Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies.

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.

BACKGROUND: Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. METHOD: We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. RESULTS: We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). CONCLUSIONS: Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.

Job strain and the risk of severe asthma exacerbations: a meta-analysis of individual-participant data from 100 000 European men and women.

BACKGROUND: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. METHODS: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. RESULTS: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). CONCLUSIONS: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

Characterizing citrullination by mass spectrometry-based proteomics.

Citrullination is an important post-translational modification (PTM) of arginine, known to play a role in autoimmune disorders, innate immunity response and maintenance of stem cell potency. However, citrullination remains poorly characterized and not as comprehensively understood compared to other PTMs, such as phosphorylation and ubiquitylation. High-resolution mass spectrometry (MS)-based proteomics offers a valuable approach for studying citrullination in an unbiased manner, allowing confident identification of citrullination modification sites and distinction from deamidation events on asparagine and glutamine. MS efforts have already provided valuable insights into peptidyl arginine deaminase targeting along with site-specific information of citrullination in for example synovial fluids derived from rheumatoid arthritis patients. Still, there is unrealized potential for the wider citrullination field by applying MS-based mass spectrometry approaches for proteome-wide investigations. Here we will outline contemporary methods and current challenges for studying citrullination by MS, and discuss how the development of neoteric citrullination-specific proteomics approaches still may improve our understanding of citrullination networks. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Job strain in relation to body mass index: pooled analysis of 160 000 adults from 13 cohort studies.

BACKGROUND: Evidence of an association between job strain and obesity is inconsistent, mostly limited to small-scale studies, and does not distinguish between categories of underweight or obesity subclasses. OBJECTIVES: To examine the association between job strain and body mass index (BMI) in a large adult population. METHODS: We performed a pooled cross-sectional analysis based on individual-level data from 13 European studies resulting in a total of 161 746 participants (49% men, mean age, 43.7 years). Longitudinal analysis with a median follow-up of 4 years was possible for four cohort studies (n = 42 222). RESULTS: A total of 86 429 participants were of normal weight (BMI 18.5-24.9 kg m(-2) ), 2149 were underweight (BMI < 18.5 kg m(-2) ), 56 572 overweight (BMI 25.0-29.9 kg m(-2) ) and 13 523 class I (BMI 30-34.9 kg m(-2) ) and 3073 classes II/III (BMI ≥ 35 kg m(-2) ) obese. In addition, 27 010 (17%) participants reported job strain. In cross-sectional analyses, we found increased odds of job strain amongst underweight [odds ratio 1.12, 95% confidence interval (CI) 1.00-1.25], obese class I (odds ratio 1.07, 95% CI 1.02-1.12) and obese classes II/III participants (odds ratio 1.14, 95% CI 1.01-1.28) as compared with participants of normal weight. In longitudinal analysis, both weight gain and weight loss were related to the onset of job strain during follow-up. CONCLUSIONS: In an analysis of European data, we found both weight gain and weight loss to be associated with the onset of job strain, consistent with a 'U'-shaped cross-sectional association between job strain and BMI. These associations were relatively modest; therefore, it is unlikely that intervention to reduce job strain would be effective in combating obesity at a population level.

Electrospray ionization tandem mass spectrometry sequencing of novel skin peptides from Ranid frogs containing disulfide bridges.

Tandem mass spectrometry sequencing, as well as Edman sequencing of peptides belonging to the Rana genus, represents a difficult task due to the presence of a disulfide bridge at the C-terminus and their rather high molecular masses (over 2000 Da). The present study throws light upon the sequence of three rather long peptides (more than 20 amino acid residues each) isolated from the skin secretion of Russian frogs, Rana ridibunda and Rana arvalis. This novel aspect involves the fact that the sequences (including two sequences established de novo) were determined exclusively by means of mass spectrometry. A combination of electron capture dissociation (ECD) and collision-induced dissociaiton (CID) data accompanied by exact mass measurements (LTQ Fourier transform ion cyclotron resonance mass spectrometer) facilitated reaching the goal. To overcome the difficulty dealing with disulphide bridges ("Rana box"), reduction of the S-S bond with dithiotreitol followed by derivatization of Cys residues with iodoacetamide was used. The sequence was determined using combined spectral data on y and b series of fragment ions. A multiple mass spectrometry (MS(3)) experiment was also used to elucidate the sequence inside the "Rana box" after cysteine derivatization. Exact mass measurements were used to differentiate between Lys and Gln residues, while characteristic losses of 29 and 43 Da (d and w fragment ions) in CID and ECD experiments allowed us to distinguish between Ile and Leu isomeric acids.

Yeast chromosomes have been significantly reshaped during their evolutionary history.

