Control of oxygen uptake during exercise.

Other than during sleep and contrived laboratory testing protocols, humans rarely exist in prolonged metabolic steady states; rather, they transition among different metabolic rates (V O2). The dynamic transition of V O2 (V O2 kinetics), initiated, for example, at exercise onset, provides a unique window into understanding metabolic control. This brief review presents the state-of-the art regarding control of V O2 kinetics within the context of a simple model that helps explain the work rate dependence of V O2 kinetics as well as the effects of environmental perturbations and disease. Insights emerging from application of novel approaches and technologies are integrated into established concepts to assess in what circumstances O2 supply might exert a commanding role over V O2 kinetics, and where it probably does not. The common presumption that capillary blood flow dynamics can be extrapolated accurately from upstream arterial measurements is challenged. From this challenge, new complexities emerge with respect to the relationships between O2 supply and flux across the capillary-myocyte interface and the marked dependence of these processes on muscle fiber type. Indeed, because of interfiber type differences in O2 supply relative to V O2, the presence of much lower O2 levels in the microcirculation supplying fast-twitch muscle fibers, and the demonstrated metabolic sensitivity of muscle to O2, it is possible that fiber type recruitment profiles (and changes thereof) might help explain the slowing of V O2 kinetics at higher work rates and in chronic diseases such as heart failure and diabetes.

A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.

CONTEXT: Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis. OBJECTIVE: Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH. DESIGN: The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene. SETTING: The study was carried out in an academic medical center. PATIENTS: All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis. MAIN OUTCOME MEASURES: Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene. RESULTS: The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay. CONCLUSIONS: Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.

Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years.

Mammals native to high altitude (HA) exhibit larger lung volumes than their lowland counterparts. To test the hypothesis that adaptation induced by HA residence during somatic maturation improves pulmonary gas exchange in adulthood, male foxhounds born at sea level (SL) were raised at HA (3,800 m) from 2.5 to 7.5 mo of age and then returned to SL prior to somatic maturity while their littermates were simultaneously raised at SL. Following return to SL, all animals were trained to run on a treadmill; gas exchange and hemodynamics were measured 2.5 years later at rest and during exercise while breathing 21% and 13% O(2). The multiple inert gas elimination technique was employed to estimate ventilation-perfusion (Va/Q) distributions and lung diffusing capacity for O(2) (Dl(O(2))). There were no significant intergroup differences during exercise breathing 21% O(2). During exercise breathing 13% O(2), peak O(2) uptake and Va/Q distributions were similar between groups but arterial pH, base excess, and O(2) saturation were higher while peak lactate concentration was lower in animals raised at HA than at SL. At a given exercise intensity, alveolar-arterial O(2) tension gradient (A-aDo(2)) attributable to diffusion limitation was lower while Dlo(2) was 12-25% higher in HA-raised animals. Mean systemic arterial blood pressure was also lower in HA-raised animals; mean pulmonary arterial pressures were similar. We conclude that 5 mo of HA residence during maturation enhances long-term gas exchange efficiency and Dl(O(2)) without impacting Va/Q inequality during hypoxic exercise at SL.

Effects of Type II diabetes on muscle microvascular oxygen pressures.

We tested the hypothesis that muscle microvascular O2 pressure (PmvO2; reflecting the O2 delivery (QO2) to O2 uptake (VO2) ratio) would be lowered in the spinotrapezius muscle of Goto-Kakizaki (GK) Type II diabetic rats (n=7) at rest and during twitch contractions when compared to control (CON; n=5) rats. At rest, PmvO2 was lower in GK versus CON rats (CON: 29+/-2; GK: 18+/-2Torr; P<0.05). At the onset of contractions, GK rats evidenced a faster change in PmvO2 than CON (i.e., time constant (tau); CON: 16+/-4; GK: 6+/-2s; P<0.05). In contrast to the monoexponential fall in PmvO2 to the steady-state level seen in CON, GK rats exhibited a biphasic PmvO2 response that included a blunted (or non-existent) PmvO2 decrease followed by recovery to a steady-state PmvO2 that was at, or slightly above, resting values. Compared with CON, this decreased PmvO2 across the transition to a higher metabolic rate in Type II diabetes would be expected to impair blood-muscle O2 exchange and contractile function.

Long-term enhancement of pulmonary gas exchange after high-altitude residence during maturation.

