the tumor chemosensitivity in patients with small cell lung cancer.

Increase of T 3 secreted through the milk in protein restricted lactating rats

Lactating rats were fed an 8% protein-restricted diet (PR), a 23% protein diet (C), and an energy-restricted pair-fed to PR group (PF). Thyroxine (T 4) and triiodothyronine (T 3) concentrations were analyzed in milk and in the serum of mothers and pups on different days of lactation. Serum T 3 was always higher ( p < 0.01) in PR mothers, while T 4 was lower ( p < 0.05) on days 4 and 21. PR group showed higher T 3 ( p < 0.001) on days 4, 8, and 12, while PF showed higher T 3 in milk ( p < 0.05) on days 12 and 16. In PR pups serum T 3 was higher ( p < 0.05), while T 4 was lower on day 4 and both were lower ( p < 0.05) on day 12. In PF pups T 3 was lower ( p < 0.05) on day 21, and T 4 was lower ( p < 0.01) on day 12. These data suggest a higher transfer of T 3 for the PR pups that could be important for their nervous system development.

Plasma concentrations of estradiol 17β and PGF2α metabolite and placental fatty acid composition and antioxidant enzyme activity in cows with and without retained fetal membranes

Fetal membrane retention is one of the most common problems in Holstein cattle after parturition. To investigate mechanisms involved, the following parameters were studied in the peri-parturition period: plasmatic concentrations of estradiol-17β (E 2) and PGFM (PGF2α metabolite), activity of antioxidant enzymes (superoxide dismutase-SOD, catalase-CAT and glutathione peroxidase-GSH-Px), thiobarbituric acid reagent substances (TBAR) concentrations and fatty acid composition of the placentae. E 2 at parturition in the NPR group (control cows, n = 10) was higher than in PR cows (placental retention, n = 10) (P < 0.05). Activity of SOD in fetal tissue of NPR animals was higher than that of the PR group. In contrast, there was no difference between the two groups in activity of GSH-Px and CAT and the TBAR content of placental tissues. PR maternal tissues had proportionally more arachidonic and linoleic acid than tissues from NPR cows. Therefore, a complex of sequential events may cause placenta retention, starting with an unbalance of antioxidant capacity of the placenta, followed by a decrease in production of estrogen, which leads to the accumulation of arachidonic and linoleic acid in placental tissues.

Restriction of fetal growth has a differential impact on fetal prolactin and prolactin receptor mRNA expression.

Prolactin is present in the fetal circulation and prolactin receptors are expressed in a wide range of fetal tissues. The factors which regulate the synthesis and secretion of prolactin, and the expression of its receptors before birth, are poorly understood. We have investigated whether experimental restriction of placental growth in the sheep has an impact on the prolactin axis in the growth restricted fetus. The majority of uterine endometrial caruncles were removed before pregnancy in 10 ewes (placental restriction; PR group). Placental, fetal liver and kidney weights were reduced in the PR compared to the control group (n = 10). The ratio of fetal prolactin mRNA : 18S rRNA was significantly lower (P < 0.01) in the PR group (1.83 +/- 0.45, n = 6) than in the control group (4.11 +/- 0.54, n = 6). The ratio of prolactin mRNA : 18S rRNA in the fetal pituitary was positively correlated with fetal and with placental weight. Using stepwise linear regression, it was determined that the level of fetal prolactin mRNA : 18S rRNA expression was best described (as judged by the maximum adjusted R2) by prolactin mRNA: 18 S rRNA = - 3.0378 + 0.17 PO2 + 2.772 glucose (adjusted R2 = 0.765, F = 17.53, P < 0.001). Fetal plasma prolactin concentrations were significantly reduced (P < 0.05) in the PR group compared to control animals between 109 and 141 days gestation. Fetal prolactin receptor (PRLR) mRNA transcripts encoding long (PRLR1) and short forms (PRLR2) of PRLR were present in the liver and kidney of animals in the PR and control groups at 140-141 days gestation. PR did not alter the levels of PRLR1 or PRLR2 mRNA in the fetal liver or kidney. The suppression of the synthesis and secretion of prolactin in the growth restricted fetus may limit the action of prolactin on the growth and metabolism of key fetal organs during suboptimal intrauterine conditions

Restriction of Fetal Growth has a Differential Impact on Fetal Prolactin and Prolactin Receptor mRNA Expression

