Childhood disadvantage and adolescent socioemotional wellbeing as predictors of future parenting behaviour.

INTRODUCTION: In extending work on early life antecedents of parenting, we investigate associations between childhood family history of disadvantage, adolescent socioemotional wellbeing, and age at first parenthood and subsequent parenting behaviour. METHODS: Parent-child interactions were recorded when participants in the longitudinal Dunedin Multidisciplinary Health and Development Study (New Zealand) had a three-year-old child. Data were available for 358 mothers and 321 fathers, aged between 17.7 and 41.5 at the time of their child's birth. Associations between parenting and antecedent data on socioeconomic disadvantage, adolescent wellbeing and mental health, as well as current adult mental health and age at parenting, were tested for using structural equation modelling. RESULTS: Family disadvantage in childhood and lower adolescent wellbeing was associated with less positive future parenting, but only adult (not adolescent) anxiety/depression symptoms were directly associated with parenting behaviour. Childhood family disadvantage was associated with further disadvantage across the life course that included less positive parenting of the next generation. In contrast, socioemotional wellbeing during adolescence and later age of onset of parenting were associated with more positive parenting. CONCLUSIONS: Reducing childhood disadvantage and improving socioemotional wellbeing during childhood and adolescence is likely to have intergenerational benefits through better parenting of the next generation.

Neuroprotective effects of novel phosphatidylglycerol-based phospholipids in the 6-hydroxydopamine model of Parkinson's disease.

Administration of VP025 (Vasogen Inc.), a novel drug formulation based on phospholipid nanoparticles incorporating phosphatidylglycerol, has previously been shown to have a neuroprotective effect in the brain. We examined the effect of VP025 in a rat model of Parkinson's disease, the 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. VP025 or phosphate-buffered saline (PBS) was administered to rats 14 days, 13 days and 1 day before the unilateral 6-OHDA lesion. Functional integrity of nigrostriatal dopaminergic neurons was assessed 7 and 21 days later by amphetamine-induced rotational testing and we observed that rotational counts were significantly less in rats that were pretreated with VP025 compared with PBS-pretreated 6-OHDA-lesioned rats. Neurochemical analysis at 10 and 28 days after lesion revealed that VP025 protected against a 6-OHDA-induced decrease in concentrations of striatal dopamine and its metabolites. Immunocytochemical studies of the ipsilateral substantia nigra showed that VP025 significantly inhibited 6-OHDA-induced loss of dopaminergic neurons. We also observed that increases in immunostaining for activated microglia and for activated p38 in dopaminergic neurons of 6-OHDA-lesioned rats were prevented by VP025. This study shows that VP025 has significant protective effects on the 6-OHDA-lesioned nigrostriatal pathway and may therefore have potential for the treatment of Parkinson's disease.

Significance of molecular marker-positive cells after autologous peripheral-blood stem-cell transplantation for non-Hodgkin's lymphoma.

PURPOSE: To evaluate the significance of molecular marker-positive cells in a cohort of non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous peripheral-blood stem-cell transplantation (PBSCT). PATIENTS AND METHODS: Twenty-eight PBSC transplants have been performed in 24 patients with poor-prognosis NHL. Molecular analysis of the t(14;18) (q32;q21) translocation (bcl-2/immunoglobulin [Ig] heavy-chain joining locus [JH] fusion) or antigen receptor gene rearrangements was performed to determine the presence of lymphoma cells at presentation, in PBSC harvests, and before and after autologous PBSCT. Kaplan-Meier estimates of survival and Cox regression analyses were used to test the effect of bone marrow involvement, tumor-cell contamination of PBSCs, disease stage, and chemotherapy sensitivity at transplantation, and presence of marker-positive cells post-PBSCT on disease-free and overall survival. RESULTS: Thirteen of 24 patients (54%) are alive following PBSCT at a median follow-up time of 654 days (range, 193 to 1,908). Nine patients are in complete remission (CR) at day 216 to 1,799 (median, 805) and four are alive following relapse (day 440, 573, 1,188, and 1,908). Eleven patients (46%) have died: three of transplant-related complications at day 0, 1, and 13, and eight of recurrent disease (day 132 to 1,330; median, 451). Longitudinal marker studies post-PBSCT showed that of 16 relapse events, 13 (81%) were positive for the lymphoma marker at or before clinically documented relapse. Marker studies became negative post-PBSCT in nine of nine patients who entered and remained in CR. Disease-free survival (DFS) was significantly shortened in patients in whom marker-positive cells were detected in serial samples posttransplantation (P = .006). Cox regression analysis showed that patients in this group had a 24 times higher risk of relapse (P = .03). CONCLUSION: The results show that the reappearance or persistence of marker-positive cells after autologous PBSCT is strongly associated with relapse.

