Feedback modeling of non-esterified fatty acids in obese Zucker rats after nicotinic acid infusions

This study investigates the impact of disease on nicotinic acid (NiAc)-induced changes in plasma concentrations of non-esterified fatty acids (NEFA). NiAc was given by constant intravenous infusion to normal Sprague–Dawley and obese Zucker rats, and arterial blood samples were taken for analysis of NiAc, NEFA, insulin and glucose plasma concentrations. The intravenous route was intentionally selected to avoid confounding processes, such as absorption, following extravascular administration. Data were analyzed using nonlinear mixed effects modeling (NONMEM, version VI). The disposition of NiAc in the normal rats was described by a two-compartment model with endogenous synthesis of NiAc and two parallel capacity-limited elimination processes. In the obese rats disposition was described by a one-compartment model with endogenous synthesis of NiAc and one capacity-limited elimination process. The plasma concentration of NiAc drove NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M ₁ ) inhibited the formation of R and the last compartment (M _N ) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. Differences in the pharmacodynamic response of the two strains included, in the obese animals, an increased NEFA baseline, diminished rebound and post-rebound oscillation, and a more pronounced slowly developing tolerance during the period of constant drug exposure. The feedback model captured the NiAc-induced changes in NEFA response in both the normal and obese rats. Differences in the parameter estimates between the obese and normal rats included, in the former group, increases in R ₀ , k _in and p by 44, 41 and 78 %, respectively, and decreases in k _out and γ by 64 and 84 %, respectively. The estimates of k _tol and IC ₅₀ were similar in both groups. The NiAc–NEFA concentration–response relationship at equilibrium was substantially different in the two groups, being shifted upwards and to the right, and being shallower in the obese rats. The extent of such shifts is important, as they demonstrate the impact of disease at equilibrium and, if ignored, will lead to erroneous dose predictions and, in consequence, poorly designed studies. The proposed models are primarily aimed at screening and selecting candidates with the highest potential of becoming a viable drug in man.     

Vitamin D, or wait and see?

No abstract available.     

Pronounced effects of the combination of a new thromboxane antagonist (GR32191) and heparin on bleeding time in man.

Potential pharmacokinetic and pharmacodynamic interactions between two oral doses of GR32191 (40 and 80 mg), a new thromboxane antagonist, and heparin (5,000 IU bolus + 1,000 IU/h for 3 h) were studied in eighteen healthy male volunteers using two separate double-blind, randomised, placebo-controlled, cross-over studies. Mean (range) bleeding time values were 8.4 min (7.5-9.7) during heparin/placebo, 12.1 min (9.2-18.6) (GR32191/placebo) and 16.3 min (11.5-21.4) (GR32191/heparin) in the 40 mg study, while these values were 8.7 min (5.5-15.5), 16.0 min (9.3 - greater than 36.0) and 23.8 min (10.7 - greater than 36.0), respectively in the 80 mg study. Compared to screening values, the combination of 80 mg of GR32191 and heparin had a greater effect on the bleeding time than the sum of the prolongations after the separate treatments (p = 0.05). In the 40 mg study this was not the case. Pharmacokinetics of heparin (as assessed by plasma anti-Xa and antithrombin activity) and GR32191 were unaltered during co-administration of the two drugs. GR32191 did not influence the effects of heparin on APTT. Heparin slightly diminished the inhibition of collagen induced platelet aggregation by 80 mg of GR32191 and the U-46619 (thromboxane A2-mimetic) induced platelet aggregation remained unchanged. Overall fibrinolytic activity (as evaluated by the fibrin plate test) was similar during all three treatments in the study with 80 mg. The combination of 80 mg of GR32191 and heparin caused a prolongation of the bleeding time which was more than expected on the basis of their individual effects.     

Hydroxyapatite coating of hip prostheses. Effect on migration into the femur.

We studied two groups of femoral hip prostheses: 43 TiAlV ridged press-fit stems, and 26 with similar stems coated with hydroxyapatite on the proximal half. At one year, radiological measurement showed a mean downward migration of 0.99 mm for the TialV prostheses and 0.12 mm for the HA-coated prostheses (p = 0.0002). Hydroxyapatite coating appeared to provide effective bio-active supplementary fixation.     

Urinary growth hormone excretion in post-menarcheal adolescent girls with type 1 diabetes

The aim of the present study was to compare measurements of urinary growth hormone (GH), serum insulinlike growth factor I (IGF-I) and IGF binding protein 3 (IGFBP3) between two groups of post-menarcheal girls, 13–18 y of age, one comprising 64 type 1 diabetic patients and the other 64 healthy girls matched for age and stage of puberty. GH was determined on two occasions in nocturnal urine samples by using a modification of an immunoradiometric method for serum. Significantly higher urinary GH concentrations but lower IGF-I and IGFBP3 levels were found in diabetic girls than in controls ( p < 0:001). A significant correlation was found between urinary GH concentrations and the daily dose of insulin (U kg ⁻¹) ( r = 0:426, p = 0:003). Urinary GH concentrations were also significantly related to HbA1c ( r = 0:380, p = 0:003). In conclusion, disturbances of the GH-IGF-I axis may be evaluated by the use of non-invasive urinary GH measurements, which is a simple alternative to frequent sampling of serum GH. Increased GH secretion seems to be related to a great need for insulin and poor metabolic control. More knowledge about underlying causal factors in the disturbed GH-IGF-I axis is required.     