AbstractProlactin is present in the fetal circulation and prolactin receptors are expressed in a wide range of fetal tissues. The factors which regulate the synthesis and secretion of prolactin, and the expression of its receptors before birth, are poorly understood. We have investigated whether experimental restriction of placental growth in the sheep has an impact on the prolactin axis in the growth restricted fetus. The majority of uterine endometrial caruncles were removed before pregnancy in 10 ewes (placental restriction; PR group). Placental, fetal liver and kidney weights were reduced in the PR compared to the control group (n = 10). The ratio of fetal prolactin mRNA : 18S rRNA was significantly lower (P &lt; 0.01) in the PR group (1.83 ± 0.45, n = 6) than in the control group (4.11 ± 0.54, n = 6). The ratio of prolactin mRNA : 18S rRNA in the fetal pituitary was positively correlated with fetal and with placental weight. Using stepwise linear regression, it was determined that the level of fetal prolactin mRNA : 18S rRNA expression was best described (as judged by the maximum adjusted R2) by prolactin mRNA: 18 S rRNA = − 3.0378 + 0.17 PO2 + 2.772 glucose (adjusted R2 = 0.765, F = 17.53, P &lt; 0.001). Fetal plasma prolactin concentrations were significantly reduced (P &lt; 0.05) in the PR group compared to control animals between 109 and 141 days gestation. Fetal prolactin receptor (PRLR) mRNA transcripts encoding long (PRLR1) and short forms (PRLR2) of PRLR were present in the liver and kidney of animals in the PR and control groups at 140–141 days gestation. PR did not alter the levels of PRLR1 or PRLR2 mRNA in the fetal liver or kidney. The suppression of the synthesis and secretion of prolactin in the growth restricted fetus may limit the action of prolactin on the growth and metabolism of key fetal organs during suboptimal intrauterine conditions

Impact of the initial doses of rocuronium and pancuronium on subsequent maintenance for neuromuscular block

To determine the impact of the neuromuscular blocking agent given for intubation on the duration of effect of multiple maintenance doses of pancuronium and rocuronium. Seventy-eight subjects were randomly assigned to receive one of four dosing combinations for intubation and neuromuscular maintenance: rocuronium for intubation and maintenance, rocuronium for intubation and pancuronium for maintenance, pancuronium for intubation and rocuronium for maintenance, or pancuronium for both. Each time that the first twitch response returned to 25% of the baseline value, the duration of the dose was determined and another maintenance dose was administered. The duration of action of the maintenance doses was compared between the groups. Twitch suppression from the first maintenance dose was shorter for subjects who received rocuronium for both doses (Group RR) compared with that for subjects that received pancuronium (Groups PR & PP) as their intubation dose (17.6 vs 34 & 59.8 min, respectively, P < 0.05). Subjects who received rocuronium followed by pancuronium (Group RP) showed a shorter duration of twitch suppression after the first maintenance dose than the group that received pancuronium for both doses (Group PP) (21.3 vs 59.8 min, P < 0.05). By the third maintenance dose, the influence of the intubating dose on the maintenance dose duration had essentially diminished. For combinations of rocuronium and pancuronium, the duration of twitch suppression after a maintenance dose is only dependent on the first agent given for the first two maintenance doses administered.

Short and long term effects of malnutrition in rats during lactation on the body weight of offspring

Epidemiological data suggests that mother nutritional condition can influence offspring body weight by means of metabolic imprinting. However, there are few experimental reports relating mother nutritional condition during lactation to offspring body weight in adulthood. The short and long term effects of maternal protein or energy malnutrition during lactation on offspring body weight were determined using lactating rats fed a 8% protein-restricted diet (PR), a control 23% protein diet (C), and an energy-restricted pair-fed to PR group (PF). Milk was analyzed for protein, lipid and lactose concentrations on days 4, 8, 12, 16 and 21 after birth. After weaning all animals received a normal diet and body weight was monitored until day 180 of age PR group had a lower (p< 0.01) milk protein concentration on day 12 and 21. PF group presented a higher (p<0.01) milk lipid concentration from day 12, and a higher (p<0.01) protein concentration from day 16, both until weaning. Total milk energy was always lower (p<0.001) in the PR group. During lactation, pups in the PR and PF groups had lower body weight (p<0.001), but after weaning body weight in the PF group surpassed that of controls on day 80 (p<0.05), while that of the PR group remained lower (p<0.05) until day 180. These results support epidemiological evidence in humans suggesting that body weight in adulthood may depend on maternal nutritional condition during gestation and/or lactation and that milk composition is a critical factor for this metabolic imprinting.

