Severe hypertriglyceridaemia in Type 2 diabetes mellitus: beneficial effect of continuous insulin infusion.

BACKGROUND: Severe hypertriglyceridaemia is a recognized complication of Type 2 diabetes mellitus (T2DM); however, there is no consensus on acute management despite the significant risk of developing associated complications such as acute pancreatitis and hyperviscosity syndrome. AIM: To identify the association between hyperglycaemia and severe hypertriglyceridaemia in patients with T2DM and assess the effect of continuous insulin infusion therapy on serum triglyceride (TG) concentrations and report any adverse events associated with this therapeutic approach. DESIGN: Retrospective review of case records. METHODS: Patients with uncontrolled hyperglycaemia and severe hypertriglyceridaemia (serum TG > 15 mmol/l) treated with continuous intravenous insulin infusion between October 2008 and September 2009 were retrospectively evaluated (n = 15). Details recorded included demographics, admission details, lipid profiles, glycaemic control, serum amylase and adverse events. Patients receiving treatment-dose unfractionated heparin infusion were excluded. RESULTS: Severe hypertriglyceridaemia is associated with hyperglycaemia in our heterogeneous group of patients with T2DM presenting with new-onset diabetes or established disease on pre-existing insulin or oral hypoglycaemic agents. Administration of continuous exogenous insulin not only achieved normoglycaemia but also dramatically corrected severe hypertriglyceridaemia in all patients (P = 0.001). CONCLUSION: The administration of continuous insulin in patients with T2DM with severe hypertriglyceridaemia is a simple and safe method of significantly reducing the immediate risk associated with this metabolic complication and should be considered in any T2DM patient presenting with severe hypertriglyceridaemia and hyperglycaemia.

Inhibition of gamma-secretases alters both proliferation and differentiation of mesenchymal stem cells.

INTRODUCTION: Human mesenchymal stem cell (hMSC) proliferation and development is regulated by many signalling pathways. gamma-Secretases play an important role in Notch signalling as well as other processes that are involved in developmental decisions, but their role in hMSC proliferation and cell fate decisions has not been explored. OBJECTIVE: To investigate the role of gamma-secretases in hMSC proliferation and differentiation. MATERIALS AND METHODS: Using the gamma-secretase inhibitor N-[N-(3,5-Difluorophenacetyl-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), we investigated their role in hMSC growth and differentiation to chondrogenic, osteogenic and adipogenic fates. RESULTS: We found that inhibiting gamma-secretases reduced the rate of hMSC proliferation, and altered hMSC differentiation in vitro. Addition of DAPT had an inhibitory effect on chondrogenesis resulting in impaired cartilage matrix production and altered chondrocyte morphology. DAPT treated chrodrocytic pellets had reduced levels of Hes1 and Hey1 suggesting that these effects are mediated via Notch signalling. Addition of the DAPT inhibitor to osteogenic cultures did not alter the appearance of bone markers, however, adipogenesis occurred in these cultures in a DAPT concentration-dependent manner. DAPT did not enhance adipogenesis in the presence of a potent adipogenic cocktail, but had an adipogenic effect when combined with dexamethasone only. CONCLUSION: We conclude that gamma-secretases play an important role in both hMSC proliferation and differentiation.

Single photon responses in Drosophila photoreceptors and their regulation by Ca2+.

1. Discrete events (quantum bumps) elicited by dim light were analysed in whole-cell voltage clamp of photoreceptors from dissociated Drosophila ommatidia. Bumps were automatically detected and analysed for amplitude, rise and decay times, and latency. 2. The bump interval and amplitude distributions, and the 'frequency of seeing' curve conformed to Poisson predictions for the absorption of single photons. 3. At resting potential (-70 mV), bumps averaged 10 pA in peak amplitude with a half-width of ca 20 ms, representing simultaneous activation of ca 15 channels. 4. The macroscopic response to flashes containing up to at least 750 photons were predicted by the linear summation of quantum bumps convolved with their latency dispersion. 5. Bump duration was unaffected by lowering the extracellular Ca2+ concentration ([Ca2+]o) from 1.5 to 0.5 mM, but increased >10-fold between 0.5 mM Ca2+ and 0 Ca2+. Bump amplitude was constant over the range 1.5-100 microM, but decreased ca 5- to 10-fold at lower Ca2+ concentrations. Bump latency increased by ca 50 % between 1.5 mM and 100 microM Ca2+o but returned to near control levels in Ca2+-free solutions. At intermediate [Ca2+]o bumps were biphasic with a slow rising phase followed by rapid amplification and inactivation. This behaviour was mimicked in high [Ca2+]o by internal buffering with BAPTA, but not EGTA. This suggests that Ca2+ influx through the light-sensitive channels must first raise cytosolic Ca2+ to a threshold level before initiating a cycle of positive and negative feedback mediated by molecular targets within the same microvillus. Quantum bumps in trp mutants lacking the major class of light-sensitive channel were reduced in size (mean 3.5 pA) representing simultaneous activation of only one or two channels; however, a second rarer (10 %) class of large bump had an amplitude similar to wild-type (WT) bumps. Bumps in trpl mutants lacking the second class of light-sensitive channel were very similar to WT bumps, but with slightly slower decay times. In InaDP215 mutants, in which the association of the TRP channels with the INAD scaffolding molecule is disrupted, bumps showed a defect in quantum bump termination, but their amplitudes and latencies were near normal.