A two-site immunoradiometric assay for human pregnancy-associated plasma protein A (PAPP-A) using monoclonal antibodies.

A rapid, sensitive immunoradiometric assay has been developed for human pregnancy-associated plasma protein A (PAPP-A) using a purified mouse monoclonal antibody as the tracer and a rabbit polyclonal antibody to this protein in the solid-phase antibody preparation. The assay showed no measurable cross-reaction (less than 0.1%) against a range of purified human placental proteins, and a good correlation with a previously described radioimmunoassay procedure when tested on samples taken throughout normal human pregnancies. No PAPP-A-like immunological activity could be detected in sera from non-pregnant women, confirming the absence of this protein from the circulation outside pregnancy.

beta-thromboglobulin and deep vein thrombosis.

The measurement of plasma beta-thromboglobulin as a potential diagnostic test for venous thrombosis has been investigated in 16 normal volunteers, 24 patients presenting with deep vein thrombosis (DVT) or pulmonary embolism and 46 patients screened by 125I fibrinogen test (IFT) for post-operative DVT. The normal mean was 33 ng/ml (range 15-117 ng/ml). Of the 24 patients with clinical thrombotic disease 22 presented with DVT confirmed by phlebogram or IFT and 2 presented with embolism confirmed by lung scan. At the time of first presentation 12 out of 24 had betaTG values greater than 70 ng/ml. All except 3 of this group of 24 patients had values of greater than 70 ng/ml at some stage during a subsequent week of daily sampling. DVT was detected in 13 out of 46 screened post-operative patients. There was a rise om betaTG observed within 24 hr of the IFT becoming positive but the mean rise did not reach significance at the 5% level. An association between DVT and high betaTG values has been confirmed. However, its clinical value cannot yet be fully elucidated until factors, probably related to blood sampling and clearance, are further investigated.

The relationship of placental protein 14 (PP14) in the mother and fetus to specific products of the human placenta.

Levels of placental protein 14 (PP14), human placental lactogen (hPL) and unconjugated oestriol (E3) were measured in maternal peripheral and umbilical arterial and venous blood obtained from 65 normal pregnancies at term delivery. PP14 levels were one order of magnitude higher in the mother than in the fetus. Neither maternal nor fetal levels of PP14 were related to the birthweight of the fetus. There was a relationship between maternal and umbilical venous levels of PP14, which suggests that fetal PP14 is derived by transfer from the mother, or that there is an independent fetal source with a control mechanism similar to that of the mother. The findings are compatible with earlier observations to the effect that PP14, in contrast to products such as hPL and E3, is not specific to the trophoblast.

The effect of horse placental tissue extracts and equine chorionic gonadotrophin on the proliferation of horse lymphocytes stimulated in vitro.

