Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Quantifying the effect of weathering on acute oil toxicity using the PETROTOX model.

Following accidental release into marine environments, crude oil progressively weathers, influencing composition, fate, and toxicity. However, published studies draw conflicting conclusions on the effects of oil weathering on ecotoxicity. Using the PETROTOX model, this study characterized the effect of weathering on acute oil toxicity for four aquatic species. Results indicated that predicted acute toxicity decreased with increased oil weathering, due to reductions in overall concentrations and bioavailability of hydrocarbon constituents.

Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model: Omega-3 fatty acids prevent liver neoplasia.

We investigated the effect of a non-mammalian omega-3 desaturase in a mouse hepatocarcinogenesis model. Mice containing double mutations (DM) in c-myc and TGF-alpha (transforming growth factor-alpha), leading to liver neoplasia, were crossed with mice containing omega-3 desaturase. MRI analysis of triple mutant (TM) mice showed the absence of neoplasia at all time points for 92% of mice in the study. Pathological changes of TM (TGFalpha/c-myc/fat-1) mouse liver tissue was similar to control mouse liver tissue. Magnetic resonance spectroscopy (MRS) measurements of unsaturated fatty acids found a significant difference (p<0.005) between DM and TM transgenic (Tg) mice at 34 and 40 weeks of age. HPLC analysis of mouse liver tissue revealed markedly decreased levels of omega-6 fatty acids in TM mice when compared to DM (TGFalpha/c-myc) and control (CD1) mice. Mass spectrometry (MS) analysis indicated significantly decreased 16:0/20:4 and 18:1/20:4 and elevated 16:0/22:6 fatty acyl groups in both GPCho and GPEtn, and elevated 16:0/20:5, 18:0/18:2, 18:0/18:1 and 18:0/22:6 in GPCho, within TM mice compared to DM mice. Total fatty acid analysis indicated a significant decrease in 18:1n9 in TM mice compared to DM mice. Western blot analysis of liver tissue showed a significant (p<0.05) decrease in NF-kappaB (nuclear factor-kappaB) levels at 40 weeks of age in TM mice compared to DM mice. Microarray analysis of TM versus DM mice livers at 40 weeks revealed alterations in genes involved in cell cycle regulation, cell-to-cell signaling, p53 signaling, and arachidonic acid (20:4) metabolism. Endogenous omega-3 fatty acids were found to prevent HCC development in mice.

Bovine in vitro oocyte maturation as a model for manipulation of the gamma-glutamyl cycle and intraoocyte glutathione.

Glutathione (GSH) is the main non-enzymatic defence against oxidative stress and is a critical intracellular component required for oocyte maturation. In the present study, several modulators of intracellular GSH were assessed for their effect on the in vitro maturation (IVM) and intracellular GSH content of bovine metaphase (MII) oocytes. Of the five GSH modulators tested, only the cell-permeable GSH donor glutathione ethyl ester (GSH-OEt) significantly increased the GSH content of IVM MII oocytes in a concentration-dependent manner without adversely affecting oocyte maturation rate. The GSH level in IVM MII oocytes was greatly influenced by the presence or absence of cumulus cells and severely restricted when oocytes were cultured in the presence of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. The addition of GSH-OEt to cumulus-denuded or BSO-treated oocytes increased the GSH content of bovine MII oocytes. Supplementation of the maturation medium with bovine serum albumin (BSA) or fetal calf serum (FCS) affected the GSH content of IVM MII oocytes, with greater levels attained under BSA culture conditions. The addition of GSH-OEt to the maturation medium increased the GSH content of IVM MII oocytes, irrespective of protein source. Spindle morphology, as assessed by immunocytochemistry and confocal microscopy, displayed distinct alterations in response to changes in oocyte GSH levels. GSH depletion caused by BSO treatment tended to widen spindle poles and significantly increased spindle area. Supplementation of the IVM medium with GSH-OEt increased spindle length, but did not significantly alter spindle area or spindle morphology. GSH-OEt represents a novel oocyte-permeable and cumulus cell-independent approach for effective elevation of mammalian oocyte GSH levels.

Total hip and knee replacement surgeries in Alberta utilization and associated outcomes.

