Health-related quality of life in women after colposcopy: results from a longitudinal patient survey.

BACKGROUND: Information concerning the health-related quality-of-life (HRQoL) consequences of colposcopy is limited, particularly over time. In a longitudinal study, we investigated women's HRQoL at 4, 8 and 12 months post colposcopy and the factors associated with this. METHODS: Women attending colposcopy at two large hospitals affiliated with the national screening programme in Ireland were invited to complete questionnaires at 4, 8 and 12 months post colposcopy. HRQoL was measured using the EQ-5D-3L and compared across a range of socio-demographic, clinical and attitudinal variables. A mixed-effects logistic multivariable model was employed to investigate associations between these variables and low HRQoL. RESULTS: Of 584 women initially recruited, 429, 343 and 303 completed questionnaires at 4, 8 and 12 months, respectively. The mean overall HRQoL score for the sample across all time points was 0.90 (SD 0.16). Approximately 18% of women experienced low HRQoL at each of the three time points. In multivariable testing, over the entire 12-month follow-up period, non-Irish nationals (OR 8.99, 95% CI 2.35-34.43) and women with high-grade referral cytology (OR 2.78, 95% CI 1.08-7.13) were at higher odds of low HRQoL. Women who were past (OR 0.20, 95% CI 0.07-0.58) or never (OR 0.42, 95% CI 0.16-1.12) smokers were at lower odds of low HRQoL than current smokers. As women's satisfaction with their healthcare increased their odds of experiencing low HRQoL fell (OR per unit increase 0.51, 95% CI 0.34-0.75). CONCLUSIONS: Women's HRQoL did not change over the 12 months post colposcopy, but some subgroups of women were at higher risk of experiencing low HRQoL. These subgroups may benefit from additional support.

Physical after-effects of colposcopy and related procedures, and their inter-relationship with psychological distress: a longitudinal survey.

OBJECTIVE: To estimate prevalence of post-colposcopy physical after-effects and investigate associations between these and subsequent psychological distress. DESIGN: Longitudinal survey. SETTING: Two hospital-based colposcopy clinics. POPULATION: Women with abnormal cytology who underwent colposcopy (±related procedures). METHODS: Questionnaires were mailed to women 4, 8 and 12 months post-colposcopy. Details of physical after-effects (pain, bleeding and discharge) experienced post-colposcopy were collected at 4 months. Colposcopy-specific distress was measured using the Process Outcome-Specific Measure at all time-points. Linear mixed-effects regression was used to identify associations between physical after-effects and distress over 12 months, adjusting for socio-demographic and clinical variables. MAIN OUTCOME MEASURES: Prevalence of post-colposcopy physical after-effects. Associations between the presence of any physical after-effects, awareness of after-effects, and number of after-effects and distress. RESULTS: Five-hundred and eighty-four women were recruited (response rate = 73, 59 and 52% at 4, 8 and 12 months, respectively). Eighty-two percent of women reported one or more physical after-effect(s). Multiple physical after-effects were common (two after-effects = 25%; three after-effects = 25%). Psychological distress scores declined significantly over time. In adjusted analyses, women who experienced all three physical after-effects had on average a 4.58 (95% CI: 1.10-8.05) higher distress scored than those who experienced no after-effects. Women who were unaware of the possibility of experiencing after-effects scored significantly higher for distress during follow-up. CONCLUSIONS: The prevalence of physical after-effects of colposcopy and related procedures is high. The novel findings of inter-relationships between awareness of the possibility of after-effects and experiencing multiple after-effects, and post-colposcopy distress may be relevant to the development of interventions to alleviate post-colposcopy distress. TWEETABLE ABSTRACT: Experiencing multiple physical after-effects of colposcopy is associated with psychological distress.

Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype.