The structure of the first eukaryotic genome, belonging to Saccharomyces cerevisiae, has been deduced; however, very little is known about its origin. In order to trace events that led to the current state of the Saccharomyces nuclear genomes, random fragments of genomic DNA from three yeasts were sequenced and compared to the S. cerevisiae database sequence. Whereas, S. cerevisiae and Saccharomyces bayanus show perfect synteny, a significant portion of the analysed fragments from Saccharomyces servazzii and Saccharomyces kluyveri show a different arrangement of genes when compared to S. cerevisiae. When the sequenced fragments were probed to the corresponding karyotype, a group of genes present on a single chromosome of S. servazzii and S. kluyveri had homologues scattered on several S. cerevisiae chromosomes. Apparently, extensive reorganisation of the chromosomes has taken place during evolution of the Saccharomyces yeasts. In addition, while one gross duplication could have taken place, at least a few genes have been duplicated independently at different time-points in the evolution.

Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse.

Prenatal nicotine exposure (PNE) is a risk factor for developing an addiction to nicotine at a later stage in life. Understanding the neurobiological changes in reward related circuitry induced by exposure to nicotine prenatally is vital if we are to combat the heightened addiction liability in these vulnerable individuals. The laterodorsal tegmental nucleus (LDT), which is comprised of cholinergic, GABAergic and glutamatergic neurons, is importantly involved in reward mediation via demonstrated excitatory projections to dopamine-containing ventral tegmental neurons. PNE could lead to alterations in LDT neurons that would be expected to alter responses to later-life nicotine exposure. To examine this issue, we monitored nicotine-induced responses of LDT neurons in brain slices of PNE and drug naive mice using calcium imaging and whole-cell patch clamping. Nicotine was found to induce rises in calcium in a smaller proportion of LDT cells in PNE mice aged 7-15 days and smaller rises in calcium in PNE animals from postnatal ages 11-21 days when compared with age-matched control animals. While inward currents induced by nicotine were not found to be different, nicotine did induce larger amplitude excitatory postsynaptic currents in PNE animals in the oldest age group when compared with amplitudes induced in similar-aged control animals. Immunohistochemically identified cholinergic LDT cells from PNE animals exhibited slower spike rise and decay slopes, which likely contributed to the wider action potential observed. Further, PNE was associated with a more negative action potential afterhyperpolarization in cholinergic cells. Interestingly, the changes found in these parameters in animals exposed prenatally to nicotine were age related, in that they were not apparent in animals from the oldest age group examined. Taken together, our data suggest that PNE induces changes in cholinergic LDT cells that would be expected to alter cellular excitability. As the changes are age related, these PNE-associated alterations could contribute differentially across ontogeny to nicotine-mediated reward and may contribute to the particular susceptibility of in utero nicotine exposed individuals to addict to nicotine upon nicotine exposure in the juvenile period.

Uncontrolled hypertension is associated with coronary artery calcification and electrocardiographic left ventricular hypertrophy: a case-control study.

We conducted a 1:2 matched case-control study in order to evaluate whether the prevalence of coronary artery calcium (CAC) and electrocardiographic left ventricular hypertrophy (LVH) or strain was higher in patients with uncontrolled hypertension than in subjects from the general population, and evaluate the association between CAC and LVH in patients with uncontrolled hypertension. Cases were patients with uncontrolled hypertension, whereas the controls were random individuals from the general population without cardiovascular disease. CAC score was assessed using a non-contrast computed tomographic scan. LVH was evaluated using the Sokolow-Lyon voltage combination and Cornell voltage-duration product, respectively. Associations between CAC, LVH and traditional cardiovascular risk factors were tested by means of ordinal, conditional and classic binary logistic regression models. We found that uncontrolled hypertension was independently associated with both an ordinal CAC score category (odds ratio (OR) 3.9 (95% CI, 1.6-9.1), P = 0.002), the presence of CAC score>99 (OR 4.5 (95% CI, 1.4-14.7), P = 0.01) and electrocardiographic LVH (OR 10.1 (95% CI, 3.4-30.2), P < 0.001) on both univariate and multivariable analyses. There was, however, no correlation between CAC and LVH. The lack of an association between CAC and LVH suggests that they are markers of different complications of hypertension and may have independent predictive values. Patients with both CAC and LVH may be at higher risk than those in whom only one of these markers is present.

Life expectancies among survivors of acute cerebrovascular disease.

BACKGROUND AND PURPOSE: Stroke survivors represent a large group of persons for whom age-differentiated life expectancy tables do not exist. Such tables are vital for many purposes. The aim of the present study was to estimate age- and sex-specific life expectancies among individuals who have survived the acute phase (1 month) of a cerebrovascular disease (CVD). METHODS: All patients who were registered with the Swedish National Hospital Discharge Registry with an admission for CVD (ICD codes 430 to 438) between January 1, 1989, and November 30, 1993, and were alive at the end of 1993 (N=103 591) were followed for mortality rates in 1994. The same was done for 1983. Actuarial analyses were used to convert death rates into life expectancies. RESULTS: Life expectancy among CVD survivors increased with time (1983 versus 1994): 22.9% for men (95% CI 18.3% to 27.6%) and 12.9% for women (95% CI 9.1% to 16.6%). The life expectancy ratio in 1983 between CVD survivors and the general population was 0.571 (95% CI 0.533 to 0.590) for men and 0.578 (95% CI 0.562 to 0.592) for women. In 1994, the corresponding ratios were 0.641 (95% CI 0.629 to 0.654) and 0.611 (95% CI 0.601 to 0.622). The life expectancy ratios between female and male survivors were 1.28 (95% CI 1.23 to 1.34) in 1983 and 1.18 (95% CI 1.15 to 1.21) in 1994. The prognosis for survivors who experienced occlusion and stenosis of the precerebral arteries was better than that for survivors of an intracerebral hemorrhage (P=4.4E-4) or occlusion of cerebral arteries (P=3.8E-8). CONCLUSIONS: Although the prognosis has improved for all ages, stroke survivors still constitute a large group of persons with a low life expectancy compared with the general population.