Commercial preparations of equine chorionic gonadotrophin (eCG) and extracts of horse placenta taken at 80 days gestation were incorporated into mixed lymphocyte culture and mitogen stimulation assays of horse peripheral blood mononuclear cells. A dose-related inhibition of lymphocyte proliferation, indicative of immunosuppressive activity, was observed in both systems, both with commercial eCG preparations and tissue extracts. Negligible inhibitory activity was observed with an extract of term placenta. The inhibitory activity of the placental samples was not related to their eCG content as measured by immunoassay. The fact that one pregnant horn allantochorion extract containing 50 IU/ml of eCG showed an identical dose-dependent lymphoproliferation-inhibitory activity to an extract of a second such allantochorion containing only 1.7 IU/ml of eCG suggests that this hormone does not inhibit lymphocyte proliferation and that commercially available eCG contains inhibitory contaminants.

Suppression of in vitro lymphocyte reactivity to phytohemagglutinin by placental protein 14.

Crude human decidual extracts containing up to 26.6 mg/l of placental protein 14 (PP14) and purified PP14 were assessed for their effects on the in vitro lymphocyte reactivity to phytohemagglutinin (PHA). Both decidual extract and purified PP14 suppressed the mitogenic response to PHA with the suppression being dose-dependent over the range of PP14 concentrations investigated (0-26.6 mg/l). On the specific reduction of the PP14 content by a monoclonal anti-PP14 immunoadsorbant the suppression was reduced. The suppressive activity of PP14 was related to the degree of proliferation of the stimulated lymphocytes. These results suggest that PP14, which is present at peak levels in the first trimester of pregnancy and constitutes up to 10% of the soluble protein content of decidual tissue, may be an immunomodulator important for the survival of the implanting embryo and maintenance of early pregnancy.

An analysis of the variation of plasma concentrations of placental protein 14 in artificial cycles.

OBJECTIVE: To analyze the factors affecting the variation of plasma concentration of placental protein 14 (PP14) in artificial cycles. DESIGN: The effects of different hormone replacement therapy (HRT) regimens were examined in a crossover design. SETTING: Jessop Hospital for Women, Sheffield, United Kingdom. PATIENTS: Eighteen women with premature ovarian failure: 6 associated with Turner's syndrome and 12 with idiopathic premature ovarian failure. INTERVENTIONS: Four different HRT regimens; 36 study cycles. MAIN OUTCOME MEASURES: Plasma PP14 concentrations on days 1, 15, 19, and 29 of the artificial cycles. RESULTS: In cycles treated with a standard HRT, the levels were similar to those of the natural cycle. Subjects with Turner's syndrome did not have elevated PP14 levels, whereas the majority (9/12 [75%]) of those with idiopathic premature ovarian failure had elevated levels on day 29 of the cycle. Levels of PP14 were reduced when either the doses of estradiol valerate were reduced to 1/3 or the doses of progesterone (P) were reduced to 1/5 of the standard HRT. CONCLUSIONS: Plasma levels of PP14 are dependent not only on P stimulation but also on adequate estrogen priming.

The effects of clomiphene citrate and cyclofenil on cervical mucus volume and receptivity over the periovulatory period.

OBJECTIVE: To determine the effects of clomiphene citrate (CC) and cyclofenil on cervical mucus (CM) volume and receptivity sampled serially over the periovulatory period. DESIGN: Using prospective luteinizing hormone (LH) timing CM volume and receptivity were compared in standard CC and cyclofenil-stimulated cycles using normal ovulatory cycles as controls. LOCATION: The Donor Insemination Unit at the University Research Clinic, Sheffield, United Kingdom. PATIENTS: Twenty anovulatory patients and 10 normally ovulating patients, all of whom were participating in a treatment cycle of donor insemination. INTERVENTIONS: The 20 anovulatory patients were allocated at random into two groups: group 1 was administered 50 mg of CC on days 2 to 6 of the menstrual cycle; group 2 was administered 400 mg of cyclofenil on days 3 to 12 of the menstrual cycle. All the patients were given a single treatment of donor insemination 24 to 36 hours after the onset of the LH surge. RESULTS: Clomiphene citrate and cyclofenil were shown to exert differential impacts on CM quantity and quality. In terms of quantity, the CC patients produced significantly lower volumes of CM than the cyclofenil patients and controls. In terms of quality, the CC patients and controls produced CM of similar receptivity, whereas the cyclofenil patients produced CM that was significantly more receptive to sperm than both the CC patients and controls. CONCLUSIONS: Neither CC nor cyclofenil exerted a detrimental impact on CM quality throughout the periovulatory period.