Perception and recognition memory in monkeys following lesions of area TE and perirhinal cortex.

Monkeys with lesions of perirhinal cortex (PR group) and monkeys with lesions of inferotemporal cortical area TE (TE group) were tested on a modified version of the delayed nonmatching to sample (DNMS) task that included very short delay intervals (0.5 sec) as well as longer delay intervals (1 min and 10 min). Lesions of the perirhinal cortex and lesions of area TE produced different patterns of impairment. The PR group learned the DNMS task as quickly as normal monkeys (N) when the delay between sample and choice was very short (0.5 sec). However, performance of the PR group, unlike that of the N group, fell to chance levels when the delay between sample and choice was lengthened to 10 min. In contrast to the PR group, the TE group was markedly impaired on the DNMS task even at the 0.5-sec delay, and three of four monkeys with TE lesions failed to acquire the task. The results provide support for the idea that perirhinal cortex is important not for perceptual processing, but for the formation and maintenance of long-term memory. Area TE is important for the perceptual processing of visual stimuli.

Inhibition of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production suppressed the intimal hyperplasia caused by poor-runoff conditions in the rabbit autologous vein grafts.

The efficacy of OPC-29030, a newly developed inhibitor of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production, was evaluated on intimal hyperplasia of experimental autologous vein grafts in a distal poor-runoff model and a hyperlipidemic model in rabbits. First, rabbits were divided into two groups, the distal poor-runoff group (PR group) and the hyperlipidemic group (HL group). After 4 weeks preparing the PR model and the HL model, the femoral vein was implanted into the ipsilateral femoral artery. Then they were subdivided into two groups, depending on the diet provided; diet group with 0.1% OPC-29030 (OPC-29030 group) and normal diet group (control group). At 4 weeks, the grafts were harvested, and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation at 2 weeks after surgery. In addition, the effect of OPC-29030 on the proliferation or migration of rat aortic smooth muscle cells in culture was investigated. In the in vivo study in the PR group, the intimal hyperplasia and the plasma 12-HETE levels in the OPC-29030 group were significantly inhibited, compared with those of the control group. However, in the HL group, the intimal hyperplasia in both the OPC-29030 and control groups showed a remarkable degree of intimal hyperplasia. There was no significant difference between those two groups. Furthermore, there was no significant difference in the plasma 12-HETE levels in the HL group irrespective of the presence of OPC-29030. The BrdU labeling index at 2 weeks after grafting was significantly lower in the OPC-29030 group compared with that in the control group in the PR group. In the in vitro study, OPC-29030 did not inhibit smooth muscle cell proliferation; however, OPC-29030 inhibited the migration. These results demonstrate the efficacy of OPC-29030 in reducing the degree of intimal hyperplasia under PR conditions, but not under hyperlipidemic conditions. The mechanism of reducing the intimal hyperplasia may be that OPC-29030 inhibited 12-HETE production, which did not inhibit proliferation while inhibiting migration of the smooth muscle cell. These results suggested the possible involvement of 12-HETE with the intimal hyperplasia under PR conditions.

Perception and Recognition Memory in Monkeys Following Lesions of Area TE and Perirhinal Cortex

Monkeys with lesions of perirhinal cortex (PR group) and monkeys with lesions of inferotemporal cortical area TE (TE group) were tested on a modified version of the delayed nonmatching to sample (DNMS) task that included very short delay intervals (0.5 sec) as well as longer delay intervals (1 min and 10 min). Lesions of the perirhinal cortex and lesions of area TE produced different patterns of impairment. The PR group learned the DNMS task as quickly as normal monkeys (N) when the delay between sample and choice was very short (0.5 sec). However, performance of the PR group, unlike that of the N group, fell to chance levels when the delay between sample and choice was lengthened to 10 min. In contrast to the PR group, the TE group was markedly impaired on the DNMS task even at the 0.5-sec delay, and three of four monkeys with TE lesions failed to acquire the task. The results provide support for the idea that perirhinal cortex is important not for perceptual processing, but for the formation and maintenance of long-term memory. Area TE is important for the perceptual processing of visual stimuli.

Low-protein diet changes thyroid function in lactating rats.

