Perioperative hyperglycemia: an unmet need within a surgical site infection bundle.

BACKGROUND: The aim of this study was to determine whether perioperative stress hyperglycemia is correlated with surgical site infection (SSI) rates in non-diabetes mellitus (DM) patients undergoing elective colorectal resections within an SSI bundle. METHODS: American College of Surgeons National Surgical Quality Improvement Program data of patients treated at a single institution in 2006-2012 were supplemented by institutional review board-approved chart review. A multifactorial SSI bundle was implemented in 2009 without changing the preoperative 8-h nil per os, and in the absence of either a carbohydrate loading strategy or hyperglycemic management protocol. Hyperglycemia was defined as blood glucose level > 140 mg/dL. The primary endpoint was SSI defined by the Centers for Disease Control National Nosocomial Infections Surveillance. RESULTS: Of 690 patients included, 112 (16.2%) had pre-existing DM. Overall SSI rates were significantly higher in DM patients as compared to non-DM patients (28.7 vs. 22.3%, p = 0.042). Postoperative hyperglycemia was more frequently seen in non-DM patients (46 vs. 42.9%). The SSI bundle reduced SSI rates (17 vs. 29.3%, p < 0.001), but the rate of hyperglycemia remained unchanged for DM or non-DM patients (pre-bundle 59%; post-bundle 62%, p = 0.527). Organ/space SSI rates were higher in patients with pre- and postoperative hyperglycemia (12.6%) (p = 0.017). Overall SSI rates were higher in DM patients with hyperglycemia as compared to non-DM patients with hyperglycemia (35.6 vs. 20.8%, p = 0.002). At multivariate analysis DM, chronic steroid use, chemotherapy and SSI bundle were predictive factors for SSI. CONCLUSIONS: This study showed that non-DM patients have a postoperative hyperglycemia rate as high as 46% in spite of the SSI bundle. A positive correlation was found between stress hyperglycemia and organ/space SSI rates regardless of the DM status. These data support the need for a strategy to prevent stress hyperglycemia in non-DM patients undergoing colorectal resections.

Construction of nanocarriers based on nucleic acids and their applications in nanobiology delivery systems.

In recent years, nanocarriers based on nucleic acids have emerged as powerful and novel nanocarriers that are able to meet the demand for cancer-cell-specific targeting. Functional dynamics analysis revealed good biocompatibility, low toxicity and programmable structures, and their advantages include controllable size and modifiability. The development of novel hybrids has focused on the distinct roles of biosensing, drug and gene delivery, vaccine transport, photosensitization, counteracting drug resistance and functioning as carriers and logic gates. This review is divided into three parts: (i) DNA nanocarriers, (ii) RNA nanocarriers and (iii) DNA/RNA hybrid nanocarriers and their applications in nanobiology delivery systems. We also provide perspectives on possible future directions for growth in this field.

Parathyroid hormone-related protein(50-69) and response to pamidronate therapy for tumour-induced hypercalcaemia.

A region-specific radioimmunoassay has been employed to measure levels of immunoreactive parathyroid hormone-related protein(50-69) (iPTHrP(50-69)) in patients with tumour-induced hypercalcaemia (TIH). This assay is based on an antiserum raised against synthetic human PTHrP(50-69). The assay showed no cross-reactivity with human or bovine parathyroid hormone(1-84). The effect of a single dose (60 mg) of pamidronate was studied in 25 consecutive patients with TIH. All were rehydrated prior to treatment. All but 2 patients (8%) became normocalcaemic after treatment; both of these had very high levels of iPTHrP(50-69). Time to achieve normocalcaemia, as an index of relative resistance to pamidronate, correlated positively with pretreatment level of iPTHrP(50-69). Absence of radiological evidence of bone metastases also predicted relative resistance to pamidronate. In this study, iPTHrP(50-69)-induced osteoclastic bone resorption was a more important mechanism in the causation of TIH than PTHrP-induced renal reabsorption of calcium as assessed by the renal thresholds for calcium and phosphate.

Clearance of exogenous parathyroid hormone-related protein in pregnant, non-pregnant and fetal sheep, goats and pigs.