We have shown that CD39 and CD73 are coexpressed on the surface of murine CD4+ Foxp3+ regulatory T cells (Treg) and generate extracellular adenosine, contributing to Treg immunosuppressive activity. We now describe that CD39, independently of CD73, is expressed by a subset of blood-derived human CD4+ CD25+ CD127lo Treg, defined by robust expression of Foxp3. A further distinct population of CD4+ CD39+ T lymphocytes can be identified, which do not express CD25 and FoxP3 and exhibit the memory effector cellular phenotype. Differential expression of CD25 and CD39 on circulating CD4+ T cells distinguishes between Treg and pathogenic cellular populations that secrete proinflammatory cytokines such as IFNγ and IL-17. These latter cell populations are increased, with a concomitant decrease in the CD4+ CD25+ CD39+ Tregs, in the peripheral blood of patients with renal allograft rejection. We conclude that the ectonucleotidase CD39 is a useful and dynamic lymphocytes surface marker that can be used to identify different peripheral blood T cell-populations to allow tracking of these in health and disease, as in renal allograft rejection.

Photochemical air pollution: transport from the New York City area into Connecticut and Massachusetts.

Photochemical air pollution resulting from primary emissions in the New York City metropolitan area is transported by prevailing winds on a 300-kilometer northeast trajectory through Connecticut and as far as northeastern Massachusetts. As a result, southwestern Connecticut has the highest ozone concentrations in the region and there is a substantial increase in ozone concentrations in Massachusetts. The ozone concentrations of air entering the New York City metropolitan area are often already above the federal standard of 0.08 part per million, but the concentration distribution is well below concentration distributions at downwind sites in Connecticut.

Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.

Beta-endorphin inhibits glucose production in the conscious dog.

The effect of human beta-endorphin (h beta E) infusion (0.2 mg/h) on glucose homeostasis was studied in 10 conscious overnight fasted dogs in which endocrine pancreatic function was fixed at basal levels with somatostatin plus intraportal replacement of basal insulin and glucagon. h beta E caused a fall in plasma glucose from 107 +/- 5 to 76 +/- 6 mg/dl by 3 h (P less than 0.01). This was due to a 25% fall in tracer-determined glucose production (Ra; P less than 0.01). A significantly larger fall in Ra was observed in four dogs in which hypoglycemia was prevented by use of an exogenous glucose infusion (45 vs. 25%, P less than 0.05). These changes occurred in the absence of changes in circulating levels of insulin, glucagon, epinephrine, norepinephrine, and cortisol. We conclude that the naturally occurring opioid peptide, beta-endorphin, inhibits glucose production by the liver in vivo. This appears to be a direct effect of the opioid on the liver, since the inhibition took place in the absence of changes in the other hormones measured. These results suggest that endorphins act on glucose homeostasis in a complex way, both by affecting other glucoregulatory hormones as demonstrated elsewhere, and by directly modulating hepatic glucose production as shown here.

Effects of morphine on glucose homeostasis in the conscious dog.

This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma glucose, P less than 0.05) that is due to inhibition of glucose production (by 25-43%, P less than 0.05). The hypoglycemia was independent of detectable changes in insulin, glucagon, epinephrine and cortisol, and was not reversed by concurrent infusion of a slight molar excess of naloxone. Therefore, we postulate that the hypoglycemic effect of morphine results from the interaction of the opiate with non-mu receptors either in the liver or the central nervous system.

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

INTRODUCTION: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology. SUBJECTS: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded. RESULTS: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls. CONCLUSION: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes.

Globally type 1 diabetes incidence is increasing. It is widely accepted that the pathophysiology of type 1 diabetes is influenced by environmental factors in people with specific human leukocyte antigen haplotypes. We propose that a complex interplay between dietary triggers, permissive gut factors and potentially other influencing factors underpins disease progression. We present evidence that A1 ß-casein cows' milk protein is a primary causal trigger of type 1 diabetes in individuals with genetic risk factors. Permissive gut factors (for example, aberrant mucosal immunity), intervene by impacting the gut's environment and the mucosal barrier. Various influencing factors (for example, breastfeeding duration, exposure to other dietary triggers and vitamin D) modify the impact of triggers and permissive gut factors on disease. The power of the dominant trigger and permissive gut factors on disease is influenced by timing, magnitude and/or duration of exposure. Within this framework, removal of a dominant dietary trigger may profoundly affect type 1 diabetes incidence. We present epidemiological, animal-based, in vitro and theoretical evidence for A1 ß-casein and its ß-casomorphin-7 derivative as dominant causal triggers of type 1 diabetes. The effects of ordinary milk containing A1 and A2 ß-casein and milk containing only the A2 ß-casein warrant comparison in prospective trials.

