A walking program for people with severe knee osteoarthritis did not reduce pain but may have benefits for cardiovascular health: a phase II randomised controlled trial.

OBJECTIVE: The primary aim was to evaluate the effect of a dosed walking program on knee pain for patients with severe knee osteoarthritis (OA). Secondary aims evaluated the effects on cardiovascular health, function and quality of life. DESIGN: Participants with severe knee OA and increased cardiovascular risk were randomly assigned to a 12-week walking program of 70 min/week of at least moderate intensity, or to usual care. The primary outcome was knee pain (0-10). Secondary outcomes were of cardiovascular risk including physical activity, blood pressure, blood lipid and glucose levels, body mass index and waist circumference; WOMAC Index scores; physical function; and quality of life. RESULTS: Forty-six participants (23 each group) were recruited. Sixteen participants (70%) adhered to the walking program. Intention to treat analysis showed no between-group difference in knee pain. The walking group had increased odds of achieving a healthy systolic blood pressure (OR = 5.7, 95% CI 1.2-26.9), and a faster walking speed (Mean Difference (MD) = 0.12 m/s, 95% CI 0.02-0.23). Per protocol analysis based on participant adherence showed the walking group had more daily steps (MD = 1345 steps, 95% CI 365-2325); more time walking (MD = 18 min/day, 95% CI 5-31); reduced waist circumference (MD = -5.3 cm, 95% CI -10.5 to -0.03); and increased knee stiffness (MD = 0.9 units, 95% CI 0.07-1.8). CONCLUSIONS: Patients with severe knee OA prescribed a 12-week walking program of 70 min/week may have had cardiovascular benefits without decreasing knee pain. Australian New Zealand Clinical Trials Registry ACTRN12615000015549.

Microphysical explanation of the RH-dependent water affinity of biogenic organic aerosol and its importance for climate.

A large fraction of atmospheric organic aerosol (OA) originates from natural emissions that are oxidized in the atmosphere to form secondary organic aerosol (SOA). Isoprene (IP) and monoterpenes (MT) are the most important precursors of SOA originating from forests. The climate impacts from OA are currently estimated through parameterizations of water uptake that drastically simplify the complexity of OA. We combine laboratory experiments, thermodynamic modeling, field observations, and climate modeling to (1) explain the molecular mechanisms behind RH-dependent SOA water-uptake with solubility and phase separation; (2) show that laboratory data on IP- and MT-SOA hygroscopicity are representative of ambient data with corresponding OA source profiles; and (3) demonstrate the sensitivity of the modeled aerosol climate effect to assumed OA water affinity. We conclude that the commonly used single-parameter hygroscopicity framework can introduce significant error when quantifying the climate effects of organic aerosol. The results highlight the need for better constraints on the overall global OA mass loadings and its molecular composition, including currently underexplored anthropogenic and marine OA sources.

The maximum tolerated dose of walking for people with severe osteoarthritis of the knee: a phase I trial.

OBJECTIVE: To determine how much physical activity, in the form of walking, can be safely and feasibly tolerated for people with severe knee osteoarthritis (OA). DESIGN: Phase I dose response trial with escalating walking doses of 10, 20, 35, 50, 70, and 95 min over 1 week, were prescribed non-randomly to people with severe knee OA. The primary stopping rule was a substantial increase in knee pain. The primary outcomes were an estimation of the maximum tolerated dose of walking; and the proportion of people who did not complete the dose for feasibility reasons. The secondary outcomes were pain, stiffness and activity limitation Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Twenty-four participants (13 women) aged 53-83 years, and average body mass index (BMI) of 34 kg/m(2) (SD 9) were recruited. Three participants were assigned to each dose between 10 and 70 min, and nine participants assigned to the 95-min dose. The trial was stopped at 95 min due to the maximum number of adverse events occurring at this dose. Therefore, the maximum tolerated dose was 70 min. No participant stopped due to reasons related to feasibility. There was a moderate association between dose and increased activity (linear R(2) = 0.31, cubic R(2) = 0.69) and reduced stiffness (linear R(2) = 0.20, cubic R(2) = 0.52), with increased benefits at moderate to higher doses. CONCLUSIONS: There is preliminary evidence that 70 min per week of moderate intensity supervised walking was safe and feasible for people with severe OA of the knee; for higher doses there was a risk of exacerbating knee pain levels.

What proportion of people with hip and knee osteoarthritis meet physical activity guidelines? A systematic review and meta-analysis.