Round cells and sperm fertilizing capacity: the presence of immature germ cells but not seminal leukocytes are associated with reduced success of in vitro fertilization.

Fifty semen samples produced for IVF by patients diagnosed as having unexplained infertility were screened for leukocytes, leukocyte subsets, and immature germ cells using a mAB-based staining procedure. Nonfertilizing ejaculates were found to contain significantly larger numbers of immature germ cells, although no significant differences in leukocyte content were observed between groups. Neither sperm density or progressive motility were significantly different between fertilizing and nonfertilizing groups. We conclude that seminal leukocytes have little if any influence on the fertilizing capacity of the spermatozoa in patients undergoing IVF for unexplained infertility, but the presence of large numbers of germinal elements is associated with reduced fertilizing capacity and may be indicative of an immature sperm population.

Salivary beta-thromboglobulin: a possible marker for deep vein thrombosis following elective hip surgery.

The concentration of the platelet specific protein B-thromboglobulin, (BTG) was measured in salivary samples obtained pre and postoperatively from 30 patients without evidence of renal disease and having total hip replacement arthroplasty. When postoperative deep-vein thrombosis (DVT) was detected using percutaneous ascending phlebography there was total correlation with elevated salivary BTG levels taking 0.33 micrograms/1 or greater on 2 consecutive occasions or more as indicating a deep venous thrombus. Eight of nine patients with a positive diagnosis of DVT on urokinase scanning would have been diagnosed using the same criterion. However BTG was elevated in a further 5 patients in whom labelled urokinase failed to demonstrate a DVT. These may have been localised in the calf and thus missed by, or lysed prior to, the scanning technique.

Formation of a vitamin B-12-serum complex on heating at alkaline pH.

The binding of vitamin B-12 to serum proteins during heating at alkaline pH was investigated by gel filtration of serum supplemented with cyano[57Co]-cobalamin. Heating for 5 min at 100 degrees C destroyed most of the vitamin B-12 binding activity of serum but, with further heating, the vitamin B-12 became incorporated into a complex that did not correspond in molecular size to the original vitamin B-12 binding proteins. Radioassay of vitamin B-12 in heated serum showed correspondingly first an increase then a progressive decrease in the apparent vitamin B-12 level suggesting that, on heating, vitamin B-12 was initially released then subsequently complexed by the serum. The formation of complexed vitamin B-12 was abolished by the presence of the reducing agent dithiothreitol during the heating step.

The radioimmunoassay of human placental protein 14 (PP14).

The development and validation of a radioimmunoassay for the measurement of human placental protein 14 in maternal serum is described. The mean concentration of this protein in serum from 22 normal pregnant women showed a decline during the third trimester from 120 micrograms/l at 27 weeks gestation to 65 micrograms/l at term. Serum samples from 16 patients with intra-uterine growth retardation tended to contain lower concentrations of placental protein 14, these results reaching significance at weeks 36-38 of gestation. Of seven patients with pre-eclampsia from whom two or more blood samples were taken, four showed increases in concentration of this protein as pregnancy proceeded, compared with the normal pattern of decreasing values.

Effect of combined heat, ozonation and ultraviolet irradiation (VasoCare) on heat shock protein expression by peripheral blood leukocyte populations.