A comparison of intermittent pneumatic compression of the calf and whole leg in preventing deep venous thrombosis in urological surgery.

PURPOSE: Intermittent pneumatic compression of the calf and/or thigh effectively decreases the incidence of deep venous thrombosis and other thrombotic sequelae but clinical data comparing these modalities are currently lacking. MATERIALS AND METHODS: A total of 90 patients undergoing major urological surgery was randomly assigned to receive calf length or thigh length pneumatic compression for antithrombotic prophylaxis. Duplex ultrasound of the lower extremities was performed preoperatively and twice postoperatively to evaluate for deep venous thrombosis. Health care providers in the operating room, recovery room and ward were asked to compare the compression systems, and a cost analysis was performed. RESULTS: A total of 47 patients wore the thigh length sequential pneumatic sleeves and 43 wore calf length uniform compression systems. A pulmonary embolus without evidence of deep venous thrombosis was detected in 1 patient (2%) using the thigh length system. A thrombus was detected in the common femoral vein by duplex ultrasonography in 1 patient (2%) with the calf length system. Nursing personnel found the calf length sleeves easier to apply and more comfortable by patient account but they were satisfied with both systems. There was a significant cost savings with the calf length pneumatic compression system. CONCLUSIONS: Calf and thigh length pneumatic compression systems similarly decrease the risk of deep venous thrombosis in patients undergoing urological surgery. The calf length system has the added advantage of being less expensive and easier to use.

Ectopic tubal pregnancy treated by operative laparoscopy.

Between July 1986 and May 1988, all 23 patients with ectopic tubal pregnancies of 5 to 10 1/2 weeks' gestation and with serum beta-human chorionic gonadotropin levels between 51 and 92,610 mIU/ml (first international reference preparation) were treated by operative laparoscopy. Twenty-two (96%) of the ectopic pregnancies were unruptured or leaking and one (4%) was ruptured. Fifteen patients (65%) were treated with electrosurgical linear salpingotomy, and three of these patients (20%) later needed subsequent operative procedures. Six patients (26%) were treated with laparoscopic partial or total salpingectomy, and two patients were treated with either fimbrial expression of the pregnancy or completion of a partial abortion. Twenty patients (87%) spent less than 24 hours in the hospital for successful treatment of the ectopic pregnancy. It is concluded that operative laparoscopy should be considered an alternative to laparotomy or minilaparotomy for the treatment of ectopic pregnancy.

PIP: Recently developed instrumentation for operative laparoscopy now allows removal of far larger volumes of fetal tissue through a process of morcellation. The author treated all 23 cases of ectopic pregnancy presenting at San Francisco's Children's Hospital between July 1986 and May 1988 with operative laparoscopy, regardless of gestational age, level of serum beta-human chorionic gonadotropin, or size of the ectopic pregnancy. The pregnancy was unruptured in 22 cases. 5 (22%) of the patients were pregnant for the 1st time, 6 (26%) had experienced a prior ectopic pregnancy, and 6 (26%) had a history of IUD use. 15 patients (65%) were treated with electrosurgical linear salpingotomy, although 3 (20%) later required subsequent operative procedures. 6 patients (26%) were treated with laparoscopic partial or total salpingectomy, and 2 (9%) were treated with either fimbrial expression of the pregnancy or completion of a partial abortion. The total hospital stay was less than 24 hours for 20 patients (87%). Subsequent intrauterine pregnancies occurred in 7 (41%) of the 17 patients who attempted another pregnancy after operative laparoscopy; no patient had another ectopic pregnancy. The intrauterine pregnancy rates for patients attempting to conceive after linear salpingotomy, partial or total salpingectomy, and other procedures were 27%, 75%, and 100%, respectively. Operative laparoscopy has numerous advantages in cases of ectopic pregnancy, including a short hospital stay, the ability to resume normal activities within a few days, and high subsequent intrauterine conception rates. However, despite evidence that this technique may be superior to standard laparotomy, under 10% of physicians use laparoscopy in the treatment of ectopic pregnancy.

Odor specificity of the enhanced neural response following early odor experience in rats.

The enhanced neural response in the olfactory bulbs of rat pups following early olfactory experience is specific to the familiar odor. Pups were exposed daily to either peppermint or cyclohexanone odor for the first 18 postnatal days. On day 19, peppermint-familiar pups exposed to peppermint had significantly higher [14C]2-deoxyglucose (2-DG) uptake in a focal glomerular area compared with the response to peppermint by cyclohexanone-familiar pups. We also found that cyclohexanone-experienced pups had a subsequent enhanced response to cyclohexanone odor in glomerular areas medial and caudal to those responding to peppermint. None of the 2-DG uptake differences were attributable to respiration differences between the groups during any part of the odor test.

Relevance and utility of courses in medical ethics. A survey of physicians' perceptions.

In the last decade the teaching of medical ethics has become almost universal in American medical schools. Its effectiveness is, however, just beginning to be evaluated. A stratified random sample of 3,000 practicing physicians who were graduated between 1974 and 1978 was surveyed to evaluate their perceptions of the utility and relevance of medical ethics teaching. Those who had courses in medical ethics perceived it to be of substantial benefit in confronting the actual ethical issues they encountered in daily practice. They favored the continuation and expansion of the teaching of medical ethics and had suggestions for its improvement. Data were also obtained on the relative frequency of specific ethical issues in practices and on the relative influence of home, personal values, medical education, medical practice, and ethics courses on respondents' approaches to ethical issues.

KIE: The American Medical Association conducted a survey in 1982 to ascertain how physicians evaluated the effectiveness of their education in preparing them to deal with the ethical issues they encountered in practice. The results, summarized in this article, indicate that physicians who had had courses in medical ethics perceived them to be of substantial practical value and recommended that their content be expanded. Data are presented on the relative frequency of specific ethical issues encountered in practice and on the relative influence of home, personal values, medical education, medical practice, and ethics courses on respondents' approaches to ethical issues.

The reversibility of female sterilization with the use of microsurgery: a report on 102 patients with more than one year of follow-up.

A prospective study of 102 patients who underwent a reversal of sterilization between January, 1977, and February, 1982 revealed a pregnancy rate of 68% after more than 1 year of follow-up. The term delivery, abortion, and ectopic pregnancy rates were 52%, 11%, and 5%, respectively. The most reversible procedure was placement of the Falope ring (83% term delivery), and the least reversible was fimbriectomy (29%). The use of the microscope in performing tubal operation was associated with term delivery rates (60%) higher than those when no microscope was used (44%); this was particularly significant after tubal cautery (50% versus 25%). A total remaining tube length of 6 cm or more after previous sterilization resulted in a much better (74%) term delivery rate after microsurgical procedures than that in patients with shorter tubes (44%). The most successful site for tubal anastomosis was isthmus-isthmus and cornu-isthmus, with 81% and 67% term delivery rates, respectively.

Reversal of female sterilization: comparison of microsurgical and gross surgical techniques for tubal anastomosis.

Between 1977 and 1979, 34 consecutive, unselected patients had a reversal of tubal sterilization. The characteristics of 23 patients with more than a 6-month follow-up after end-to-end anastomosis are given, as are details of the operative procedures used. The overall intrauterine pregnancy rate was 56%, and the most reversible sterilization procedures, in terms of intrauterine pregnancies, were the Pomeroy, Uchida, and Falope ring (67%). The least reversible were unipolar tubal cautery (42%) and fimbriectomy (50%). Eleven patients had a microsurgical procedure (with the microscope) and 12 a gross surgical procedure. The use of the microscope was not associated with a significantly better pregnancy rate in cases matched for poststerilization tubal length, proximal and distal to the uterus. But insufficient numbers of tubal cautery reversals have been performed for an evaluation of the use of the microscope in this particular situation. The site of the anastomosis and the postoperative length of the tube were good predictors of intrauterine pregnancies. Five of six patients who had isthmus-isthmus anastomoses on at least one side had term vaginal deliveries. Likewise, 10 of 16 patients in whom the length of the longest tube was 6 cm or more had viable pregnancies, but only one of seven patients had a viable pregnancy with tubes of 5 cm or less.

Oestradiol-17beta and pituitary responsiveness to luteinizing hormone releasing factor in the rat: a study using rectangular pulses of oestradiol-17beta monitored by non-chromatographic radioimmunoassay.

Plasma concentrations of oestradiol-17beta were measured by a non-chromatographic radioimmunoassay during the oestrous cycle, after the s.c. injection of 2-5 or 10 microgram oestradiol benzoate (OB), or the s.c. implantation of Silastic capsules containing crystalline oestradiol-17beta. The profile of endogenous plasma oestradiol-17beta concentrations was similar to that reported by other workers, and lay between the concentrations produced by the low and high doses of OB. The rectangular pulses of increased plasma oestradiol concentrations, produced during the period of implantation of the Silastic capsules, were used to determine the time taken for oestradiol-17beta to exert its facilitatory effect on the gonadotrophin response to LH-releasing factor (RF). In animals ovariectomized at dioestrus, oestradiol, at concentrations similar to those reached during the peak of the spontaneous surge, first reduced the LH response. However, after 7 h, responsiveness increased significantly to reach a peak at 12 h. The FSH response was also greatest 12 h after ovariectomy. In animals ovariectomized at metoestrus the effect of oestradiol on the LH response was significantly less than in rats ovariectomized at dioestrus, and the FSH responses were lower than those in animals bearing empty capsules and examined at the same time after ovariectomy. These findings together with the effects of long-term exposure to sodium pentobarbitone are considered with respect to the possible mechanisms, including the priming effect of LH-RF, which may produce increased pituitary responsiveness after ovariectomy and exposure to oestrogen.

Effect of oestradiol-17beta exposure on the spontaneous secretion of gonadotrophins in chronically gonadectomized rats.

The effect of oestradiol-17beta (administered in Silastic capsules) on gonadotrophin secretion in long-term gonadectomized rats has been investigated. In female rats, a daily afternoon surge of LH occurred which could be blocked by administering sodium pentobarbitone at 13.00 h. This, together with the fact that there was no significant difference between the LH-response to LH-releasing factor in the morning compared with the afternoon, supports the view that the LH surges are due to a neural rhythm. There was no significant diurnal variation in plasma FSH concentration, but an apparent diurnal variation was disclosed by administering sodium pentobarbitone on alternate days. There was no diurnal variation in plasma gonadotrophin concentrations in male animals implanted with an oestradiol capsule, or in animals of either sex bearing empty capsules.

Steroids and pituitary responsiveness in female, androgenized female and male rats.

Spontaneous gonadotrophin release and the gonadotrophin response to LH releasing factor (RF) were studied in pro-oestrus, androgenized female and male rats. The animals were either intact or gonadectomized (about 32 h previously) and treated with various steroids. The gonadotrophin response (especially LH) was much lower in intact males and androgenized females than in pro-oestrous females. Oestrogen plus progesterone increased plasma gonadotrophin concentrations and responses in ovariectomized rats, but inhibited the increase in the plasma gonadotrophin concentration and the LH response which followed castration in males. As in the normal female, ovariectomy decreased the LH response but increased the plasma FSH concentration and response in the androgenized female; oestrogen and progesterone had relatively little effect. Apart from reducing the postcastration rise in plasma FSH, testosterone had no significant effect in gonadectomized male or female animals. These results show that the effect of steroids on the gonadotrophin response to LH-RF as well as the spontaneous secretion of gonadotrophin depends upon sexual differentiation of the hypothalamo-hypophysial system. Studies with various metabolites of progesterone indicated that the facilitatory action of this steroid could be due, in part, to a 5alpha-reduced derivative.

Site of modulatory action of oestrogen and progesterone on gonadotrophin response to luteinizing hormone releasing factor.

The effect of oestrogen and progesterone on the spontaneous release of gonadotrophins and on the gonadotrophin response to luteinizing hormone releasing factor has been examined in female rats subjected to hypothalamic deafferentation or pituitary stalk section. The results indicate that both steroids act at the level of the medial basal hypothalamus as well as the anterior pituitary gland; progesterone, for its full effect, also requires the integrity of connexions of the hypothalamus with other areas of the brain.

Proteins in human uterine fluid.

The proteins in saline washings from uteri of women at different stages of the menstrual cycle were examined by polacrylamide gel electrophoresis at pH 4-5 and pH 8-9, isoelectric focusing in polyacrylamide, and immunoelectrophoresis. The components present were mainly serum proteins but small amounts of uterine-specific proteins were also detected. Measurement of the activities of several glycosidases in uterine washings revealed that alpha-L-fucosidase, beta-N-acetylgalactosaminidase and beta-N-acetylglucosaminidase were elevated when compared with serum.