In a previous study, our laboratory showed that young dogs born at sea level (SL) and raised from 2.5 mo of age to beyond somatic maturity at a high altitude (HA) of 3,100 m show enhanced resting lung function (Johnson RL Jr, Cassidy SS, Grover RF, Schutte JE, and Epstein RH. J Appl Physiol 59: 1773-1782, 1985). To examine whether HA-induced adaptation improves pulmonary gas exchange during exercise and whether adaptation is reversible when animals return to SL before somatic maturity, we raised 2.5-mo-old foxhounds at HA (3,800 m) for 5 mo (to age 7.5 mo) before returning them to SL. Lung function was measured under anesthesia 1 mo and 2 yr after return to SL and during exercise approximately 1 yr after return. In animals exposed to HA relative to simultaneous litter-matched SL controls, resting circulating blood and erythrocyte volumes, lung volumes, septal volume estimated by a rebreathing technique, and lung tissue volume estimated by high-resolution computed tomography scan were persistently higher. Lung diffusing capacity, membrane diffusing capacity, and pulmonary capillary blood volume estimated at a given cardiac output were significantly higher in animals exposed to HA, whereas maximal oxygen uptake and hematocrit were similar between groups. We conclude that relatively short exposure to HA during somatic maturation improves long-term lung function into adulthood.

Blood flow and O2 extraction as a function of O2 uptake in muscles composed of different fiber types.

We examined how the greater vasodilatory capacity of slow--(ST) versus fast-twitch (FT) muscles impacts the relationship between blood flow (Q ) and O2 uptake (VO2) and, consequently, the O2 extraction (a-vO2 diff.)-to-VO2 relationship. Q was measured with radiolabelled microspheres, while VO2 was calculated by the Fick principle using measurements of microvascular O2 pressure (phosphorescence quenching) at rest, low--(2.5 V) and high-intensity contractions (4.5 V) for soleus (Sol; ST, n=5), mixed-gastrocnemius (MG; FT, n=7) and white-gastrocnemius (WG; FT, n=7). The slope of the Q-to-VO2 relationship (delta Q/delta VO2] ) was not different among muscles (Sol = 5.5 +/- 0.2, MG = 6.0 +/- 0.11 and WG = 5.8 +/- 0.06; P > 0.05). In contrast, the intercept was greater (P < 0.05) for Sol (16.3 +/- 2.7 ml min(-1) 100 g(-1)) versus MG and WG (in ml min(-1) 100 g(-1): 1.39 +/- 0.26 and 1.45 +/- 0.23, respectively; MG and WG, P > 0.05). In addition, the a-vO2 diff.-to-VO2] relationship for Sol was shifted rightward compared to MG and WG. These data suggest that the increase in Q for a given change in VO2 is similar for slow- and fast-twitch muscles, at least for the range of metabolic rates and muscles studied herein and that a-vO2 diff. differences result from the lower resting Q in FT muscles.

Long-term follow-up of females with unbalanced X;Y translocations-reproductive and nonreproductive consequences.

BACKGROUND: Females with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases. METHODS: Comprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male). RESULTS: The translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity-intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%). CONCLUSIONS: Our findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature.

Molecular abnormalities of FSH and LH action.

The identification of naturally occurring genetic mutations in individuals with disorders of reproductive function is the first logical step to therapy. To date, diagnostic investigations have been assisted by polymerase chain reaction and the development of an increasing number of effective screening techniques to scan genomic DNA (deoxyribonucleic acid) for causative mutations. The continued expansion of these technologies, coupled with high throughput gene sequencing, will ultimately result in automated DNA diagnosis for the practicing clinician at the point of care. At that time, the direct examination of a patient's DNA will be the definitive means of establishing the presence of specific genetic changes that cause or increase one's susceptibility to disease. This presentation selects important candidate genes in the human hypothalamic-pituitary-ovarian axis (HPG), reviews our knowledge of the spontaneously occurring human mutations that affect these genes, and reviews the biological implications of this information. To date, causative mutations in candidate genes have provided important insights into the transcription factors, receptors, and hormones that regulate the HPG axis at many levels. A major challenge in this field is that mutations in many of these genes and others remaining to be identified lead to infertility. The reduction in reproductive fitness due to these mutations limits the ability of investigators to use traditional genetic linkage and association studies to identify and clone important unidentified reproductive genes. Fortunately analysis of human gametes and new strategies that are being developed for the identification and mapping of complex human diseases will become increasingly important in continuing studies of idiopathic human infertility. At this time, it is helpful for the reader to become acquainted with some of the prototype mutations in candidate genes, their phenotypic consequences, and their prevalence. This presentation is designed to describe the known mutations in the gonadotropin genes and the genes encoding their respective receptors. The phenotypic effects of these mutations is compared, and evidence for causation is reviewed.