OBJECTIVE: To determine the proportion of people with hip and knee osteoarthritis that meet physical activity guidelines recommended for adults and older adults. METHOD: Systematic review with meta-analysis of studies measuring physical activity of participants with hip and knee osteoarthritis using an activity monitor. Physical activity levels were calculated using the mean average [95% confidence interval (CI)] weighted according to sample size. Meta-analyses determined the proportion of people meeting physical activity guidelines and recommendations of (1) ≥150 min per week of moderate to vigorous physical activity (MVPA) in bouts of ≥10 min; (2) ≥150 min per week of MVPA in absence of bouts; (3) ≥10,000 steps per day and ≥7000 steps per day. The Grades of Research, Assessment, Development and Evaluation (GRADE) approach was used to determine the quality of the evidence. RESULTS: For knee osteoarthritis, 21 studies involving 3266 participants averaged 50 min per week (95% CI = 46, 55) of MVPA when measured in bouts of ≥10 min, 131 min per week (95% CI = 125, 137) of MVPA, and 7753 daily steps (95% CI = 7582, 7924). Proportion meta-analyses provided high quality evidence that 13% (95% CI = 7, 20) completed ≥150 min per week of MVPA in bouts of ≥10 min, low quality evidence that 41% (95% CI = 23, 61) completed ≥150 min per week of MVPA in absence of bouts, moderate quality evidence that 19% (95% CI = 8, 33) completed ≥10,000 steps per day, and low quality evidence that 48% (95% CI = 31, 65) completed ≥7000 steps per day. For hip osteoarthritis, 11 studies involving 325 participants averaged 160 min per week (95% CI = 114, 216) of MVPA when measured in bouts of ≥10 min, 189 min per week (95% CI = 166, 212) of MVPA, and 8174 daily steps (95% CI = 7670, 8678). Proportion meta-analyses provided low quality evidence that 58% (95% CI = 18, 92) completed ≥150 min per week of MVPA in absence of bouts, low quality evidence that 30% (95% CI = 13, 50) completed ≥10,000 steps per day, and low quality evidence that 60% (95% CI = 47, 73) completed ≥7000 steps per day. CONCLUSION: A small to moderate proportion of people with knee and hip osteoarthritis met physical activity guidelines and recommended daily steps. Future research should establish the effects of increasing physical activity in this population to meet the current physical activity guidelines.

Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.

BACKGROUND: Few high-quality trials have examined the effects of progressive resistance training (PRT) on people with multiple sclerosis (MS). OBJECTIVE: To determine the effectiveness of PRT for people with MS, focusing on improving the gait deficits common in this population. METHODS: Using a single blind randomized controlled trial, people with relapsing-remitting MS were randomly allocated to either a PRT program targeting the lower limb muscles twice a week for 10 weeks (n = 36), or usual care plus an attention and social program conducted once a week for 10 weeks (n = 35). Outcomes were recorded at baseline, week 10 and week 22. RESULTS: Participants attended 92% of training sessions, with no serious adverse events. At 10 weeks, no differences were detected in walking performance. However, compared with the comparison group PRT demonstrated increased leg press strength (16.8%, SD 4.5), increased reverse leg press strength (29.8%, SD 12.7), and increased muscle endurance of the reverse leg press (38.7%, SD 32.8). Improvements in favor of PRT were also found for physical fatigue (Mean difference -3.9 units, 95%CI -6.6 to -1.3), and the physical health domain of quality of life (Mean difference 1.5 units, 95%CI 0.1 to 2.9). At week 22 almost no between-group differences remained. CONCLUSION: PRT is a relatively safe intervention that can have short-term effects on reducing physical fatigue, increasing muscle endurance and can lead to small improvements in muscle strength and quality of life in people with relapsing-remitting MS. However, no improvements in walking performance were observed and benefits do not appear to persist if training is completely stopped.

Many physiotherapists lack preparedness to prescribe physical activity and exercise to people with musculoskeletal pain: A multi-national survey.

OBJECTIVES: Determine physiotherapists' (i) awareness of physical activity, and exercise prescription guidelines; (ii) perceived role, knowledge, confidence, skills and training in prescribing and progressing aerobic exercise and resistance training to people with musculoskeletal pain; (iii) professional development preferences; and (iv) perceived influences of external factors on exercise prescription for people with musculoskeletal pain. DESIGN: Multi-national cross-sectional survey. METHODS: An open online survey was developed specifically for this study. RESULTS: 1,352 physiotherapists from 56 countries participated. The majority of respondents correctly stated physical activity guidelines for adults (60%) and children (53%), but only 37% correctly stated guidelines for older adults. Eleven percent and 16% could name an accepted guideline for aerobic exercise and resistance training, respectively. Most agreed their role included prescribing aerobic exercise (75%) and resistance training (89%). Fewer reported they had the confidence, training or skills to prescribe aerobic exercise (38-50%) and resistance training (49-70%). Workshops were the most preferred (44%) professional development option. Most respondents believed appointment scheduling and access to equipment and professional development (62-79%) affected their ability to prescribe effective exercise. CONCLUSION: Many physiotherapists lack knowledge and training to provide physical activity advice, and to prescribe aerobic exercise and resistance training to people with musculoskeletal pain.