Interferon alpha-2b dependent recalcitrant genital warts

Aggressive and chronic disfiguring large penile warts, where previous treatment had been unsuccessful, were flattened in a non-immunocompromised patient treated with interferon alpha-2b 5 x 10(6) I.U. subcutaneously three times a week. Cessation of therapy resulted in rapid recurrence of lesions, indicating persistence of the viral infection. Systemic interferon therapy, however, was the only remedy that could suppress the disease. Only transient and mild systemic toxicity was observed. Subcutaneously injected interferon alpha-2b should be considered in patients with otherwise therapy resistant large or disseminated genital warts.     

Caraparu virus (group C <Emphasis Type="Italic">Orthobunyavirus</Emphasis>): sequencing and phylogenetic analysis based on the conserved region 3 of the RNA polymerase gene

Here, for the first time, we report the nucleotide sequence of Caraparu virus (CARV) L segment and the analysis of the RNA polymerase region 3 encoded by this segment. The 1,404 bp nucleotide sequence shares the highest identity with Bunyamwera, La Crosse, Oropouche, and Akabane virus sequences. The amino acid sequence was deduced and aligned with sequences from members of the Bunyaviridae family and used for phylogenetic analysis. The CARV clustered in the Orthobunyavirus genus. The premotif A and motifs A–E are present in the region 3 of the Bunyaviridae family, were also conserved in CARV L protein, as well as other conserved regions among Orthobunyavirus genus. The nucleotide sequence data reported in this article have been submitted to the GenBank nucleotide sequence database: EF122411     

The applicability of home blood pressure measurement in clinical practice: a review of literature

Purpose

To review the literature on home blood pressure measurement (HBPM), to examine its validity and applicability for clinical practice and to provide recommendations regarding HBPM assessment.

Findings

HBPM can eliminate the white coat effect and offers the possibility to obtain multiple measurements under standardized conditions, which increases knowledge of overall blood pressure value. Although it is not entirely capable of replacing ambulatory blood pressure measurement (ABPM), HBPM correlates better with target organ damage and cardiovascular mortality than office blood pressure measurement (OBPM), it enables prediction of sustained hypertension in patients with borderline hypertension, and proves to be an appropriate tool for assessing drug efficacy. Additional advantages of HBPM are that it may increase drug compliance and patient’s awareness of hypertension. Overall, OBPM yield higher blood pressure values than HBPM. Differences between OBPM and HBPM tend to increase with age and are generally higher in patients without antihypertensive treatment than in patients with antihypertensive treatment.

Recommendations

Measurements should be performed according to accepted guidelines and recordings should be performed with a memory equipped automatic validated device. From the data reviewed here, we recommend that HBPM be assessed monthly by taking two measurements in the morning within 1 hour after awakening and two in the evening for three consecutive days, the data from the first day should be dismissed. A subject should be labeled hypertensive if his/her HBPM value is equal to or greater than 137 mmHg systolic and/or 84 mmHg diastolic.     

The practice guideline 'pelvic inflammatory disease' (first revision) from the Dutch College of General Practitioners; a response from the perspective of gynaecology

In 2005, the Dutch College of General Practitioners revised their guideline on pelvic inflammatory disease (PID). It is difficult to diagnose PID because of the variability in the presentation of the disease. The revised guideline is a solid guide in the diagnostic process. History taking and physical examination are the most important diagnostic techniques, but require experience. Any diagnostic uncertainty justifies the consultation ofa specialist. The value ofsupplementary diagnostics in a specialist setting is limited. In case of suspected PID, cervical material should always be cultured for Chlamydia trackomatis and Neisseria gonorrhoeae, even if treatment has already been started. Laparoscopy is considered to be the gold standard in the diagnosis of PID. but is only performed if other methods do not suffice. Fast and adequate treatment considerably decreases the risk of serious complications, such as fertility disorders. Therefore, adequate antibiotic therapy covering at least the above-mentioned pathogens should be started if other causes of abdominal pain, such as ectopic pregnancy, appendicitis and torsion of the adnexal mass, have been excluded.     

Blinded histopathological characterisation of POLE exonuclease domain‐mutant endometrial cancers: sheep in wolf's clothing

Aims

POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE‐mutant ECs.

Methods and results

Fifty‐one POLE‐mutant endometrioid, 67 POLE‐wild‐type endometrioid and 15 POLE‐wild‐type serous ECs were included (total N = 133). An expert gynaecopathologist, blinded to molecular features, evaluated each case (two or more slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, and PMS2. POLE‐mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoral lymphocytes and 59% showed tumour‐infiltrating lymphocytes, as compared with 43% and 28% of POLE‐wild‐type endometrioid ECs, and 27% and 13% of their serous counterparts (P < 0.01, all comparisons). Of POLE‐mutant ECs, 33% contained tumour giant cells; this proportion was significantly higher than that in POLE‐wild‐type endometrioid ECs (10%; P = 0.003), but not significantly different from that in serous ECs (53%). Serous‐like features were as often (focally) present in POLE‐mutant as in POLE‐wild‐type endometrioid ECs (6–24%, depending on the feature). The majority of POLE‐mutant ECs showed wild‐type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%).

Conclusions

A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoral lymphocytes, MLH1, and p53 expression) can assist in prescreening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being detected from 7% to 33%. This facilitates the use of this important prognostic biomarker in routine pathology.