Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.     

Cognitive functioning in Alzheimer's disease and vascular dementia: further evidence for similar patterns of deficits

The purpose of the present study was to examine possible differences in patterns of cognitive performance between population-based samples of Alzheimer's disease (AD; n = 51) and vascular dementia (AD; n = 14) patients between 75 and 96 years of age. The two demented groups were comparable in age, years of education, gender distribution, and severity of dementia. The selection of cognitive tasks (letter and category fluency, Block design, Clock reading and setting, and episodic face recognition) was thought to address some of the inconsistencies in previous research. The main finding was that AD and AD patients were comparable on most tasks, although robust dementia-related deficiencies were found when comparing the results of the demented participants with those of the control participants. These findings suggest that AD and AD may affect several basic cognitive functions in an equal manner.     

NATH,a novel gene overexpressed in papillary thyroid carcinomas

In this study a replica cDNA screening (RCS) approach to identify genes differentially expressed in papillary thyroid carcinomas (PTC) was used, as compared to non-neoplastic thyroid tissues. RCS is based on hybridization of radioactively labeled cDNA probes made from the biopsies to replica membranes with 15 000 clones from a PTC cDNA library. Among the genes overexpressed in PTC, and especially in clinically aggressive tumors with histologic evidence of poorly differentiated or undifferentiated areas, a novel gene named NATH was found. NATH has two mRNA species, 4.6 and 5.8 kb, both harboring the same open reading frame encoding a putative protein of 866 amino acids. The NATH protein is homologous to yeast N-acetyltransferase (NAT)1 and to mouse NARG1 (mNAT1) and contains four tetratricopeptide repeat (TPR) domains, suggesting that NATH may be part of a multiprotein complex. Overlapping RT-PCR fragments from several PTC biopsies confirmed the NATH mRNA sequence. Northern blots, semiquantitative RT-PCR experiments, TaqMan real-time RT-PCR experiments, and in situ hybridization verified the overexpression of NATH mRNA localized to tumor cells in PTC biopsies. NATH was expressed at a low level in most human adult tissues, including the normal thyroid gland. Increased NATH expression was seen especially in a Burkitt lymphoma cell line and in adult human testis. Recombinant in vitro expression showed that NATH protein was located mainly in the cytoplasm, and was present as a single protein band of the expected 105 kDa molecular weight. Heterologous expression of NATH in the papillary carcinoma cell line (NPA) and 293 cells did not alter the cellular proliferation rate. The biological function of NATH remains to be elucidated, but the overexpression in classic PTC and especially in poorly differentiated or undifferentiated components may indicate a function in the progression of papillary thyroid carcinomas.     

Tumor control probability for selective boosting of hypoxic subvolumes,including the effect of reoxygenation

PURPOSE: To study the effect on tumor control probability of selectively boosting the dose to hypoxic subvolumes. METHODS AND MATERIALS: A Monte Carlo model was developed that separates the tumor into two compartments, one of which receives a primary dose, and one of which receives a higher boost dose. During radiation delivery, each compartment consists of three clonogen subpopulations: those that are well oxygenated, those that are temporarily hypoxic (geometrically transient hypoxia), and those that are permanently hypoxic (geometrically stable hypoxia). The spatial location of temporary hypoxia within the tumor volume varies over time, whereas, the spatial location of permanent hypoxia does not. The effect of reoxygenation was included. Clonogen proliferation was not included in the model. RESULTS: A modest boost dose (120%-150% of the primary dose) increases tumor control probability to that found in the absence of permanent hypoxia. The entire hypoxic subvolume need not be included to obtain a significant benefit. However, only tumors with a geometrically stable hypoxic volume will have an improved control rate. CONCLUSIONS: Tumors with an identifiable geometrically stable hypoxic volume will have an improved control rate if the dose to the hypoxic volume is escalated. Further work is required to determine the spatiotemporal evolution of the hypoxic volumes before and during the course of radiotherapy.     

Early failures among 7,174 primary total knee replacements: a follow-up study from the Norwegian Arthroplasty Register 1994-2000