In the sheep, goat and pig, radiolabelled parathyroid hormone related protein (PTHRP) and immunoreactive PTHRP(1-34) and (1-86) were rapidly cleared from the circulation. Metabolic clearance rates (MCR) were in the range of 1.25-7.5 ml/min per kg and were slightly slower than that of intact PTH in man (10 ml/min per kg); while the mean MCR of labelled PTHRP(1-86) in fetal sheep and goats was significantly faster than that in their respective mothers (14.4 vs 4.0 ml/min per kg respectively). This may reflect increased metabolism of PTHRP by fetal tissues, e.g. the placenta. Similar rates of clearance of radiolabelled PTHRP(1-141), (1-86) and (1-34) suggest that clearance involves the amino terminus of the molecule.

Plasma vitamin D-binding protein and free 1,25-dihydroxyvitamin D3 index in pregnant ewes and their fetuses in the last month of gestation.

A radioimmunoassay for ovine vitamin D-binding protein (DBP) has been developed. This assay can also effectively measure DBP in goat plasma. A suitable ovine DBP antiserum raised in a rabbit produced a single monospecific line of precipitation when reacted against purified sheep DBP and sheep plasma. The preliminary purification of 125I-labelled ovine DBP was carried out using adsorption chromatography, and the final purification immediately before addition to the assay tubes was achieved by high-pressure liquid chromatography. Displacement of 125I-labelled ovine DBP by dilutions of sheep and goat plasma or standard DBP gave parallel curves, and only weak competition was observed with calf and pig plasma. The assay detected as little as 26 pmol DBP/l with intra- and interassay coefficients of variation of 3 and 14% respectively. The mean plasma concentration of DBP in nine pregnant sheep (110-120 days of gestation) was 8.7 +/- 0.3 (S.E.M.) mumol/l. These levels were significantly (P less than 0.02; paired t-test) higher than those in matched fetal plasma (6.7 +/- 0.4 mumol/l) obtained in utero through a catheter in a carotid artery. Plasma DBP concentrations in pregnant sheep were also significantly (P less than 0.02) higher than in five normal non-pregnant sheep (6.8 +/- 0.5 mumol/l). The mean concentrations of total 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in maternal and fetal plasma were 92.0 +/- 8.7 pmol/l and 152.5 +/- 18.0 pmol/l respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of parathyroid hormone-related protein in extracts of fetal parathyroid glands and placental membranes.

A radioimmunoassay based on an antiserum to human parathyroid hormone-related protein PTHrP(1-16) was used with PTHrP(1-34) standard to measure the concentration of immunoreactive PTHrP in extracts of fetal parathyroid glands from lambs and calves and also placental membranes obtained from several species, including man. Dilution curves from these sources were parallel to those obtained for PTHrP(1-34) standard. It was demonstrated that this parallelism was not the result of tracer damage caused by enzymic activity in the tissue extracts. Extracts of human placental membranes were subjected to high-pressure liquid chromatography with a linear acetonitrile gradient. Co-elution of cytochemical biological activity with 125I-labelled PTHrP(1-34) was noted. These results provide further evidence for both the fetal parathyroid glands and the placenta containing material resembling PTHrP which may be responsible for sustaining the activity of the placental calcium pump which maintains the fetus hypercalcaemic relative to its mother.

The effect of fetal thyroparathyroidectomy on the transport of calcium across the ovine placenta to the fetus.

The ovine fetal placenta has been perfused with autologous fetal blood under controlled conditions in eleven experiments in which the fetus was first removed. Eight of these experiments involved four pairs of twins, one lamb of which had been thyroparathyroidectomized (TXPTX) three to seven days earlier. By this time the normal placental calcium gradient from mother to fetus had either decreased or been reversed. The mean rate of transport of calcium from the mother was unchanged by previous fetal TXPTX, but the final calcium gradient achieved from the mother to the perfusing blood was significantly less than with placentae from intact fetuses. No significant alteration in fetal plasma I,25-dihydroxyvitamin D (I,25(OH)2D) concentration was observed as a result of the fetal TXPTX, indicating that hypocalcaemia can compensate for the lack of PTH in fetal production of I,25(OH)2D. Fetal thyroidectomy with replacement of thyroxine did not lead to reversal of the placental calcium gradient, indicating that calcitonin was not involved. It is suggested that in the ovine fetus, parathyroid hormone promotes the active transport of calcium from mother to fetus, so that in its absence the fetus must obtain its calcium for growth by reducing its calcaemia and thereby allow net diffusion of calcium to replace the action of the placental calcium pump. The price paid for this compensation is marked hypocalcaemia and defective calcification of osteoid.