The re-administration of whole blood subjected to heat, ozonation and ultraviolet irradiation (VasoCare therapy) has been shown to elicit clinical benefits in individuals with vascular disease. Given that these stressors induce heat shock protein (Hsp) expression and that heat shock protein reactivity is implicated in the pathogenesis of vascular disease, this study assessed the effect of VasoCare on intracellular expression of Hsp60 and Hsp70 by treated peripheral blood leukocytes. Contrary to expectations, VasoCare induced a significant reduction (approximately 40%) in the proportion of peripheral blood mononuclear cells expressing intracellular Hsp60 and Hsp70, whereas it had no effect on heat shock protein expression by peripheral blood neutrophils. Cell surface heat shock protein expression was not detectable. The reduced expression of Hsp60 by mononuclear cells was concomitant with an increase in the levels of Hsp60 in treated plasma. Although the mechanism underlying the clinical effectiveness of VasoCare therapy has yet to be established, it may be that re-administration of treated blood or soluble factors derived therefrom modifies in vivo immune responsiveness to heat shock proteins or associated molecules.

Measurements of hCG and PAPP-A in uncommon types of ectopic gestation.

Seven out of 54 women with ectopic gestation had uncommon features such as extra-tubal implantation or multiple intratubal pregnancy. Depressed levels (less than 10th centile) or apparent absence of circulating human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein A (PAPP-A) were seen respectively in 5 and 7 of 7 women studied. Normal levels of hCG were seen in two women, one with an abdominal and one with an angular pregnancy. These data suggest that the synthesis of placental proteins in ectopic pregnancies is independent of the site of implantation and the number of embryos. Measurements of maternal levels of the 2 placental proteins seem to be applicable as auxiliary diagnostic tests for ectopic pregnancy, regardless of the site of implantation.

Treatment of severe Raynaud's syndrome by injection of autologous blood pretreated by heating, ozonation and exposure to ultraviolet light (H-O-U) therapy.

OBJECTIVE: To determine the effect of re-injection of small samples of autologous blood, pretreated with heat, ozone and ultraviolet light (H-O-U therapy) in patients with severe Raynaud's syndrome. EXPERIMENTAL DESIGN: Open trial in 4 patients. SETTING: Temperature/humidity controlled vascular laboratory. PATIENTS: Severe Raynaud's syndrome of more than 5 years duration and defined as more than 5 attacks daily or 10 attacks in one week, at least half of which were painful and lasting for more than 30 minutes. Three patients were refractory to infusions of Iloprost. INTERVENTIONS: Patients were treated daily or on alternate days for a two to three weeks period by re-injection of citrated autologous blood pre-treated with heat, ozone and ultraviolet light (H-O-U therapy). MEASURES: Clinical observations; mean equilibrated hand temperature (infrared thermography); distributive and microcirculatory blood-flow (venous occlusion strain-gauge plethysmography, infrared photoplethysmography, laser Doppler flowmetry) iontophoresis of acetylcholine and sodium nitroprusside; estimations: serum levels of 6-keto-PGF1alpha and serum levels of anti-hsp65 antibody. RESULTS: Reduction or abolition of Raynaud's attacks for at least three months after treatment. Mean equilibrated hand temperature increased but did not normalise. Blood flow parameters improved but did not reach statistical significance. Iontophoresis of acetylcholine showed an increase in laser Doppler flowmetry which was statistically significant. Serum levels of 6-keto-PGF1alpha, fell significantly in three patients. Serum levels of anti-hsp65 antibody fell in the one patient which was followed sequentially. CONCLUSIONS: H-O-U therapy may prove useful in patients with severe Raynaud's syndrome.

The variation of endometrial protein PP14 in different parts of the human endometrium.

The levels of the endometrial protein PP14 were shown to vary greatly in different sites in the endometrium (coefficient of variation ranged from 55% to 92%, mean = 73%). The variation was found to have no consistent pattern in the seven subjects studied and was unlikely to be the result of problems related to tissue sampling, processing or assay (intra-assay coefficient of variation of the PP14 assay used was less than 10%). Such a large variation in results suggests that the measurement of PP14 concentration in endometrial tissue may be of limited diagnostic value.