Recovery of microvascular PO2 during the exercise off-transient in muscles of different fiber type.

The speed with which muscle energetic status recovers after exercise is dependent on oxidative capacity and vascular O(2) pressures. Because vascular control differs between muscles composed of fast- vs. slow-twitch fibers, we explored the possibility that microvascular O(2) pressure (Pmv(O(2)); proportional to the O(2) delivery-to-O(2) uptake ratio) would differ during recovery in fast-twitch peroneal (Per: 86% type II) compared with slow-twitch soleus (Sol: 84% type I). Specifically, we hypothesized that, in Per, Pmv(O(2)) would be reduced immediately after contractions and would recover more slowly during the off-transient from contractions compared with Sol. The Per and Sol muscles of six female Sprague-Dawley rats (weight = approximately 220 g) were studied after the cessation of electrical stimulation (120 s; 1 Hz) to compare the recovery profiles of Pmv(O(2)). As hypothesized, Pmv(O(2)) was lower throughout recovery in Per compared with Sol (end contraction: 13.4 +/- 2.2 vs. 20.2 +/- 0.9 Torr; end recovery: 24.0 +/- 2.4 vs. 27.4 +/- 1.2 Torr, Per vs. Sol; P

Mechanistic basis for the gas exchange threshold in Thoroughbred horses.

The exercising Thoroughbred horse (TB) is capable of exceptional cardiopulmonary performance. However, because the ventilatory equivalent for O2 (VE/VO2) does not increase above the gas exchange threshold (Tge), hypercapnia and hypoxemia accompany intense exercise in the TB compared with humans, in whom VE/VO2 increases during supra-Tge work, which both removes the CO2 produced by the HCO buffering of lactic acid and prevents arterial partial pressure of CO2 (PaCO2) from rising. We used breath-by-breath techniques to analyze the relationship between CO2 output (VCO2) and VO2 [V-slope lactate threshold (LT) estimation] during an incremental test to fatigue (7 to approximately 15 m/s; 1 m x s(-1) x min(-1)) in six TB. Peak blood lactate increased to 29.2 +/- 1.9 mM/l. However, as neither VE/VO2 nor VE/VCO2 increased, PaCO2 increased to 56.6 +/- 2.3 Torr at peak VO2 (VO2 max). Despite the presence of a relative hypoventilation (i.e., no increase in VE/VO2 or VE/VCO2), a distinct Tge was evidenced at 62.6 +/- 2.7% VO2 max. Tge occurred at a significantly higher (P < 0.05) percentage of VO2 max than the lactate (45.1 +/- 5.0%) or pH (47.4 +/- 6.6%) but not the bicarbonate (65.3 +/- 6.6%) threshold. In addition, PaCO2 was elevated significantly only at a workload > Tge. Thus, in marked contrast to healthy humans, pronounced V-slope (increase VCO2/VO2) behavior occurs in TB concomitant with elevated PaCO2 and without evidence of a ventilatory threshold.

Dynamics of microvascular oxygen pressure in the rat diaphragm.