OBJECTIVE: Between 1994/95 and 1996/7, the healthcare system in Alberta underwent a radical transformation that saw the regionalization of service delivery and a reduction in overall healthcare funding. The aim of this study is to examine trends in utilization and associated post-operative complications and readmissions for two procedures, total hip arthroplasty (THA) and total knee arthroplasty (TKA) during this period of restructuring. METHODS: This is a six-year retrospective analysis using hospital separation and healthcare insurance plan registry databases. During the study period, we looked at trends in inpatient procedure volumes, average lengths of stay, post-operative complications during the index hospital stay and readmissions within one year. RESULTS: Over a six-year period, the age-sex standardized provincial rate of THAs increased by 18% while the rate of TKAs increased by 73%. Average lengths of stay decreased for both procedures by over 50%. The rate of procedures with at least one post-operative complication within the index episode of care decreased over the study period by 19% for THA and 21% for TKA. Readmissions due to complications of surgery increased overall by 32% for THA and 2% for TKA. Regional and sex differences were observed throughout the period. CONCLUSIONS: While the overall rate of hospitalizations has decreased in Alberta, the rates of THA and TKA procedures have increased. The lengths of stay following these procedures have, at the same time, reduced dramatically. Adverse outcomes as measured by complication rates associated with these procedures have decreased, though readmissions due to complications after surgery have increased.

Hypnosis in a case of long-standing idiopathic itch.

OBJECTIVE: This article presents the results of a brief hypnosis treatment of a woman with chronic, idiopathic vaginal and anal itch. METHODS: The patient was referred after 3 years of unsuccessful outcomes with standard topical and oral treatments prescribed by her family physician and three dermatologists. Treatment consisted of five sessions of self-hypnosis training in techniques of relaxation, deepening, and imagery, and home practice with an individualized instructional tape. RESULTS: After treatment, the patient reported substantial tissue healing, confirmed by her treating physician, that coincided with significant reductions in her scores of itch intensity, itch-related sleep disruption, and distress from pre- to posttreatment. These improvements continued at 4 months of follow-up, and the patient reported complete resolution of physical symptoms. CONCLUSIONS: The fact that these changes coincided with only minor improvements in general anxiety scores suggests that the resolution of the patient's itch condition was treatment-specific rather than the result of methodological artifact, participant reporting bias, or a general sense of feeling better. These findings suggest that hypnosis is a cost-effective treatment for idiopathic itch conditions, especially those that are unresponsive to standard medical treatments.

Fatal shoulder dystocia: a review of 56 cases reported to the Confidential Enquiry into Stillbirths and Deaths in Infancy.

OBJECTIVE: To use information collected by the Confidential Enquiry into Stillbirths and Deaths in Infancy to help obstetric, midwifery and paediatric practice in the management of shoulder dystocia. DESIGN: Review of casenotes by a multidisciplinary focus group. SAMPLE: All 56 cases reported to the Confidential Enquiry into Stillbirths and Deaths in Infancy from England, Wales and Northern Ireland in 1994 and 1995, where stillbirth or neonatal death was attributed to shoulder dystocia. MAIN OUTCOME MEASURES: Case notes were reviewed with respect to a range of perinatal variables. Comparisons were made with normative data from other studies when appropriate. RESULTS: Maternal obesity and big babies were over-represented in pregnancies complicated by fatal shoulder dystocia. Fetal compromise was recorded in 26% of labours. The median time interval between delivery of the head and the rest of the body was only five minutes. The lead professional at the time the head was delivered was a midwife in 65% of cases. Middle grade or senior obstetric staff were supervising 47% of cases by the time the body was delivered. CONCLUSIONS: Antenatal prediction of shoulder dystocia is imprecise, and the majority of deliveries are attended by midwives. A relatively brief delay in delivery of the shoulders may be associated with a fatal outcome.

Update on adolescent health care in pediatric practice.

PURPOSE: To determine current adolescent health care practices of pediatricians and evaluate whether changes have taken place during the past decade. METHODS: A questionnaire completed by 101 pediatricians in 1985 was abbreviated and adapted by Committee on Youth of Chapter 2, District II of the American Academy of Pediatrics and sent to 1,633 members of the Chapter in June 1993. RESULTS: Forty-three percent of the 436 respondents in 1993 were female, 43% < or = 40 years of age and 53% were in private practice. Most accept new patients > or = 16 years of age (76%), continue to see patients > or = 19 years of age (63%), and interview adolescents without their parents (86%). Although between one-third and two-thirds of respondents report having equipment for gynecologic examinations, most indicate they are "not entirely comfortable" treating adolescent issues and therefore refer to others for management. Between one-quarter and one-half indicate they are "very interested" in learning more about adolescent issues and an additional 40-50% are "somewhat interested." Obstacles to providing adolescent care include: "image as a baby doctor" (65%), fear that parents would object (61%), no separate hours (57%), difficulty in providing confidential care (56%), and difficulty in charging appropriate fees (47%). Females and younger pediatricians are more comfortable with some aspects of gynecologic care and more likely to be satisfied with the adolescent care they are providing. There were few differences between responses in 1993 and 1995. CONCLUSIONS: Few of the pediatricians surveyed provide comprehensive care to adolescent patients. Future policy decisions and medical education must respond to these realities in pediatric practice.

