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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Loss of functional K(ATP) channels in pancreatic β-cells causes persistent hyperinsulinemic hypoglycemia of infancy
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulin-secreting cells from a homogeneous group of five infants with PHHI lack ATP-sensitive K+ channel (K(ATP)) activity. As a consequence, PHHI β-cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.
Maternal-fetal argon transfer using skin-surface mass spectrometry during human labor
Objective: Feasibility study of a potential means to assess placental function by measurement of maternal-fetal inert gas transfer during human labor using skin-surface mass spectrometry. Methods: Skin-surface mass spectrometer probes were attached to the maternal forearm and fetal scalp (after rupture of the membranes) of six women during labor. Measurements of maternal and fetal argon were made before, during, and after the inhalation of 75% argon in oxygen for 2 min. Results: Argon was first measured from the maternal skin after a median time of 44.5 sec (range 33.0-45.8) and the level rose steadily to reach a median peak partial pressure of 94.3 mm Hg (range 68.4-103.7) at a median time of 160 sec (range 138.3-175.0). The maternal level then fell steadily at an exponential rate. Argon was first measured from the fetal scalp after a median interval of 90 sec (range 60.0-123.3) and rose more slowly to a median peak partial pressure of 24.3 mm Hg (range 17.0-38.9) at a median time of 288.5 sec (range 256-390). The median (range) fetal/maternal (F/M) ratio of skin-surface argon peak values was 0.26 (0.22-0.39) and showed good reproducibility within each case. The overall coefficient of variation of mean values from the six women was 9%. Maternal and fetal curves were smooth and showed no influence of uterine contractions while the probes remained in good contact with the skin. Dislodgement of the fetal probe was not a problem in the absence of maternal movement but was likely during the second stage of labor. This was readily apparent from the irregular fetal record which showed alterations with uterine contractions. Conclusions: Continuous assessment of maternal-fetal inert gas transfer, with its potential for investigating placental function during labor, is possible. However, the practical application of this idea awaits development of less expensive and simpler technology, which can then be evaluated in pregnancies complicated by placental dysfunction.
Maternal-Fetal argon transfer using mass spectrometry during fetal hypoxia in pregnant ewes
Objective: To develop a method of maternal-fetal inert gas transfer to assess placental function. Methods: Seven pregnant ewes were prepared, under general anesthesia, for acute and chronic experiments with intravascular mass spectrometer catheters placed into the maternal and fetal femoral arteries. The ratio of peak levels of argon in fetal and maternal circulations following 2 min inhalation of 75% argon in oxygen was used as a test of placental gas transfer to compare different methods of inducing fetal hypoxia. Results: With 2 min inhalation of 75% argon in oxygen, argon appeared in the maternal circulation after 10 sec. The level of argon rose rapidly and peaked by 135 sec before falling less quickly. Argon was identified in the fetal circulation by 40 sec after which it rose slowly to reach a lower peak by 175 sec. Fetal argon was no longer measurable after 20 min. The fetal/maternal (F/M) ratio of peak argon levels was quite reproducible (mean 0.31, SEM 0.008, n = 35). No fetal argon was found following complete umbilical cord occlusion. Fetal hypoxemia, produced by partial uterine artery occlusion, reduced the F/M ratio (0.19, SEM 0.02, P < 0.001). However, a similar degree of fetal hypoxemia, produced by reducing the maternal inspired oxygen fraction, was associated with a rise in the F/M ratio (0.47, SEM 0.03, P < 0.02), implying increased transfer of the inert gas to the fetus. Conclusion: These results suggest that the effective placental exchange area (matching of maternal and fetal circulations within the placenta) may increase as well as decrease, according to circumstances. Maternal-fetal inert gas transfer is a sensitive indicator of effective placental gas exchange area, and mass spectrometry has the potential to assess this measure of fetal-placental reserve.
Prenatal maternal influences on the control of thermoregulation and breathing during non-rapid eye movement sleep in developing lambs
This study examines the extent to which altering maternal metabolism via chronic cold exposure (i.e., winter shearing) and changes in feed intake over the final month of gestation influences development changes in breathing control during non-rapid eye-movement sleep (Non-REM) of neonatal lambs. In lambs born from well-fed (100% of total energy requirement) unshorn ewes metabolic rate and breathing frequency was lower between 4-30 days of age than those born from under-fed ewes (60% of total requirements for unshorn ewes). Laryngeal braking of expiratory airflow was observed in ca 40% of breaths during non-REM sleep at 14 and 30 days of age in lambs born from well-fed ewes compared with ca 10% of breaths in the under-fed group. The combined effects of under-feeding plus chronic cold exposure (of shorn ewes) resulted in newborn lambs which possess brown adipose tissue with an increased thermogenic activity, and exhibited a higher metabolic rate and breathing frequency over the first day of neonatal life. Laryngeal braking of expiratory airflow was commonly observed in lambs born from shorn ewes between 4-30 days of age, despite maternal under-feeding ewes. It is concluded that changes in maternal metabolism can influence developmental changes in breathing control which may be linked to effects on the control of thermoregulation.