Identifying facilitators and barriers to physical activity for adults with Down syndrome.

BACKGROUND: Adults with Down syndrome are typically sedentary, and many do not participate in the recommended levels of physical activity per week. The aim of this study was to identify the facilitators and barriers to physical activity for this group. METHOD: Semi-structured interviews were conducted to elicit the views of adults with Down syndrome and their support people about what factors facilitate physical activity and what factors are barriers to activity. A sample of 18 participants (3 men, 15 women) was recruited through two agencies providing services for adults with disabilities; six participants were adults with Down syndrome and 12 participants were support people (four were parents of adults with Down syndrome and eight participants were employed by day programmes attended by the adults with Down syndrome). The interviews were recorded, transcribed verbatim and independently coded by two researchers. RESULTS: Three themes around facilitators to physical activity were identified: (1) support from others; (2) that the physical activity was fun or had an interesting purpose; and (3) routine and familiarity. Three themes around barriers were also identified: (1) lack of support; (2) not wanting to engage in physical activity; and (3) medical and physiological factors. CONCLUSIONS: The results suggest that support people play a key role, both as facilitators and barriers, in the participation by adults with Down syndrome in physical activity. Many of the barriers and facilitators of activity for adults with Down syndrome indentified are similar to those reported for adults without impairment. Our findings are also consistent with established theories in the field of health behaviour change.

Psychosocial predictors of failure to return to work in non-chronic non-specific low back pain: a systematic review.

OBJECTIVES: To identify psychosocial predictors of failure to return to work in non-chronic (lasting less than 3 months) non-specific low back pain (NSLBP). METHODS: A systematic review of prognostic studies was carried out. Medline, Embase, PsychINFO, CINAHL and PEDro electronic bibliographic databases up to April 2006 were searched. Included studies took baseline measures in the non-chronic phase of NSLBP (ie, within 3 months of onset), included at least one psychosocial variable and studied a sample in which at least 75% of participants had NSLBP. Baseline measures had to be used to predict at least one work-specific outcome. RESULTS: The search identified 24 studies meeting the inclusion criteria. From these studies there is strong evidence that recovery expectation is predictive of work outcome and that depression, job satisfaction and stress/psychological strain are not predictive of work outcome. There is moderate evidence that fear avoidance beliefs are predictive of work outcome and that anxiety is not predictive of work outcome. There is insufficient evidence to determine whether compensation or locus of control are predictive of work outcome. CONCLUSIONS: To predict work outcome in non-chronic NSLBP, psychosocial assessment should focus on recovery expectation and fear avoidance. More research is needed to determine the best method of measuring these constructs and to determine how to intervene when a worker has low recovery expectations.

A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase/17,20-lyase deficiency.

CONTEXT: Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Novel single amino acid changes in P450c17 provide potentially important insights into key structural domains for enzyme function. OBJECTIVE, DESIGN, AND SETTING: We report a novel missense mutation in P450c17 in a 17-yr-old female presenting with a malignant mixed germ cell tumor with yolk sac elements who demonstrated clinical and biochemical features of combined 17alpha-hydroxylase/17,20-lyase deficiency. METHODS: Quantitative urinary steroid analysis was performed by high resolution gas chromatography. All eight coding exons of CYP17 were PCR amplified and sequenced. The position of arginine at codon 96 was modeled using the CYP17 structure 2c17 (www.rcsb.org). The CYP17 genes were subcloned into pcDNA3, expressed in HEK-293 cells, and chromatographed. PATIENT AND RESULTS: 17alpha-Hydroxylase deficiency was confirmed by marked reductions in urinary and serum cortisol, androgens, and estradiol. Mutational analysis revealed a novel homozygous R96Q missense mutation in P450c17, affecting an amino acid in a key substrate-binding region of the enzyme, leading to complete inactivity. CONCLUSION: The description of a second missense mutation at codon 96 (R96W and R96Q) in the substrate-binding region of P450c17 provides strong evidence for the key role of this amino acid in 17alpha-hydroxylase/17,20-lyase function. An association between a malignant germ cell tumor and 17alpha-hydroxylase deficiency has not been reported previously, although the presence of gonadoblastoma in the ovary of a patient with this condition has recently been described.