Lactating rats were fed with free access to an 8% protein-restricted diet (PR); the control group was fed a 23% protein diet (C). An energy-restricted (pair-fed) group was given the same food as the animals in the control group, but the amounts of food consumed by both PF and PR were about the same. The body weight and serum albumin concentration of PR and PF dams were significantly (P < 0. 05) lower than that of the controls. The PR group had a significant increase in serum-free triiodothyronine (FT3) concentration, 24-hr mammary gland and milk radioiodine (I131) uptake (67%, 278%, and 200%, respectively) as compared with the controls. On the other hand, those animals had a significantly lower serum-free thyroxine (FT4) concentration and 2- and 24-hr thyroid I131 uptake (67%, 64%, and 74%, respectively). Protein malnutrition during lactation did not alter thyroid or liver 5'-deiodinase activity significantly. However, PF dams had a significantly lower (25%) thyroid 5'-deiodinase activity. These data suggest that protein-restricted lactating dams had an adaptive change in the thyroid function, which could be important to increase the transference of iodine or triiodothyronine through the milk to their pups and prevent sequelae of neonatal hypothyroidism.

Metabolic response during sport rock climbing and the effects of active versus passive recovery.

The objectives of this study were to 1) continuously assess oxygen uptake during and after difficult sport rock climbing and 2) to evaluate the effects of active versus passive recovery on post-climbing blood lactate and hand grip strength. Fifteen expert rock climbers attempted to climb (i.e., red point lead) a 20 m difficult route (5.12 b, YDS scale) set on an indoor climbing wall. Subjects were assigned to either active recovery (AR; n = 8), consisting of recumbent cycling at 25 Watts, or passive recovery (PR; n = 7). Expired air was analyzed during climbing and through a 10-minute recovery period by a lightweight battery-powered open circuit system. Oxygen uptake (VO2) and heart rate (HR) were measured continuously and averaged over 20-second intervals. These data were expressed as averages over the entire climb (VO2avg and HRavg) and as peak values. An estimated resting VO2 of 250 ml x min(-1) was subtracted from the interval VO2 values to provide net VO2 data which were subsequently converted to absolute VO2 values in liters for climbing (C - VO2net) and recovery (R - VO2net). Total net VO2 was calculated as the sum of C - VO2net plus R - VO2net. Blood samples were obtained via fingerprick at pre-climb and at 1-, 10-, 20-, and 30-minutes post-climb and analyzed for whole blood lactate. Handgrip strength was measured via dynamometry at pre-climb and at 1-, 10-, 20-, and 30-minutes post-climb. Mean climbing time was 2.57 +/- 0.41 min. During climbing, VO2avg and HRavg means were 1660 +/- 340 ml x min(-1) and 148 +/- 16 b x min(-1) respectively with mean peaks of 2147 +/- 413 ml x min(-1) and 162 +/- 17 b x min(-1). Relative VO2avg was 24.7 +/- 4.3 ml x kg(-1) x min(-1) with a mean peak value of 31.9 +/- 5.3 ml x kg(-1) x min(-1). Mean values for C - VO2net and R - VO2net were 4.009 +/- 0.929 L and 2.809 +/- 0.518 L respectively for the PR group with mean total net VO2 at 6.818 +/- 1.291 L. For the AR group mean values for C - VO2net and R - VO2net were 4.216 +/- 1.174 L and 7.691 +/- 3.154 L respectively with a mean total net VO2 of 11.906 +/- 4.172 L. There was no difference between the groups for C - VO2net, however R - VO2net and total net VO2 were significantly different (p < 0.05) between PR and AR. Blood lactate increased significantly with climbing in both AR and PR groups. Lactate remained elevated in the PR group until 30 minutes post-climb, but had returned to pre-climb level by 20 minutes in the AR group. Handgrip strength was significantly decreased at 1-minute post-climb for the AR group, but was not significantly changed for the PR group. Although climbers may be able to attain a plateau in VO2, the observed accumulation of lactate in the blood combined with the elevated recovery VO2 indicate a higher overall energy demand than indicated via the recorded VO2 during climbing. Low intensity active recovery appears to significantly reduce accumulated blood lactate within 20 minutes following difficult climbing, however further research is required to establish whether this strategy is advantageous for subsequent climbing performance.

