l-Tryptophan and neuroendocrine regulation in neurologic patients: gonadotrophin secretion, sexual motivation and responsiveness during l-tryptophan treatment in patients with multiple sclerosis (MS)

(1) Patients suffering from multiple sclerosis (MS) were treated with l-tryptophan for one month in a dosage of 500 mg together with 50 mg of peripheral decarboxylase inhibitor three times daily. Placebo was given for a month, as well. The dosage of l-tryptophan was earlier seen to accelerate serotonin metabolism in the central nervous system of these patients. (2) Plasma immunoreactive gonadotrophin and somatotrophin levels were assayed during l-tryptophan and placebo periods. (3) Sexual motivation and sexual responsiveness of patients were tested by using sexual stimulation and interviews. (4) l-Tryptophan treatment slightly lowered plasma lutrophin levels in men. (5) l-Tryptophan treatment did not alter the patient's responses to the sexual stimulation tests and to interviews.     

Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

Objective Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. Methods In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. Results During the pioglitazone phase, the mean peak plasma repaglinide concentration (C_max) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. Conclusions Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.     

Serum antibody response to periodontal pathogens and herpes simplex virus in relation to classic risk factors of cardiovascular disease

BACKGROUND: Increasing evidence links chronic infections, especially burden of several infections, with increased risk for cardiovascular diseases (CVD). We studied joint immune response against two major periodontal pathogens and herpes simplex virus (HSV) in relation to established risk factors of CVD. METHODS: Serum antibody levels to HSV, Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were determined by ELISA. The study included 1107 subjects, 734 from Finland and 373 from Russia. RESULTS: Combined antibody response to periodontal pathogens was associated inversely (OR, 95% CI) with high-density lipoprotein (HDL) cholesterol concentration (beta = 0.35; 0.20, 0.60; P < 0.001) and directly with HSV antibody quartiles: compared with the first quartile, ORs (95% CI) for quartiles 2-4 were 1.43 (0.88-2.32), 1.74 (1.07-2.82), and 1.89 (1.18-3.02), respectively (P for trend <0.001), after adjusting for age, gender, area, education, smoking, BMI, alcohol, triglycerides, and number of teeth. In linear regression analysis, the 3-pathogen antibody score (comprising antibody levels against periodontal pathogens and HSV) was inversely associated with HDL cholesterol concentration (beta = -0.067/1 mmol/l; -0.235, -0.018; P < 0.05). CONCLUSIONS: HSV infection may promote infection by periodontal pathogens. Furthermore, the infectious burden comprising HSV and periodontitis may increase the risk for CVD by clearly decreasing HDL cholesterol concentrations.     

The public health nurse as a guide in infant child-care and education

The prime aim of the study was to develop the child-care and education guidance provided by public health nurses at health centres for parents of children aged 1 or 2. The research was partly carried out according to the principles of action research. The researcher's purpose was to influence the public health nurses' child-care and education guidance by designing measures and forms for the documentation and evaluation of the development, environment, and care practices of children aged 1 or 2. Methods were improved by the collaboration between the researcher and the nurses in the course of the research. In addition, the investigator designed a child-care and guidance programme for parents of such children. The premise of the public health nurse's action was the WHO's process model for nursing. The study focused on public health nurses and on children aged 1-2 and their parents. The overall action model of the public health nurses (needs assessment, goal-setting, implementation of action and evaluation) improved in the course of the experiment. The methods facilitated the implementation of action and provided it with clear objectives. The reliability and validity of the methods were reasonably high. The parents of the experimental group felt significantly more often then than those of the control group that they had obtained information about the development, care, and education of the child aged 1-2 from the public health nurses. The guidance had also helped the parents solve child rearing problems. The level of development in the children of the experimental group was higher than that of the control group at 24 months, in certain areas.     

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.     

Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians

OBJECTIVE: Apolipoprotein E (APOE) genotype is a regulator of hepatic lipoprotein metabolisms and has been linked with longevity. The relationship between APOE genotype and plasma C-reactive protein (CRP), which is produced by the liver during inflammation, has not been studied in nonagenarians. The aim of the present study was to establish whether APOE genotype is related to plasma concentrations of CRP and lipids, or longevity among nonagenarians. DESIGN AND PATIENTS: This cross-sectional study consisted of 291 Finnish nonagenarians and three previously described and genotyped control populations from the same area (i.e. newborns, 40-year-olds, and 70-year-olds). RESULTS: In all nonagenarians and especially in women (P= 0.038), CRP level decreased linearly in the genotype order of epsilon2/2, epsilon2/3, epsilon3/3, epsilon2/4, epsilon3/4 and epsilon4/4. Total (P= 0.009) and low-density lipoprotein (LDL) cholesterol (P = 0.076) levels, in turn, were increased in the epsilon4 allele carriers. In newborns, the epsilon4 frequency was 0.192, in 40-year-olds 0.181, in 70-year-olds 0.179 and in nonagenarians 0.095 (P < 0.0001). The decrease in the epsilon4 allele frequency in the elderly was more clearly seen in women than in men. CONCLUSIONS: APOEepsilon4 allele seems to be associated with decreased inflammatory response as measured by CRP among nonagenarians. This finding may partly explain why some epsilon4 allele carriers can reach very old age despite increased risk of hypercholesterolaemia.     

Association between ghrelin gene variations and blood pressure in subjects with impaired glucose tolerance

BACKGROUND: Ghrelin is a gut-brain hormone, which stimulates food intake and controls energy balance. Recently, it has been shown that ghrelin may also play a role in the regulation of blood pressure (BP) by acting at the sympathetic nervous system. In the present study we genotyped six variants of the ghrelin gene and its promoter, and tested whether these single nucleotide polymorphisms (SNPs) were associated with BP levels in participants of the Finnish Diabetes Prevention Study. METHODS: The Finnish Diabetes Prevention Study was a longitudinal study where 522 subjects with impaired glucose tolerance were randomized into either an intervention or control group. DNA was available from 507 subjects (mean body mass index [BMI] 31.2+/-4.5 kg/m2, age 55+/-7 years). All six SNPs were screened by the restriction fragment length polymorphism method. RESULTS: Subjects with the most common genotype combination of the following four SNPs, -604G/A, -501A/C, Leu72Met, and Gln90Leu, had the lowest systolic (131+/-11 v 137+/-13 mm Hg, P=.003) and diastolic BP levels (79+/-7 v 83+/-7 mm Hg, P=.004) at the baseline of the study and during 3 years of follow-up compared to all other genotypes. Adjustments for age, gender, antihypertensive medication, BMI, waist circumference, and alcohol intake did not change this association. CONCLUSIONS: Several ghrelin gene variations were associated with BP levels in subjects with impaired glucose tolerance.