Relationship between intrafollicular concentrations of parathyroid hormone-related peptide (PTHrP) and steroid hormones in oestrogenic and non-oestrogenic ovarian follicles in the mare.

The objective of the present study was to determine whether parathyroid hormone-related peptide (PTHrP) is present in the equine follicular fluid and if so, how it is related to the follicular development in the horse. For this purpose, ovaries were collected from 40 Thoroughbred and Thoroughbred Cross mares at slaughter during the period from February to May. Normal growing follicles were dissected from the ovaries of each mare and their diameters measured. A total of 174 follicles was used in this study. The follicular fluid was aspirated from each follicle and assayed for PTHrP, oestradiol (E), testosterone (T) and progesterone (P). The follicles were classified as either oestrogenic or non-oestrogenic if the follicular fluid content of oestradiol was >40 or <40 ng/ml, respectively. PTHrP concentrations were significantly (P<0.05) higher in oestrogenic follicles, but T and P concentrations did not differ. Furthermore, E:T ratio was significantly (P<0.05) greater in oestrogenic follicles compared to the non-oestrogenic ones. The mean diameter of oestrogenic follicles was significantly (P<0.05) greater than that of non-oestrogenic ones. The higher concentrations of PTHrP observed in the follicular fluid of healthy oestrogenic follicles suggest that it may have a role in the control of ovarian function.

The relationship between the concentration of ionised calcium and parathyroid hormone-related protein (PTHrP[1-34]) in the milk of mares.

Once lactation is established in mares, there is little change in the ionised calcium concentration in their milk. In contrast, the concentration of PTHrP(1-34) in the milk increases to a maximum level by the end of the second week of lactation, near which it remains for the rest of the lactation. As found in other species, the concentration of PTHrP(1-34) in mare's milk is considerably higher than that in plasma, sampled at the same time. No significant correlation could be demonstrated between the concentrations of PTHrP(1-34) and ionised calcium in the milk except during the last 10 weeks of lactation.

Effects of danazol on mineral homeostasis in normal postmenopausal women: preliminary communication.

The effects of danazol on calcium homeostasis in normal postmenopausal women was examined in a 14-day study utilizing a dosage of 800 mg per day. Danazol caused significant falls in plasma ionized calcium and in the fasting urinary calcium/creatinine ratio, indicating inhibition of bone resorption. Retention of phosphate was also observed as expected with this anabolic agent. The plasma total alkaline phosphatase was also depressed by the drug, which had no effect on hepatocellular function as measured by plasma AST. Certain effects induced by treatment with danazol were still apparent two weeks after cessation of treatment. The drug was well tolerated and androgenic side effects were not seen. It is suggested that the minimal dose regimen of danazol which exerts a calcium-sharing effect should be identified, and that this regimen should be considered for use in a prospective study of the effects of danazol on bone mineral content in the postmenopause.

The involvement of calmodulin in the secretion of calcitonin from the porcine thyroid gland.

The effect of the calmodulin antagonist W7 has been studied in the pig in vivo by measuring directly the secretion rate of calcitonin (CT) in the thyroid venous blood after surgical isolation of the thyroid and subsequent perfusion of the gland in situ. Over the concentration range of W7 9-100 mumol/l in the perfusing plasma there was a significant increase in CT secretion rate associated with the addition of W7 to the perfusing blood. There was no significant change in the perfusing plasma calcium concentration. It is suggested that calmodulin plays an important role in calcium homeostasis within the porcine thyroid C-cell.

The secretion of parathyroid hormone-related protein in the saliva of sheep and its effects on the salivary clearance of phosphate, calcium, magnesium, potassium and sodium ions.