Long-term Effects of Outpatient Rehabilitation of COPD: A Randomized Trial

To examine the short- and long-term effects of an outpatient pulmonary rehabilitation program for COPD patients on dyspnea, exercise, health-related quality of life, and hospitalization rate. Secondary-care respiratory clinic in Barcelona. We conducted a randomized controlled trial with blinding of outcome assessment and follow-up at 3, 6, 9, 12, 18, and 24 months. Sixty patients with moderate to severe COPD (age 65 +/- 7 years; FEV(1) 35 +/- 14%) were recruited. Thirty patients randomized to rehabilitation received 3 months of outpatient breathing retraining and chest physiotherapy, 3 months of daily supervised exercise, and 6 months of weekly supervised breathing exercises. Thirty patients randomized to the control group received standard care. We found significant differences between groups in perception of dyspnea (p < 0.0001), in 6-min walking test distance (p < 0.0001), and in day-to-day dyspnea, fatigue, and emotional function measured by the Chronic Respiratory Questionnaire (p < 0. 01). The improvements were evident at the third month and continued with somewhat diminished magnitude in the second year of follow-up. The PR group experienced a significant (p < 0.0001) reduction in exacerbations, but not the number of hospitalizations. The number of patients needed to treat to achieve significant benefit in health-related quality of life for a 2-year period was approximately three. Outpatient rehabilitation programs can achieve worthwhile benefits that persist for a period of 2 years.

Nutritional Status Affects Intestinal Carotene Cleavage Activity and Carotene Conversion to Vitamin A in Rats

Validation of an in vivo method we developed recently and its application to assess the role of dietary factors in carotene conversion were tested in rats. We compared the ratio of area under plasma vitamin A time-curves (AUC(0-12h)) obtained after a dose of beta-carotene to that after a dose of vitamin A, with the in vitro intestinal supernatant beta-carotene dioxygenase activity. In separate experiments, vitamin A (AD) and protein deficiencies (PD) were produced in male WNIN weanling rats. Corresponding food-restricted (AR and PR) and unrestricted rats (AA and PA) served as controls. Three rats in each of the AD, AR and AA groups received oral doses of 50-300 microgram beta-carotene or 25-150 microgram vitamin A and four rats in each of the PD, PR and PA groups received only 100 microg beta-carotene or vitamin A. The plasma vitamin A AUC(0-12h) with beta-carotene or vitamin A were significantly and positively correlated (r = 0.714-0.918, n = 9-12, P < 0.05) with the dose in AD, AR and AA groups. The AUC(0-12h) slope ratios in AD, AR and AA rats were 0.33, 0.20 and 0.26, respectively. The beta-carotene dioxygenase activity (pmol retinal. h(-1). mg protein(-1)) was significantly higher in the AD group (14.9 +/- 2.43) compared to both AR (6.7 +/- 0.62) and AA (6.3 +/- 1.37) groups and was parallel with in vivo conversion of beta-carotene to vitamin A. The AUC(0-12h) ratio was lower in PD rats (0.13) compared to PR (0.26) and PA (0.5) groups. Similarly, the in vitro enzyme activity (pmol retinal. h(-1). mg protein(-1)) in PD rats was significantly lower (3.6 +/- 1.30) compared to PR (13.7 +/- 0.92) and PA groups (13.8 +/- 1.6). Thus the results validate the methodology and confirm the role of nutritional factors in carotene conversion to vitamin A.

Impact of Restriction of Placental and Fetal Growth on Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 and Type 2 Messenger Ribonucleic Acid in the Liver, Kidney, and Adrenal of the Sheep Fetus1

We have investigated the effects of fetal growth restriction, induced by restriction of placental growth and function (PR), on 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD-1) and 11betaHSD-2 messenger RNA (mRNA) expression in fetal tissues in the sheep, using Northern blot analysis. Fetal liver, kidney, and adrenals were collected from normally grown fetuses at 90 days (n = 6), 125 days (n = 6), and 141-145 days (n = 7) and from PR fetuses at 141-145 days (n = 6). Expression of 11betaHSD-1 mRNA in the fetal liver increased significantly between 125 days (7.4+/-0.8) and 141-145 days gestation (27+/-5.3). There was also an approximately 2-fold increase in the ratio of 11betaHSD-1 mRNA/18S rRNA expression in the PR group (53.8+/-7.9) compared with that in control animals at 141-145 days gestation. There was a significant decrease in 11betaHSD-2 mRNA in fetal adrenals between 125 days (41.6+/-2.4) and 141-145 days (26.7+/-1.1) gestation, but there was no effect of PR on the expression of adrenal 11betaHSD-2 mRNA. 11betaHSD-2 mRNA expression in the fetal kidney increased between 90 days (16.8+/-1.7) and 141-145 days gestation (31.7+/-4.3), but there was no effect of PR on the levels of 11betaHSD-2 mRNA in the fetal kidney. In summary, 11betaHSD-2 mRNA is differentially regulated in the fetal adrenal and kidney in the sheep fetus during late gestation. There is also a specific increase in the expression of 11betaHSD-1 mRNA in the liver of growth-restricted fetuses in late gestation. This suggests that there is increased hepatic exposure to cortisol in the growth-restricted fetus, which may be important in the reprogramming of hepatic physiology that occurs after growth restriction in utero.