The relative amplitudes and rates of increase of muscle blood flow (and O(2) delivery) and O(2) uptake responses determine the O(2) pressure within the muscle microvasculature (Pm(O(2))) across the rest-to-contraction transition. Skeletal muscle function is a primary determinant of pulmonary O(2) uptake kinetics; however, it has never been determined whether the dynamics of muscle Pm(O(2)) are faster in a highly oxidative muscle [e.g., diaphragm (Dia), citrate synthase activity of 39 micromol. min(-1). g(-1)] compared with less oxidative muscles [e.g., spinotrapezius (Spino), citrate synthase activity of 14 micromol. min(-1). g(-1), male Sprague-Dawley rats; Delp MD and Duan C, J Appl Physiol 80: 261-270, 1996]. Phosphorescence quenching techniques (porphyrin dendrimer, R2) were used to determine Pm(O(2)) across the transition to electrically stimulated contractions (1 Hz) within the rat Dia. After a delay of 10.4 +/- 1.3 (SE) s at the beginning of Dia contractions, Pm(O(2)) decreased close to monoexponentially from 42 +/- 2 to 27 +/- 3 Torr (P < 0.05) with an extremely fast time constant of 7.1 +/- 1.1 s. Thus Dia Pm(O(2)) decreased with significantly (P < 0.05) faster kinetics than reported previously for the Spino muscle (delay, 19.2 +/- 2.8 s; time constant Pm(O(2)), 21.7 +/- 2.1 s; Behnke BJ, Kindig CA, Musch TI, Koga S, and Poole DC, Respir Physiol 126: 53-63, 2001). With the use of two specialized muscles with similar fiber-type composition but widely disparate oxidative capacities (Delp MD and Duan C, J Appl Physiol 80: 261-270, 1996), these data demonstrate that Pm(O(2)) kinetics are significantly faster in the highly oxidative Dia compared with the low-oxidative Spino muscle and that this effect is not dependent on muscle fiber-type composition.

Ventilatory dynamics and control of blood gases after maximal exercise in the Thoroughbred horse.

Despite enormous rates of minute ventilation (Ve) in the galloping Thoroughbred (TB) horse, the energetic demands of exercise conspire to raise arterial Pco(2) (i.e., induce hypercapnia). If locomotory-respiratory coupling (LRC) is an obligatory facilitator of high Ve in the horse such as those found during galloping (Bramble and Carrier. Science 219: 251-256, 1983), Ve should drop precipitously when LRC ceases at the galloptrot transition, thus exacerbating the hypercapnia. TB horses (n = 5) were run to volitional fatigue on a motor-driven treadmill (1 m/s increments; 14-15 m/s) to study the dynamic control of breath-by-breath Ve, O(2) uptake, and CO(2) output at the transition from maximal exercise to active recovery (i.e., trotting at 3 m/s for 800 m). At the transition from the gallop to the trot, Ve did not drop instantaneously. Rather, Ve remained at the peak exercising levels (1,391 +/- 88 l/min) for approximately 13 s via the combination of an increased tidal volume (12.6 +/- 1.2 liters at gallop; 13.9 +/- 1.6 liters over 13 s of trotting recovery; P < 0.05) and a reduced breathing frequency [113.8 +/- 5.2 breaths/min (at gallop); 97.7 +/- 5.9 breaths/min over 13 s of trotting recovery (P < 0.05)]. Subsequently, Ve declined in a biphasic fashion with a slower mean response time (85.4 +/- 9.0 s) than that of the monoexponential decline of CO(2) output (39.9 +/- 4.7 s; P < 0.05), which rapidly reversed the postexercise arterial hypercapnia (arterial Pco(2) at gallop: 52.8 +/- 3.2 Torr; at 2 min of recovery: 25.0 +/- 1.4 Torr; P < 0.05). We conclude that LRC is not a prerequisite for achievement of Ve commensurate with maximal exercise or the pronounced hyperventilation during recovery.

The randomized world is not without its imperfections: reflections on the Women's Health Initiative Study.

In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy, came to a premature halt. An interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin often prescribed to postmenopausal women increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism. The combination hormone therapy reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks. The WHI trial presents a challenge for patients, physicians, and epidemiologists, since many observational studies have shown cardiovascular benefits of long-term hormone replacement therapy (HRT). At the same time, a companion paper in the same journal reported an epidemiologic study with a 13.4-year mean follow-up suggesting that estrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer. The medical community is still recovering from these twin shocks and trying to digest the results of both of these studies. The WHI study calls into question the long-term use of HRT in healthy women. The benefit of the temporary use of estrogen in controlling disruptive symptoms of the menopause is not being contested. Absent from many news releases are the hedging and equivocation typical of other reported clinical trials. There are still some "hanging chads" out there, and this commentary is designed to examine the uncertainties that remain after the WHI report. It is also intended to suggest development of alternative strategies to control symptoms of the menopausal transition that will reduce risks of HRT. The evidence from the WHI study will need to be incorporated into medical decision making, but clinical decisions, like most human decisions, are complex and in the final analysis must be based on information from many sources.

Grading a developmental continuum--elegy on the rise and fall of the endometrial biopsy.