Gay patients. Context for care.

Gays and lesbians are a part of our society and our practices: real people with real lives, not stereotypes. Understanding their inner world and their social milieu is the first step to providing care that is holistic and appropriate. The "coming out" process and other unique health issues are described. Guidance is provided on how to identify and relate to gay and lesbian patients.

Peribulbar and retrobulbar anesthesia with prilocaine: a comparison of two methods of local ocular anesthesia.

Prilocaine (Citanest) has been shown to be a satisfactory alternative to lignocaine, with certain important advantages, including superior diffusion. The latter may be especially important in peribulbar anesthesia, where the level of diffusion is a critical factor in providing a timely, high-quality block. In a prospective randomized study, we compared the effectiveness of peribulbar vs retrobulbar administration of prilocaine. Eighty-seven patients undergoing elective intraocular surgery were randomized to receive either retrobulbar or peribulbar anesthesia with prilocaine 3% with felypressin and hyaluronidase. Pain of injection, akinesia, and anesthesia were evaluated at predetermined intervals after injection. Except for the fact that lid akinesia occurred earlier in the peribulbar group, there was no difference in the quality or rate of onset of overall akinesia in the two groups. Nor were there any differences in the pain associated with injection. Both groups had excellent operative anesthesia and akinesia.

A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man.

PTH-related peptide (PTHrP) is one of the etiological factors associated with hypercalcemia of malignancy in humans and rodents. In both in vivo and in vitro animal systems its actions mimic those of PTH; however, its bioactivity in humans has not previously been assessed. Therefore, we compared the actions of the synthetic human (h) analogs hPTHrP-(1-34) and hPTH-(1-34) when given by iv infusion to 15 healthy subjects, aged 25 +/- 3 yr. Three 12-h test infusions were given to each subject in the order: hPTH-(1-34) at a dose of 8 pmol/kg.h, an equimolar dose (8 pmol/kg.h) of PTHrP-(1-34) (low dose), and a 10-fold higher dose (80 pmol/kg.h) of hPTHrP-(1-34) (high dose). PTH infusion resulted in significant increases from basal values in serum total ionized calcium, urinary phosphate and cAMP, and serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2d3]. No significant increases from basal values in any of these variables were observed during low dose PTHrP infusion. However, a 10-fold higher dose of PTHrP significantly increased serum calcium from 2.36 +/- 0.07 to 2.63 +/- 0.16 mmol/L (P less than 0.003), ionized calcium from 1.22 +/- 0.03 to 1.39 +/- 0.09 mmol/L (P less than 0.003), urinary phosphate from 0.21 +/- 0.19 to 0.31 +/- 0.16 mmol/L glomerular filtrate (P less than 0.05), urinary cAMP from 37 +/- 18 to 53 +/- 28 nmol/L glomerular filtrate (P less than 0.01), and serum 1,25-(OH)2D3 from 29.8 +/- 12.1 to 46.0 +/- 20.3 pmol/L (P less than 0.01). For each variable these changes were statistically equivalent to the increases observed during PTH infusion. The molar concentrations of circulating immunoreactive PTH-(1-34) and PTHrP-(1-34) (at the higher dose) achieved during infusion were at a ratio of 1:3. These results suggest that the in vivo actions of synthetic hPTHrP-(1-34) are comparable to those of hPTH-(1-34), but its biological activity after infusion may be less than that of hPTH-(1-34). Moreover, the increased concentrations of serum 1,25-(OH)2D3 observed with administration of hPTHrP-(1-34) are unlike the changes seen in hypercalcemia of malignancy in which levels of this vitamin D metabolite are frequently depressed.

Morphological consequences of bisacodyl on normal human rectal mucosa: effect of a prostaglandin E1 analog on mucosal injury.

Bisacodyl causes acute injury to the human rectal mucosa. Our objectives were to test whether pretreating the human rectum with an enema of 400 micrograms of a prostaglandin E1 analog (misoprostol) would ameliorate the mucosal injury provoked by an enema of 10 mg of bisacodyl, and to follow the evolution of the bisacodyl-induced injury in normal volunteers. Mucosal biopsies were taken 10 cm from the anus with an endoscopic forceps through a straight sigmoidoscope. Histological sections were interpreted blindly. In a preliminary experiment without bisacodyl, biopsies obtained from six subjects after misoprostol administration were indistinguishable from those taken from another six subjects after enemas of saline. In a parallel treatment experiment involving 30 subjects, all subjects sustained injury to the superficial epithelium and upper third of the crypt within 30 min after bisacodyl. Pretreatment with misoprostol also failed to prevent deeper injury to the lower third of colonic crypts. In a cross-over trial, a subset of four volunteers had biopsies at five different intervals after an enema of bisacodyl or saline. For up to 30 hours after bisacodyl, there was histological evidence of mild inflammation. Bisacodyl-induced colitis might confound the assessment of patients with suspected inflammatory bowel disease.

The use of a human endometrial carcinoma cell line (RL-95) for in vitro testing of chemotherapeutic agents.

RL-95, a moderately well-differentiated adenosquamous endometrial carcinoma cell line, can be used as a model for testing chemotherapeutic agents in vitro. Cells are grown in T-75 flasks, transferred to scintillation vials, and grown for 24 hr. Following this, medium is removed and new medium containing Adriamycin (Adr) and cis-platinum (CP) is added. Effects of the two drugs are measured by cell counts and DNA synthesis. To measure DNA synthesis, cells are incubated with [3H]thymidine (3H-THY) for up to 24 hr. Decreased DNA synthesis is reflected in decreased 3H-THY uptake. Cell kill is obtained with levels of drugs that are clinically achievable. Evidence is presented for increased cytotoxicity with concomitant, rather than sequential, chemotherapy. Results are also confirmed by testing the agent on MCF-7, a well-known breast cancer cell line. The results indicate that (1) endometrial carcinoma responds to Adriamycin and cis-platinum chemotherapeutic agents in vitro, and (2) RL-95 can be used as a model for testing varying concentrations, time of exposure, and combinations of chemotherapeutic agents.

Human rectal mucosa: proctoscopic and morphological changes caused by laxatives.

To determine whether laxatives alter the proctoscopic and morphological appearances of the human rectum, 10 normal subjects were studied prospectively, and the following manipulations were assessed in a randomized, blinded manner: no treatment; oral mannitol to induce diarrhea; isotonic saline enema; Fleet's Phospho-Soda enema; and bisacodyl (Dulcolax), 10 mg, by enema or suppository. The rectal mucosa after mannitol-induced diarrhea, or after saline enema could not be distinguished from untreated rectum by proctoscopy, light microscopy, or scanning electron microscopy. Fleet's enema, and bisacodyl invariably changed proctoscopic appearances, and frequently altered light and scanning microscopic aspects. Both Fleet's enema and bisacodyl caused sloughing of surface epithelium. In addition, bisacodyl decreased the uptake of hematoxylin and eosin by crypt epithelial cells so that the affected cells had a partially erased appearance (16 of 25 biopsies examined by light microscopy). The lamina propria of 3 of these 25 biopsies contained polymorphonuclear cells. Transmission electron microscopy revealed that the abnormal crypt epithelial cells contained fewer cytoplasmic organelles and less nuclear chromatin. All lesions resolved within 7 days. Fleet's enema and bisacodyl by rectum may mislead the proctologist and the pathologist by altering normal rectal mucosa.

Disappointment with triethers as markers for measuring triglyceride absorption in man.

Glycerol triethers were tried as non-absorbable, oil-phase markers for indirectly measuring triglyceride absorption in the human proximal jejunum. Tritium labelled 1-hexadecyl-2, 3-didodecyl glycerol, or 1,2,3-trioleyl glycerol, or 1,2,3-tridecyl glycerol was dissolved in linseed oil and egg yolk lipids; an aqueous emulsion of the lipid mixture was infused into the stomach. Unexpectedly, postprandial jejunal contents contained proportionately less triether than triglyceride compared with the test meals. These triethers were found to separate from an aqueous phase at a faster rate than the triglyceride. This dissociation occurred in the stomach and thwarted quantification of triglyceride absorption by this test system.