Differential effects of placental restriction on IGF-II, ACTH receptor and steroidogenic enzyme mRNA levels in the foetal sheep adrenal.

We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for Insulin-like Growth Factor II (IGF-II), the IGF binding protein IGFBP-2, Steroidogenic Factor 1 (SF-1) and adrenocorticotrophic hormone (ACTH) receptor (ACTH-R) and the steroidogenic cytochrome P-450 enzymes: cholesterol side chain cleavage (CYP11A1), 17alpha-hydroxylase (CYP17) and 21-hydroxylase (CYP21A1); and 3beta-hydroxysteroid dehydrogenase/Delta5Delta4 isomerase (3betaHSD). Endometrial caruncles were removed from non-pregnant ewes before mating (placental restriction group; PR). The total adrenal: foetal weight ratio was higher in PR (n=6 foetuses) than in control foetuses (n=6 foetuses). There was no difference in plasma ACTH concentrations between the PR and control foetuses between 130 and 140 days gestation. Adrenal IGF-II mRNA levels were lower (P<0.05) in the PR group, however, adrenal IGFBP-2 mRNA levels were not different between the PR and control groups. Adrenal ACTH-R mRNA levels were also lower whilst CYP11A1 mRNA levels were increased (P<0.005) in the PR group. We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ACTH are important in foetal adrenal activation during chronic, sustained hypoxaemia.

The natural history of multiple sclerosis: a geographically based study. 7. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation.

Classifications of multiple sclerosis subtypes have been largely based on clinical phenomenology. Nevertheless, definitions of relapse, remission and progression have been imprecise. Recently an international consensus group, as part of a reclassification of disease subtypes, recommended dropping the term 'relapsing-progressive' (RP) and retaining the term 'progressive-relapsing' (PR) multiple sclerosis. The term 'RP' multiple sclerosis had been applied when the early course combined both relapses and progression and was believed to identify some patients with a worse than average outcome. The PR group consisted of patients with primary progressive disease who later in their course developed relapses. Since the terminology has been largely arbitrary, we have evaluated the validity of the terms 'RP' and 'PR' multiple sclerosis in the context of long-term outcome within a large population-based cohort of progressive multiple sclerosis patients seen at the London Multiple Sclerosis Clinic (Canada) between 1972 and 1984. Mean follow-up of the entire cohort was 25 years. Designation of RP multiple sclerosis did identify a more rapidly progressive subgroup. To realign these natural history data with consensus recommendations, these patients were reassigned to secondary progressive (SP) or to primary progressive (PP) multiple sclerosis, with progression defined as at least 1 year of progressive deterioration. PP multiple sclerosis patients with relapses after a year were designated as having PR multiple sclerosis. Relapses in primary progressive multiple sclerosis occurred in 27.8% of patients at some point even two to three decades after onset. In general these relapses were mild and remitting, but served to blur the distinction between progressive and relapsing-remitting disease. The long-term outcomes of time to Kurtzke disability scores (DSS) of 3, 6, 8 and 10 were compared among the progressive subtypes. Times to these disability end-points and to death were not different between PR and PP multiple sclerosis. Survival curves for progressive patients have been amended to incorporate the reassignment of PR multiple sclerosis patients into the PP group and the RP multiple sclerosis patients into the PP and SP subgroups. The time to reach DDS 3, 6, 8 and 10 for a population-based cohort of primary and secondary progressive patients resulting from the elimination of the categories of RP multiple sclerosis and PR multiple sclerosis has been established. These results provide justification for retaining only PP and SP multiple sclerosis as the subgroups of progressive disease.