Due to the original study design the frequency distribution of the slide categories sent to each of the three expert pathologists was essentially bimodal. The intraclass correlation coefficient for the 1-14 continuous categories reveals excellent agreement (0.82), whereas the kappa statistic for the dichotomized outcomes (>2 day lag) is poor (0.54). The discrepancy between the intraclass correlation coefficient and kappa values seems to be due to the bimodal distribution of the slide ratings. Some impartial mechanism was needed to make an unbiased selection of the slides used for endometrial dating. Imprecision in endometrial dating is due primarily to the limitations of the instrument and not the observer. Maturation stage of the endometrium is not critical for predicting a successful pregnancy.

Nitric oxide synthase inhibition speeds oxygen uptake kinetics in horses during moderate domain running.

Within the moderate exercise intensity domain, the speed of oxygen uptake (V(O(2))) kinetics at the transition to a higher metabolic rate is thought to be limited by an inertia of the oxidative machinery. Nitric oxide (NO)-induced inhibition of O(2) consumption within the electron transport chain may contribute to this inertia. This investigation tested the hypothesis that a reduction or removal of any such NO effect via infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME; a NOS inhibitor) would speed V(O(2)) kinetics at the onset of moderate exercise. Five Thoroughbred geldings underwent four transitions to running speeds of 7 m sec(-1) (two control, C, 2 L-NAME [20 mg kg(-1)]) on an equine treadmill during which pulmonary gas exchange was determined using a bias flow system. Consistent with exercise in the moderate intensity domain, in none of the transitions was a V(O(2)) slow component elicited. The L-NAME treatment significantly accelerated V(O(2)) kinetics via a reduction of the primary amplitude time constant (C, 17.3 +/- 1.7; L-NAME, 11.8 +/- 1.5 sec, P < 0.05) concomitant with faster overall dynamics (i.e. T(50) and T(75) both P < 0.05) and a trend toward a decreased O(2) deficit (C, 6.4 +/- 0.7; L-NAME, 4.7 +/- 1.2 L; P = 0.06). These data support the notion that NO contributes prominently to the oxidative enzyme inertia and thus the speed of V(O(2)) kinetics at the onset of moderate intensity exercise in the horse.

Arterial blood gas control in the upright versus recumbent Asian elephant.

In the elephant, there is concern that lateral recumbency (LR) impairs respiratory muscle and lung function resulting in clinically significant arterial hypoxemia. Using healthy adult female Asian elephants (Elephas maximus, n=6), the hypothesis was tested that, given the O(2) binding characteristics of elephant blood, substantial reductions in arterial O(2) pressure (Pa(O(2))) in LR could be tolerated without lowering arterial O(2) content appreciably. Fifteen minutes of LR decreased Pa(O(2)) from 103+/-2 (upright, U) to 77+/-4 mmHg (P<0.05) and hemoglobin O(2) saturation (U, 97.8+/-0.1, LR, 95.3+/-0.5%, P<0.05). However, due to a recumbency-induced hemoconcentration, arterial O(2) content was unchanged (U, 18.2+/-2.4, LR, 18.3+/-2.1 ml O(2) per 100 ml). In addition, there was a mild hyperventilation in LR that reduced arterial CO(2) pressure (P(CO(2))) from 39.4+/-0.3 to 37.1+/-1.0 mmHg (P<0.05). These data indicate that the Asian elephant can endure at least short periods of LR without lowering arterial O(2) content.

Dynamics of oxygen uptake following exercise onset in rat skeletal muscle.

Technical limitations have precluded measurement of the V(O(2)) profile within contracting muscle (mV(O(2))) and hence it is not known to what extent V(O(2)) dynamics measured across limbs in humans or muscles in the dog are influenced by transit delays between the muscle microvasculature and venous effluent. Measurements of capillary red blood cell flux and microvascular P(O(2)) (P(O(2)m)) were combined to resolve the time course of mV(O(2)) across the rest-stimulation transient (1 Hz, twitch contractions). mV(O(2)) began to rise at the onset of contractions in a close to monoexponential fashion (time constant, J = 23.2 +/- 1.0 sec) and reached it's steady-state value at 4.5-fold above baseline. Using computer simulation in healthy and disease conditions (diabetes and chronic heart failure), our findings suggest that: (1) mV(O(2)) increases essentially immediately (< 2 sec) following exercise onset; (2) within healthy muscle the J blood flow (thus O(2) delivery, J Q(O(2)m)) is faster than JmV(O(2)) such that oxygen delivery is not limiting, and 3) a faster P(O(2)m) fall to a P(O(2)m) value below steady-state values within muscle from diseased animals is consistent with a relatively sluggish Q(O(2)m) response compared to that of mV(O(2)).