We studied primary total knee replacements (TKRs), reported to the Norwegian Arthroplasty Register, operated on between 1994 and 2000. A Cox multiple regression model was used to evaluate differences in survival among the prosthesis brands, their types of fixation, and whether or not the patella was resurfaced. In Norway in 1999, the incidence of knee prosthesis operations was 35 per 100,000 inhabitants. Cement was used as fixation in 87% of the knees, 10% were hybrid and 2% uncemented implants. Bicompartmental (not resurfaced patella) prostheses were used in 65% of the knees. With all revisions as endpoint, no statistically significant differences in the 5-year survival were found among the cemented tricompartmental prostheses brands: AGC 97% (n 279), Duracon 99% (n 101), Genesis I 95% (n 654), Kinemax 98% (n 213) and Tricon 96% (n 454). The bicompartmental LCS prostheses had a 5-year survival of 97% (n 476). The type of meniscal bearing in LCS knees had no effect on survival. Survival with revision for all causes as endpoint showed no differences among types of fixation, or bi- or tricompartmental prostheses. Pain alone was the commonest reason for revision of cemented bicompartmental prostheses. The risk of revision because of pain was 5.7 times higher (p < 0.001) in cemented bicompartmental prostheses than cemented tricompartmental ones, but the revisions mainly involved insertion of a patellar component. In tricompartmental prostheses the risk of revision because of infection was 2.5 times higher than in bicompartmental ones (p = 0.03). Young age (< 60) and the sequelae after a fracture increased the risk of revision. The 5-year survival of the 6 most used cemented tricompartmental knee prostheses brands varied between 95% and 99%, but the differences were not statistically significant. There were more revisions because of pain in bicompartmental than in tricompartmental knees. In tricompartmental knees, however, there were more revisions because of an infection. The relatively few patients with uncemented and hybrid implants showed no improvements in results compared to cemented knee prostheses.     

Early postoperative mortality after 67,548 total hip replacements: causes of death and thromboprophylaxis in 68 hospitals in Norway from 1987 to 1999

Patients in the Norwegian Arthroplasty Register with a total hip replacement (THR) have a lower long-term mortality than the age- and gender-matched Norwegian population. We analyzed the early postoperative mortality after 67,548 THR operations in 68 hospitals reported to the Norwegian Arthroplasty Register between 1987 and 1999. Data on deaths and causes of death were obtained from from Statistics Norway, and on thromboprophylaxis from a separate questionnaire sent to all hospitals. During the years 1987-2000 the 68 hospitals reported use of 6 thromboprophylaxis drugs and 24 different combinations of drugs and stockings. In 1988, only 3 of 29 hospitals reported use of low molecular weight heparin (LMWH), but in 1999, 67 of the 68 hospitals used LMWH. In the first postoperative week, the daily mortality was about 2.5 deaths per 10,000 THR patients. By the 70th postoperative day, the daily mortality had declined to about 0.57 deaths per 10,000 patients. The daily mortality of the age- and gender-matched Norwegian population was 0.95 deaths per 10,000 individuals. Early postoperative mortality increased with age, was higher in men than women, and was usually due to vascular disease. We found only a slight reduction in the 60-day postoperative mortality during the period 1987-1999. All underlying diagnoses for a prosthesis operation had a higher 60-day postoperative mortality than primary osteoarthrosis.     

Femoral head size is a risk factor for total hip luxation

On the basis of the Norwegian Arthroplasty Register, which has recorded nearly all primary hip prostheses and revisions in Norway since 1987, we studied risk factors for prosthesis luxation leading to revision. 7 prosthesis brand combinations used in 42,987 primary operations were included from 1987-2000. We found that femoral head size was an important risk factor; 28 mm heads led to revision more often than 32 mm ones (failure rate ratio (FRR) 4.0, 95% confidence interval (CI) 2.2-7.3). Charnley (22 mm head) performed equally well or better than the 28 mm heads. The Exeter stem and cup is the type of prosthesis on the Norwegian market with more than two femoral head sizes (26, 28, 30, 32 mm) and 26 mm heads led to revision due to luxation significantly more often than 30 mm heads (FRR 4.1, 95%CI 2.2-8.1). Old age, preoperative diagnosis, and choice of prosthesis brand combination were also important factors affecting the revision rate due to luxation. A posterior approach increased the risk of revision more than a lateral one (FRR 1.9, 95%CI 1.4-2.5). Gender, trochanteric osteotomy and duration of the operation did not affect the results.     

Blastocyst surface charge and implantation in the mouse

During delay of implantation, the mouse blastocyst possesses several negatively charged sites on its surface and it is surrounded closely by the uterine epithelium. After activation for implantation by an injection of estrogen, the surface charge of the blastocyst remains unchanged for 8 hrs after the injection, although the blastocyst now lies free in the uterine secretion. Fourteen hrs after the injection, the surface charge is slightly less negative,but at 20 hrs the number of negative sites is markedly reduced. At this stage the blastocyst has resumed close contact with the uterine surface and has begun to invade the endometrium.It is concluded that the blastocyst can form close contact with the uterine surface both when inactive and possessing many negative surface sites and also when invasive and possessing few negative sites. The change in surface charge, which precedes blastocyst attachment, seems to occur simultaneously with a decrease in trophoblast antigenicity. Attention is drawn to the similarity in changes for the trophoblast at implantation to those of cultured cells at transformation.