Investigation into possible causes of interference in serum testosterone measurement in women.

BACKGROUND: Direct (non-extracted) testosterone immunoassays may give spuriously high results in women. The presumed interferents may be removed if testosterone is extracted into an organic phase before being measured. We aimed to clarify possible causes and effects of interference in testosterone measurement in women. METHODS: Women who had a blood sample referred to Hope Hospital Clinical Biochemistry laboratory for measurement of serum testosterone concentration over a six-month period were studied. Clinical and treatment data were recorded. A difference (direct-minus-extracted testosterone) of less than 1.0 nmol/L was used to define a group with low interference. A difference of 2.5 nmol/L or more was used to define a group with significant interference. RESULTS: The distribution of interference in 1271 serum samples from female patients was unimodal. There were no group differences in clinical presentation or treatment. The median degree of interference was 1.4 nmol/L. In 42 female patients with varying degrees of interference, identified on routine assay, regression analysis showed strong association between dehydroepiandrosterone sulphate (DHEA-S) and interference (direct-minus-extracted testosterone) (r = 0.77, P < 0.001). CONCLUSIONS: Given that DHEA-S is present in very variable amounts in blood, it is possible that even with a low cross reactivity, DHEA-S or one of its metabolites significantly interferes in the testosterone assay when at higher concentrations.

Progressive resistance exercise for people with multiple sclerosis.

PURPOSE: This study aimed to determine if participation in a progressive resistance exercise (PRE) programme can: (1) increase the ability to generate maximal muscle force, (2) increase muscle endurance, (3) increase functional activity, and (4) improve overall psychological function of people with multiple sclerosis (MS). METHODS: A pre-post single group research design with a 4-week baseline familiarisation phase was used. Nine people (mean age 45.6 years, SD 10.7) with MS attended a gymnasium three times over 4 weeks for familiarization. Participants then completed a twice-weekly 10-week PRE programme, with two sets of 10 - 12 repetitions of each exercise. Outcome measures of muscle strength (1RM for arms and legs), muscle endurance (repetitions at half 1RM), walking speed, the 2-min walk test (2MWT), a timed stairs test, and the impact of MS on physical and psychological function were taken at weeks 2, 4, and 14. RESULTS: Participants attended 94.3% (SD 8.2%) of the training sessions, with no adverse events. After accounting for baseline stability, significant improvements (P < 0.05) were found in arm strength (14.4%), leg endurance (170.9%), fast walking speed (6.1%), and there was a trend for increased distance in the 2MWT (P = 0.06). The perceived impact of MS on physical function was reduced (P = 0.02). CONCLUSIONS: Adults with MS benefited from a PRE programme by improving muscle performance and physical activities, without adverse events. These findings suggest that PRE may be a feasible and useful fitness alternative for people with mild to moderate disability due to MS.

A qualitative analysis of a progressive resistance exercise programme for people with multiple sclerosis.

PURPOSE: This qualitative study explored the perceptions of adults with multiple sclerosis about the positive and negative effects of a progressive resistance strengthening programme; and identified factors that might facilitate or create barriers to participation. METHODS: Seven women and two men (mean age 45.6 years, SD 10.7) with multiple sclerosis participated in a 10-week gymnasium based progressive resistance strengthening programme held twice a week. Participants were interviewed at the end of the programme. The recorded interviews were transcribed and then independently coded by three researchers. From these codes, the main themes emerged. RESULTS: Reports about the programme were very positive with physical, psychological and social benefits noted. Most participants said that they had less fatigue as a result of the programme. Few negative outcomes were reported and these were minor such as aches and pains. Key extrinsic factors for programme completion were the leaders' encouragement and knowledge of exercise; and the group aspect of the programme. Key intrinsic factors were enjoyment, determination, seeing the signs of progress, and a previously held positive attitude about the benefits of exercise. CONCLUSIONS: The results of this study suggest that progressive resistance strength training is a feasible fitness option for some people with multiple sclerosis. Factors perceived to be important for programme completion suggest that choosing encouraging leaders with knowledge of exercise, and exercising in a group may contribute to programme success.

Steroid profiling in the study of rat testicular steroidogenesis.