Continuous, noninvasive measurement of fetal oxygen and carbon dioxide levels in labor by use of mass spectrometry
Clinical evaluation of the continuous, simultaneous measurement of fetal scalp surface oxygen and carbon dioxide partial pressures by mass spectrometry was undertaken for 52 labors. The mass spectrometer (MM8-80, V.G. Gas Analysis, Winsford, England) was easy to operate and had good long-term stability. The mean drifts for both oxygen and carbon dioxide over the study periods were <2 mm Hg. The mean (±SD) cervical dilatation at the time of transducer application was 6.1 (±1.9) cm and the mean (±SD) duration of the studies was 169 (±122) minutes; 10.5% of the transducer applications were unsuccessful. Falls in fetal scalp surface oxygen levels and rises in carbon dioxide levels were more frequent with late than with variable and with variable than with early fetal heart rate declerations and with increasing severity and frequency of decelerations. Fetal scalp surface pressure changes also occurred with fetal heart rate variability changes, including some related to behavioral state changes. There was not a constant reciprocal relationship between oxygen and carbon dioxide changes, and fetal heart rate patterns were not related to actual blood gas levels. Fetal scalp surface measurements were related to both fetal blood sample and umbilical artery results. Trends in both oxygen and carbon dioxide levels during the course of labor were compared and related to other fetal variables, and most of the time the scalp surface measurements were an accurate guide to systemic blood gas levels. Maternal oxygen administration resulted in significant increase in fetal scalp surface oxygen levels, and on two of eight occasions it also led to decreases in fetal carbon dioxide levels. Scalp surface gas measurement by means of mass spectrometry is a powerful new method of intrapartum fetal monitoring, which should increase the precision of fetal surveillance as well as allow the accurate assessment of both established and new methods for optimizing labor and delivery. © 1984.
Studies on the control of respiration and behaviour during development in ewe-reared lambs
Radiotelemetric recordings have been made in a series of newborn lambs with implanted electrodes and transducers and an external back-pack transmitter. Cardiac, respiratory and behavioral data have been gathered. These data have been analysed firstly with respect to age. The cardiac and respiratory data have then been related to both sleep state and age. An unexpected rise in both heart and respiratory rates was found after birth and marked differences were obvious in respiratory control in REM sleep states.
Continuous transcutaneous and intraarterial oxygen measurement during experimental hypoxemia in infant monkeys
The relationship between PaO2 and tcPO2 is an important one and provides a physiologic measure of impaired circulatory control or vascular damage. The central and peripheral mechanisms involved have to be studied further. Although tcPO2 equates well with PaO2 in many circumstances, appropriate oxygen conserving, centrally mediated vasoconstriction can overcome the thermally induced local vasodilation. Investigation of the control of peripheral circulation on both clinical medicine and the experimental animal is advanced by the technique of transcutaneous oxygen recording.
Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of β cells to diazoxide and somatostatin
The neonatal disorder persistent hyperinsulinemic hypoglycemia of infancy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (K(ATP)) channel in pancreatic β cells, leading to insulin hypersecretion. Diazoxide (a specific K(ATP) channel agonist in normal β cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition. To investigate the mechanism of action of these agents in PHHI β cells that lack K(AT), currents, we applied patch clamp techniques to insulin-secreting cells isolated from seven patients with PHHI. Five patients showed favorable responses to medical therapy, and two were refractory. Our data reveal, in drug-responsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneous electrical events that underlie insulin hypersecretion. The drug-resistant patients, both of whom carried a mutation in one of the genes that encode K(ATP) channel subunits, also lacked this novel K+ channel. There were no effects of diazoxide and somatostatin on β cell function in vitro. These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom K(ATP) channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI treatment.
Environmental effects on thermoregulation and breathing patterns during early postnatal development in hand‐reared lambs
This study examines the effect of hand‐rearing developing lambs in a warm (WR; 25 degrees C) or cool (CR; 10‐15 degrees C) ambient temperature on the control of thermoregulation and breathing patterns, when maintained at a fixed level of nutrition over the first month of postnatal life. Measurements were made during non‐rapid eye movement sleep whilst lambs were maintained for at least 1 h at warm (28‐19 degrees C) and cold (14‐5 degrees C) ambient temperatures at 1, 7, 14 and 30 days of age. All lambs were able to maintain normal body temperature, but oxygen consumption was higher in CR lambs at 14 and 30 days of age. At 1 day of age shivering was rarely observed in any lambs, but at 7 and 14 days of age more WR than CR lambs responded to cold exposure via shivering. Plasma concentrations of triiodothyronine were higher at 7 and 14 days of age in CR lambs. Breathing frequencies were similar in WR and CR lambs, and from 7 days of age the incidence of expiratory laryngeal braking was higher in warm compared with cold study temperatures. By 30 days of age the recruitment of this mechanism was greater in CR lambs. Mean growth rate was slower over the first week of postnatal life in CR compared with WR lambs. This difference decreased over the first month of life, as growth rate increased from 83 to 130 g day‐1 in the CR group but remained constant at approximately 150 g day‐1 in the WR lambs. Total weight of the lungs and heart, but not the liver, were lower at 1 month but not at 1 week of postnatal life in CR lambs. It is concluded that a modest decrease in the ambient temperature in which postnatal lambs are reared, when on a fixed feed intake, alters lung size, the recruitment of laryngeal braking and the control of body temperature. © 1995 The Physiological Society