Parathyroid hormone-related protein (PTHrP(1-34)) was infused into five sheep, each fitted with a large rumen cannula. After infusion, significant increases were observed in the total and ionized calcium concentrations in plasma but not in saliva. In contrast, significant decreases in the plasma concentrations of phosphate and potassium and corresponding increases in their salivary concentrations and clearance rates were observed. The salivary concentration of endogenous PTH1P(1-34) was significantly greater than that in plasma sampled simultaneously, but during the infusion of PTHrP(1-34) both plasma and salivary concentrations of PTHrP(1-34) increased.

The effects in the rat of two fragments of parathyroid hormone-related protein on uterine contractions in situ.

Synthetic parathyroid hormone fragment PTH(1-34) has been reported recently to inhibit uterine contractions stimulated by a variety of agonists. We have studied the effect in this system of the parathyroid hormone-related protein fragment PTHrP(1-34) which shows 60% homology with PTH over the first thirteen amino acid residues. The effects of two different PTHrP fragments on acetylcholine-stimulated uterine contractions in vitro were studied. Whereas synthetic hPTHrP(75-86 amide) (10(-9)-10(-7) M) was without effect, synthetic hPTHrP(1-34) (10(-9)-10(-7) M) was capable of inhibiting, in a dose-related fashion, uterine muscle contractions precontracted with 10(-6) M-acetylcholine. In a second series of experiments the bovine PTH(3-34) fragment itself was shown to have no stimulatory effect on acetylcholine-stimulated contractions. Also this fragment in an equimolar concentration (10(-7) M) failed to antagonize the effects of PTHrP(1-34) on acetylcholine-stimulated uterine contractions. However, a 100-fold excess molar concentration of bPTH(3-34) (10(-6) M) completely abolished the inhibitory action of hPTHrP(1-34) (10(-8) M) on acetylcholine-stimulated uterine contractions. These results clearly show that the inhibitory action of PTH(1-34) and PTHrP(1-34) on uterine contractions depends on the integrity of the amino-terminal region of the molecule.

Comparison of effects of verapamil, low calcium diet and betamethasone on duodenal calcium absorption efficiency in the chick.

The results indicate that oral administration of verapamil for 2 weeks to the chick is followed by an increase in the efficiency of the duodenal absorption of calcium. In these chicks both a decrease in serum calcium level and an increase in the activity of renal 1 alpha-hydroxylase were observed. The increased calcium absorption following prolonged treatment with verapamil resembles that induced by a low calcium diet. The mechanism of both responses presumably involves an increased production of 1,25-dihydroxyvitamin D3. Both verapamil- and low calcium diet-induced adaptations are capable of overcoming the inhibitory action of betamethasone on intestinal calcium absorption. No effects on calcium absorption were noted if verapamil was administered intraperitoneally which suggests that verapamil exerts its action directly on the intestinal mucosa.

Effects of parathyroid hormone and parathyroid hormone-related protein on the rates of absorption of magnesium, calcium, sodium, potassium and phosphate ions from the reticulo-rumen of sheep.

Not only parathyroid hormone (PTH) but also parathyroid hormone-related protein (PTHrP) may play a role in calcium and phosphate homeostasis in ruminants. In five trained sheep, each with a large rumen cannula, the isolated rumen wash technique was used to measure electrolyte absorption rates from the rumen. After two control periods of measurement, 20 micrograms PTH(1-34) (n = 4), or PTHrP(1-34) (n = 5), was injected intravenously as a loading dose, followed by an infusion of 0.67 micrograms min-1 over 2 h. Both PTH(1-34) and PTHrP(1-34) significantly increased the absorption rates of calcium and phosphate from the reticulo-rumen. The increases in the absorption rates of magnesium, sodium and potassium observed were not significant. The same technique was also used to demonstrate that increasing the intraruminal calcium concentration from 1 to 4 mmol l(-1) caused corresponding increases in the net rate of absorption of both calcium and inorganic phosphate from the reticulo-rumen. Rumen epithelium was taken from four sheep and mounted in Ussing chambers so that fluxes of calcium could be measured in both directions using 45Ca. It was found that the addition of 100 ng ml-1 PTH(1-34) or PTHrP(1-34) to the serosal side increased the net calcium flux rates across the ruminal epithelium. It is concluded that both PTH and PTHrP can influence calcium and phosphate homeostasis in sheep not only by their recognized actions on bone and kidney but also on the absorption of these ions from the forestomachs.