Twenty authentic steroids, derivatized as O-methyl oximes (MO), trimethylsilyl (TMS) ethers or as MO-TMS ethers have been subjected to capillary gas chromatography using two different columns. Virtually all of the steroid derivatives have been resolved, one difficult pair to separate being 5,16-androstadien-3 beta-ol and 5 alpha-androst-16-en-3 beta-ol on the non-selective phase OV-1. Where syn and anti forms of MO derivatives arose, these were also resolved under the conditions utilised. This technique of 'steroid profiling' has been applied to the separation and quantification of metabolites of pregnenolone which were formed during incubations of the microsomal and cytosolic fractions from rat testes. The majority of the metabolites were found in the microsomal incubation. These compounds included some odorous 16-androstenes as well as other C21 and C19 steroids, the formation of which was consistent with the 5-ene and 4-ene pathways of testosterone biosynthesis being operative. In addition, evidence was obtained for 16 alpha-hydroxylation of C21 steroids. Very much less metabolic activity was found in the cytosolic fraction of rat testes. Metabolic pathways have been proposed which both confirm and extend earlier work. We conclude that the rat testis can only form some of the odorous, possibly pheromonal, 16-androstenes and that these are quantitatively less important than in the porcine testis.

Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.

BACKGROUND: The aim of the present study was to obtain a naturalistic measure of diurnal hypothalamic-pituitary-adrenal (HPA) axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. METHOD: Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in CFS patients and healthy controls. RESULTS: Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls. LIMITATIONS: The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted. CONCLUSION: The main findings of this study are to provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.

Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation?

We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol, plasma ACTH, and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight, 2, 8, and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF, plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma, although suspected, was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites, including 3 alpha,11 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha,11 beta,17 alpha,20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings, a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed, but no tumor was found. However, ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone, and 2) postoperatively when the patient was receiving steroid replacement only, and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar, offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case, providing an example of a previously unreported cause of hypercortisolemia.

Development of a circadian variation of plasma oxytocin concentration in the late gestation rhesus monkey.

The 24-h pattern of oxytocin (OT) concentrations in maternal plasma was investigated serially from 112-168 days gestation in four chair-restrained pregnant rhesus monkeys. No change in the mean daily plasma OT concentration was observed with advancing gestational age; there was a change in the pattern of plasma OT secretion throughout the period, however. About 21 days from delivery (150.8 +/- 1.8 days gestational age), plasma OT levels showed occasional fluctuations, distributed throughout the day. About 8 days from delivery (163.2 +/- 2.4 days gestational age), a clear circadian pattern of OT was detected, with an acrophase at 2200 h. These results suggest that there is a relationship between the pattern of OT secretion and advancing pregnancy. This may account partially for the increase in uterine activity known to occur in term rhesus monkeys.

Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients.

11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.

Changes in fetal rhesus monkey plasma dehydroepiandrosterone sulfate: relationship to gestational age, adrenal weight and preterm delivery.

These studies were performed to assess the concentrations of dehydroepiandrosterone sulfate (DHAS) in the rhesus monkey fetal circulation from midgestation through the neonatal period, to determine the relation between changes in fetal adrenal size and DHAS levels both during gestation and after surgical stress, and to explore possible relations between changes in the concentration of DHAS in the fetal circulation and the initiation of labor. When plasma DHAS was quantified in cord blood and in serial samples from chronically catheterized rhesus monkey fetuses, a significant increase in plasma DHAS concentration occurred after 150 days gestational age (404 +/- 37 vs. 1093 +/- 159 ng/ml), and an additional increase was found after 159 days (2246 +/- 712 ng/ml). A diurnal change in fetal plasma DHAS occurred in chronically catheterized fetuses, with evening samples having higher values than morning samples. Further, there was an increase in plasma DHAS concentrations in the 4-5 days after fetal surgery. A significant increase in fetal plasma DHAS concentration occurred in the newborn rhesus monkey. Although plasma DHAS concentrations remained significantly higher than in the late gestation fetus, they decreased by approximately half within the first 2 weeks of life. A close correlation existed between fetal plasma DHAS and fetal adrenal weight in control fetuses delivered by hysterotomy and fetuses that were delivered 5 days after fetal surgery. Adrenal weights in the latter were significantly higher than those in comparably aged fetuses delivered by hysterotomy that had not undergone the stress of fetal surgery. The possible relationship between the increase in plasma DHAS and the initiation of labor was studied by monitoring the changes in daily morning DHAS concentrations in long term catheterized fetuses and comparing these values to the mean cross-sectional DHAS values corresponding to that gestational age. In all but one case, the values of DHAS, although they increased preceding delivery, were still within the range found in fetuses of the same gestational age that were not in labor. These data indicate that increases in DHAS are intimately related to parallel increases in fetal adrenal weight, that there are striking increases in DHAS levels near the end of gestation, that an increase in DHAS is a component of the fetal response to surgical stress, and that there is no immediately apparent, direct relationship between fetal DHAS and preterm delivery.

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now decreased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blots of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme.