Enhanced Intestinal Absorption of Oxytocin Peptide Analogues in the Absence of Pancreatic Juice in Pigs

Purpose. The present investigation was done to study the intestinal absorption of three oxytocin peptide analogues and to elucidate the role of pancreatic juice on their absorption. Methods. In conscious chronically catheterized pigs (6–8 weeks of age) plasma concentration of the peptides, [Mpa¹, D-Tyr(Ethyl)², Thr⁴, Orn⁸]-oxytocin (F314), [Mpa¹, D-Tyr(Ethyl)², Val⁴, D-Arg⁸]-oxytocin (CAT), and [Mpa¹, D-Tyr(Ethyl)², Thr⁴, Orn⁸, desGly⁹, carba⁶]-oxytocin (F327) after intraduodenal administration, during presence or diversion of the pancreatic juice via a pancreatic duct catheter, were determined by radioimmunoassay. The stability of the peptides to degradation was determined in vitro by incubation with activated pancreatic juice, chymotrypsin or trypsin, followed by reversed phase HPLC analyses. Results. All peptides were absorbed with a bioavailability of about 0.5% in the presence of pancreatic juice, but increased to 1.0%, 2.1%, and 13.5% for F314, CAT, and F327, respectively, when the pancreatic juice was diverted from the intestine. After incubation with pancreatic juice 95% of F314, 98% of F327, and 100% of CAT was found intact. When incubated with trypsin CAT remained intact while F314 and F327 were degraded by 54% and 46%, respectively. Incubation with purified chymotrypsin did not degrade the test peptides. Conclusions. The results indicate that the increased absorption of peptides observed under conditions of diverted pancreatic juice cannot only be explained by the absence of pancreatic enzymes, but also by changed absorptive properties in the gastrointestinal tract.     

Translational crossroads for biomarkers.

A group of investigators met at a Specialized Programs of Research Excellence Workshop to discuss key issues in the translation of biomarker discovery to the development of useful laboratory tests for cancer care. Development and approval of several new markers and technologies have provided informative examples that include more specific markers for prostate cancer, more sensitive tests for ovarian cancer, more objective analysis of tissue architecture and an earlier indication of response to treatment in breast cancer. Although there is no clear paradigm for biomarker development, several principles are clear. Marker development should be driven by clinical needs, including early cancer detection, accurate pretreatment staging, and prediction of response to treatment, as well as monitoring disease progression and response to therapy. Development of a national repository that uses carefully preserved, well-annotated tissue specimens will facilitate new marker development. Reference standards will be an essential component of this process. Both hospital-based and commercial laboratories can play a role in developing biomarkers from discovery to test validation. Partnering of academe and industry should occur throughout the process of biomarker development. The National Cancer Institute is in a unique position to bring together academe, industry, and the Food and Drug Administration to (a) define clinical needs for biomarkers by tumor type, (b) establish analytic and clinical paradigms for biomarker development, (c) discuss ways in which markers from different companies might be evaluated in combination, (d) establish computational methods to combine data from multiple biomarkers, (e) share information regarding promising markers developed in National Cancer Institute-supported programs, and (f) exchange data regarding new platforms and techniques that can accelerate marker development.     

The fluid content of the human intervertebral disc. Comparison between fluid content and swelling pressure profiles of discs removed at surgery and those taken postmortem.

The fluid content of the disc, which governs its mechanical response and biological behavior, varies with external load. Because load on the disc changes after death, the fluid content and swelling pressure profiles of human discs taken at autopsy were measured, and compared with discs removed during surgical procedures. In general, discs taken at surgery had a lower fluid content in the nucleus and a higher fluid content in the outer anulus than discs removed at autopsy. In discs removed at surgery, the swelling pressure of the nucleus was higher than that of the anulus, whereas in autopsy discs the swelling pressure profile was flat. These changes are though to result from changes in load after death, and could influence the results of in vitro mechanical tests on the disc.     

Effects of radiation on fixation of non-cemented porous-coated implants in a canine model

A non-weight-bearing porous-coated rod was implanted bilaterally in the proximal part of the humerus in thirty-five adult male mongrel dogs. In all of the animals, one limb was treated with radiation and the opposite limb served as the control. In twenty-one animals, the dose was 1000 centigrays (rads) and in fourteen, it was 500 centigrays. The strength of fixation and the volume fraction of ingrowth of bone were determined two, four, and eight weeks after the operation in the group that received 1000 centigrays and two and four weeks after the operation in the group that received 500 centigrays. Treatment with 500 centigrays had no significant effect on the strength of fixation or the amount of ingrowth of bone. In contrast, at two weeks, treatment with 1000 centigrays had reduced the strength of fixation to 50 per cent of the control value (p less than 0.01), although, at four and eight weeks, the strength of fixation was not significantly different than that in the control limb. The amount of ingrowth of bone in the irradiated limb was significantly reduced at two weeks (30 per cent of the control value) (p less than 0.01), four weeks (70 per cent of the control value) (p less than 0.05), and eight weeks (56 per cent of the control value) (p less than 0.05).     

Identification of N2 as a metabolite of acetylhydrazine in the rat

 In the pathogenesis of isoniazid-induced hepatic injury, cytochrome P450-dependent metabolic activation of the metabolite, acetylhydrazine (AcHz), is the crucial step. Exhalation of [¹⁴C]-carbon dioxide has previously been used to quantify indirectly this pathway. In contrast, according to the current concept of AcHz bioactivation, molecular nitrogen is produced directly, but has not yet been identified. Here, we measured [¹⁵N]-nitrogen and ¹⁴CO₂ exhalation, after the administration of [¹⁵N₂]-[¹⁴C]-AcHz, in rats. Laser magnetic resonance (LMR) spectroscopy, a new sensitive and specific technique for the measurement of ¹⁵N and ¹⁴N in gas samples, was used. To demonstrate the involvement of cytochrome P450, rats were treated with phenobarbital (PB) or PB + cobalt(II) chloride (CoCl₂) (n=3 in each group). Time-dependent ¹⁵N₂ exhalation differed significantly between treatment groups (p<0.001). At 240 min, cumulative exhalation of ¹⁵N was 1.92±0.43% (mean±SE) of the dose in the control group, 2.53±0.23% in the PB group, and 1.00±0.15% in the PB+CoCl₂ group (p<0.05 compared to controls, p<0.01 compared to PB). Cumulative exhalation of ¹⁴CO₂ in 24 h ranged from 15.1 to 21.9%, with no significant difference between treatment groups. In conclusion, N₂ is a metabolite of AcHz. N₂ formation reflects the cytochrome P450-mediated activation of AcHz and can be used as an index of this pathway. Generally, LMR spectroscopy is valuable for monitoring any N₂-liberating process in vivo. Received: 14 March 1995/Accepted: 15 August 1995     

A 2‐year report on maxillary and mandibular fixed partial dentures supported by Astra Tech dental implants. A comparison of 2 implants with different surface textures.

In 50 partially edentulous patients, 133 (48 maxillary; 85 mandibular) Astra Tech dental implants of 2 different surface textures (machined; TiO‐blasted) were alternately installed, supporting 52 fixed partial dentures (FPDs). Before abutment connection 2 machined implants (1 mandibular; 1 maxillary) were found to be non-osseointegrated and were replaced. Another implant could not be restored due to a technical complication. Two FPDs were remade because of technical complications, both because of abutment fractures. Thus, after 2 years in function, the cumulative survival rates were 97.7% and 95.7% for implants and prostheses, respectively. There was no statistically significant difference in survival rate between the 2 types of implants, 100%(TiO‐blasted) vs 95.3%(machined), P =0.24. After 2 years in function, when both jaw and type of implants were combined, the mean (SD) marginal bone loss was 0.24 (0.69) mm. No statistically significant difference in bone loss was found between the 2 tvues of implant after 2 years of loading, 0.04 (0.82) mm, P >0.30.     

Fractures after Stroke

Fractures are a serious complication after stroke. Among patients with femoral neck fractures, a large subgroup have had a previous stroke. This study aimed to investigate the incidence of fractures after stroke. Included in the study were 1139 patients consecutively admitted for acute stroke. Fractures occurring from stroke onset until the end of the study or death were registered retrospectively. Hip fracture incidence was compared with corresponding rates from the general population. Patients were followed up for a total of 4132 patient-years (median 2.9 years). There were 154 fractures in 120 patients and median time between the onset of stroke and the first fracture was 24 months. Women had significantly more fractures than men (χ² = 15.6; p < 0.001). In patients with paresis most of the fractures affected the paretic side (χ² = 22.5; p < 0.001) and 84% of the fractures were cause by falls. Hip fracture was the most frequent fracture and the incidence was 2–4 times higher in stroke patients compared with the reference population. Fractures are thus a common complication after stroke. They are usually caused by falls and affect the paretic side. It is necessary to focus on the prevention of post-stroke fractures, including the prevention of both falls and osteoporosis.     

Free insulin profiles in insulin-dependent diabetics treated with one or two insulin injections per day

Twenty-four hour profiles of free insulin and blood glucose were determined in 12 healthy controls and 10 insulin-dependent diabetics treated with insulin regimens based on intermediate-acting insulin injected subcutaneously once or twice a day. The diabetics were ambulatory and in a good glycemic control, i.e. without hyperglycemic symptoms or frequent hypoglycemias and with HbA1 less than 9% (reference value 5.9-7.8%). Body weight was normal and median age (32 years) was the same in both groups. Free insulin was determined after polyethylene glycol precipitation of antibody-bound insulin. The controls had a low basal insulin level (median fasting value 3.9 mU/l) and postprandial peaks with a maximum within 30-60 min. There was no rise in plasma free insulin or blood glucose in the early morning hours. The free insulin profiles in the diabetics were highly unphysiological with hyperinsulinemia between the meals and during the night. The highest plasma free insulin value during the 24 hours was reached before lunch (approximately 5-fold compared to normals, p less than 0.01). Postprandially the free insulin concentrations did not reach the peak levels of the normals. After breakfast, blood glucose rose considerably in the diabetics (p less than 0.02 compared to normals) while the rise after lunch and dinner was not higher than in the healthy controls. The difficulties in glycemic control in the diabetic group, i.e. a blood glucose rise after breakfast and hypoglycemias in some patients, could largely be explained by the unphysiological insulin profiles.