Prostaglandin E2 metabolite levels during diabetic ketoacidosis.

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.

Dropout and relapse during diabetes care.

OBJECTIVE: To determine factors associated with dropout and relapse during chronic diabetes care. RESEARCH DESIGN AND METHODS: Private practice outpatient treatment-education program for adult diabetes was surveyed. Retrospective analysis was done, involving 422 patients for up to 3 yr. RESULTS: Of the patients in the study, 12% dropped out after the initial visit, and 33% of the residual cohort dropped out during each subsequent 6-mo period. Factors associated with dropout included distance from home to clinic > 100 miles, lack of insulin treatment, and cigarette smoking. In patients who remained in follow-up, a significant decrease in HbA1C occurred during the first 6 mo, but 40% of the patients relapsed between 6 and 12 mo. Frequency of relapse declined as time passed. Relapse was more frequent in women. CONCLUSIONS: Dropout from treatment and relapse after temporary improvement account for a substantial amount of uncontrolled diabetes, and overcoming the obstacles of dropout and relapse has potential for significant improvement in diabetes care.

Chemistry of 99mTc tracers. II. In vitro conversion of tagged HEDP and pyrophosphate (bone-seekers) into gluconate (renal agent). Effects of Ca and Fe (ii) on in vivo distribution.

Sodium gluconate transforms the bone-seekers 99mTc-HEDP and 99mTc-pyrophosphate into the renal agent 99mTc-gluconate. In these in vitro processes, pyrophosphate is displaced faster than HEDP, while the HEDP reaction is accelerated by calcium ions. The in vivo distributions of these bone and kidney agents are altered by the prior local injection of calcium or iron(II). These transformation and translocation phenomena are explained in terms of the mechanistic behavior of Tc(IV) complexes.

Chemistry of technetium radiopharmaceuticals. I. Exploration of the tissue distribution and oxidation state consequences of technetium (IV) in Tc-Sn-gluconate and Tc-Sn-EHDP using carrier 99Tc.

The distribution in rats of the renal agent Tc-Sn-gluconate using both 99mTc and carrier amounts of 99Tc was similar. The same behavior was shown with the bone agent Tc-Sn-EHDP. The radiopharmaceutical consequences of the observed Tc(IV) oxidation state in these systems are explored.

A role for endogenous prostaglandins in defective glucose potentiation of nonglucose insulin secretagogues in diabetics.

Noninsulin dependent diabetics have insulin responses to nonglucose secretagogues that are subnormal for their plasma glucose levels. Since endogenous prostaglandins have been implicated in the abnormal insulin responses to glucose in diabetics, the present study was performed to explore whether prostaglandins might also play a role in the defective insulin responses to nonglucose stimuli. We examined the effects of infusions of either prostaglandin E2 (PGE2) or sodium salicylate (SS), a PG synthesis inhibitor, on the acute insulin responses (AIR's) to arginine and isoproterenol and on the glucose potentiation of the insulin response to arginine in both normal and diabetic subjects. The AIR to arginine was augmented by SS in diabetics (SS = 61 +/- 12 microunits/ml, control = 37 +/- 5 microunits/ml, n = 11, p less than .01). SS, however, had no effect on the AIR to arginine in normal subjects (SS = 39 +/- 4 microunits/ml. control = 34 +/- 4 microunits/ml, n = 6, p = ns). Similarly, SS augmented the AIR to an isoproterenol pulse in diabetics (SS = 38 +/- 9 microunits/ml, control = 18 +/- 3, n = 9, p less than .05) but not in normal subjects (SS = 19 +/- 4 microunits/ml, control = 21 +/- 4 microunits/ml, n = 8, p = ns), suggesting a SS-sensitive defect in the insulin response to these nonglucose stimuli in diabetics. Conversely, PGE2 inhibited the AIR to arginine in diabetics (PGE = 28 +/- 5 microunits/ml, control = 39 +/- 7 microunits/ml, n = 7, p less than .05), but not in normal subjects (PGE = 74 +/- 7 microunits/ml, control = 80 +/- 14 microunits/ml, n = 5, p = ns). The effect of SS on glucose potentiation of the AIR to arginine was studied by measuring the AIR to arginine at two different levels of plasma glucose, one before and one after an insulin infusion, with glucose potentiation defined as the ratio delta AIR/delta prestimulus glucose. Glucose potentiation was significantly less in diabetics than in normals and SS significantly improved glucose potentiation toward normal values in diabetics but did not change glucose potentiation in normals. These findings suggest that endogenous PG's may play a role in the defective glucose potentiation of the AIR to nonglucose secretagogues in diabetics resulting in impaired insulin responses to these stimuli. This defect is partially reversible by an inhibitor of PG synthesis.