Selected enquiries into the causation of premature ovarian failure.

In most species, reproductive senescence can be explained in the same general terms as physiological senescence. In fact, in some species rapid physiological senescence occurs on the completion of reproduction. The programme in women is unusual in that ovarian function comes to a relatively abrupt halt at 45-50 years of age, when the impact of somatic senescence on most other functions is minimal. Early reproductive senescence has been reported in other species (chimpanzees, macaques and toothed whales) but it is more attenuated and less abrupt. The proximate cause of physiological menopause seems to be oocyte depletion, but less obvious neuroendocrine changes precede or result from the gradual loss of oocytes. This is not surprising as many age-specific processes are controlled by hormones. Hormones provide a way for an animal to co-ordinate the ageing of different tissues. The failure to comprehend completely the reasons for the biological uniqueness of women makes the study of the more extreme examples of premature ovarian failure an important exercise. The premature loss of ovarian function in certain eukaryotic women highlights the role of those special maintenance and repair systems that must be functional in the selection process for healthy germ cells. The purpose of this article is to indicate selected areas of clinical and basic investigation that may provide clues to the mechanisms of untimely ageing of the human ovary. Studies of those human extremes with premature loss, or extended ovarian function, may provide critical insights into the unique discordance between somatic and reproductive senescence that is characteristic of normal women.

Familial 46,XY sex reversal without campomelic dysplasia caused by a deletion upstream of the SOX9 gene.

BACKGROUND: 46,XY sex reversal is a rare disorder and familial cases are even more rare. The purpose of the present study was to determine the molecular basis for a family with three affected siblings who had 46,XY sex reversal. METHODS: DNA was extracted from three females with 46,XY sex reversal, two normal sisters, and both unaffected parents. All protein coding exons of the SRY and NR5A1 genes were subjected to PCR-based DNA sequencing. In addition, array comparative genomic hybridization was performed on DNA from all seven family members. A deletion was confirmed using quantitative polymerase chain reaction. Expression of SOX9 gene was quantified using reverse transcriptase polymerase chain reaction. RESULTS: A 349kb heterozygous deletion located 353kb upstream of the SOX9 gene on the long arm of chromosome 17 was discovered in the father and three affected siblings, but not in the mother. The expression of SOX9 was significantly decreased in the affected siblings. Two of three affected sisters had gonadoblastomas. CONCLUSION: This is the first report of 46,XY sex reversal in three siblings who have a paternally inherited deletion upstream of SOX9 associated with reduced SOX9 mRNA expression.

Plasticity of microvascular oxygenation control in rat fast-twitch muscle: effects of experimental creatine depletion.

Aging, heart failure and diabetes each compromise the matching of O2 delivery (Q˙O2)-to-metabolic requirements (O2 uptake, V˙O2) in skeletal muscle such that the O2 pressure driving blood-myocyte O2 flux (microvascular PO2, PmvO2) is reduced and contractile function impaired. In contrast, ß-guanidinopropionic acid (ß-GPA) treatment improves muscle contractile function, primarily in fast-twitch muscle (Moerland and Kushmerick, 1994). We tested the hypothesis that ß-GPA (2% wt/BW in rat chow, 8 weeks; n=14) would improve Q˙O2-to-V˙O2 matching (elevated PmvO2) during contractions (4.5V @ 1Hz) in mixed (MG) and white (WG) portions of the gastrocnemius, both predominantly fast-twitch). Compared with control (CON), during contractions PmvO2 fell less following ß-GPA (MG -54%, WG -26%, P<0.05), elevating steady-state PmvO2 (CON, MG: 10±2, WG: 9±1; ß-GPA, MG 16±2, WG 18±2 mmHg, P<0.05). This reflected an increased Q˙O2/V˙O2 ratio due primarily to a reduced V˙O2 in ß-GPA muscles. It is likely that this adaptation helps facilitate the ß-GPA-induced enhancement of contractile function in fast-twitch muscles.