Some empirical evidence on post-patent barriers to entry in the Canadian pharmaceutical industry.

In this paper we present some empirical evidence and comment upon the significance of being a pioneering drug in the Canadian pharmaceutical market. We analyse prices and market shares of 21 first entrant drugs in the Canadian pharmaceutical industry. The Canadian experience described in this paper is, we believe, of considerable relevance to U.S. policy makers. Canadian public policy, both federal and provincial, has already created the competitive environment that some U.S. policy makers seek. This paper documents the effect of such a system on the price of drugs and the market shares, hence the revenues, of patent-holders.

Immunohistological detection of C5b-9 complement complexes in normal and pathological human livers.

The immunohistological localization of components and neoantigens of the C5b-9 human terminal complement complex was studied in 30 human liver biopsies. C5b-9, apparently in the soluble SC5b-9 form, was invariably detected in normal liver capsule and normal portal tract connective tissue. In livers with fibrosis and or cirrhosis, the pathological connective tissue contained variable amounts of SC5b-9 which was distributed in a similar way to that seen in normal livers. There was no significant C5b-9 deposition outside of the portal tract and capsule in any of the liver biopsies. In particular, in pathological livers, there was no deposition in relation to cellular infiltrates or areas of hepatic necrosis. These data support the concept that C5b-9 is a common component of connective tissue but do not indicate that C5b-9 mediated pathways are involved in the pathogenesis of hepatic injury.

Hydrolysis kinetics of the monophosphate ester triclofos sodium.

The hydrolysis kinetics of the monophosphate ester triclofos sodium were studied in the pH 0.00--7.80 range, the 80.1--98.4 degrees range, and ionic strengths of 0.02--1.50. The pK1 and pK2 values for triclofos were 1.00 +/- 0.05 and 5.80 +/- 0.05, respectively. The pH dependency observed was consistent with a theory in which the hydrolysis rates of the triclofos species follow the order: monoanion greater than unionized greater than dianion. The apparent first-order rate constants at 80.1 degrees associated with each species were 6.4 +/- 0.6 X 10(-3), 28.0 +/- 0.5 X 10(-3), and 0.3 +/- 0.1 hr-1, respectively, Different Arrhenius activation energies were observed at pH 0.00, 3.50, and 7.80, at which values the unionized, monoanion, and dianion forms were the dominant species present, respectively. The reaction showed a modest positive kinetic salt effect at pH 3.50 and a modest negative effect at pH 7.80. Various mechanistic possibilities are discussed.

Encopresis: developmental, behavioral and physiological considerations for treatment.

Encopresis (soiling in the clothing) is a complex condition presenting a treatment challenge for health care providers. It is a disruptive event, placing both the child and family at risk for crisis. The definition, incidence, etiology and relevant medical, behavioral and developmental theory are discussed. A multi-dimensional encopretic evaluation and management model is presented that addresses encopresis at developmental, behavioral and physiological levels. This system includes a detailed historical, demographic, behavioral and school-performance profile of the child; appropriate physical and laboratory examinations; and a treatment approach that incorporates bowel evacuation, a high-fiber diet, techniques of behavior modification, and maintenance on either contingent rectal cathartics or oral laxatives. If there are significant behavioral concerns and/or the family is dysfunctional, collaborative psychiatric management can be arranged.