Models to study the pathogenesis of thyroid autoimmunity.

In vitro and in vivo models to study the pathogenesis of thyroid autoimmunity are reviewed. Animal models with experimentally induced or spontaneously developed autoimmune thyroid disease as well as transplantation models have been used extensively in these studies, but also the use of thyroid cell cultures from both humans and animals has contributed to the present state of knowledge. Cytokines may play a role in the pathogenic mechanism in thyroid autoimmunity. The major in vitro and in vivo effects of for example interleukin-1, tumour necrosis factor and gamma-interferon on differentiated thyroid cell functions are inhibitory. The advantage of using cell cultures has been the possibility of studying an influence on thyrocytes from a single agent individually, such as cytokines, hormones or growth factors. The disadvantage is that an organism is under the influence of a multitude of factors that can only be investigated in vivo in intact organisms. Both types of models have therefore been important in the understanding of thyroid autoimmunity.

Hepato-biliary scintigraphy and hepatography with Tc-99m diethyl-acetanilido-iminodiacetate in obstructive jaundice.

Tc-99m diethyl-IDA was used for combined serial hepato-biliary scintigraphy and processing of hepatographic curves, using a scintillation camera and an image-processing system. Patients with obstruction of the common bile duct, proven by operation, were investigated. Hepatograms from an area of interest corresponding to the periphery of the right liver lobe varied predictably with changes in the serum levels of alkaline phosphatase and bilirubin. Both anatomical and functional information was obtained. The investigation could be carried out even under reduced liver function. Hepatic uptake of the agent was noted at serum alkaline phosphatase levels up to 1000 U/l and serum bilirubin levels up to 170 mumol/l.

Neonatal stimulation of the thyroid gland with iodine or suppression during adolescence with triiodothyronine changes the prevalence of autoimmune thyroiditis in BB rats.

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.

Thyrotropin stimulates specifically the expression of the autoantibody binding domains of the thyroperoxidase molecule.

To get some insight on the in vitro effect of TSH on the expression of two thyroid specific antigens (thyroglobulin (Tg) and thyroid peroxidase (TPO)) on the cell surface of cultured human thyroid cells an indirect immunofluorescence-activated cell sorter (FACStar IV, Becton-Dickinson) was used. Only half of the cultures responded to TSH by increased surface expression of the thyroid specific antigen Tg. In these cells, TSH stimulation of TPO expression showed a difference in epitopes recognized by murine monoclonal antibodies. Epitopes of domain D, recognized by monoclonal antibody 1, 30, 40 and 53 which are not involved in autoimmunity, were unaffected by TSH stimulation, (n = 2-10). In contrast, TSH regulated the surface expression of the TPO epitopes recognized by monoclonal antibody 15, 18, 24 and 60, which are known to be related to the serum autoantibody binding domain of TPO, (n = 6-8; p < 0.05). This indicated that increased activity of the thyroid cells selectively stimulated the expression of autoantigenic epitopes on the cell surface and supports the concept that increased cellular activity might predispose to the autoimmune processes leading to autoimmune thyroid disease.

Linomide does not prevent spontaneous autoimmune thyroiditis in NOD mice.

Linomide is a potent immunomodulator and has been reported to prevent type 1 diabetes mellitus in non-obese diabetic (NOD) mice and to reduce the incidence of other autoimmune diseases in animal models. The mechanisms of action seem to involve antigen expression by down regulation of macrophage activity and to antagonise the activation of Th1 cells during the cellular immune response. With the purpose to investigate the effect of Linomide on the incidence of spontaneous autoimmune thyroiditis (AIT) in female NOD mice we administered Linomide in drinking water (100 mg/kg/day) to NOD mice from 5th to 19th week of age. The mice were sacrificed at the end of week 19. None of the mice developed diabetes during the study period. The incidence of thyroiditis was evaluated on paraffin HE-stained sections and graduated on a scale from 0 to 4. Thirty-two percent of 37 mice treated with Linomide developed thyroiditis compared to 45% of 22 controls (p=0.31, chi2 =1.00). Among the mice who developed thyroiditis no difference in the degree of thyroiditis was found. Therefore no beneficial effect of Linomide on the incidence of spontaneous AIT in NOD mice could be demonstrated.

Effect of intrathymic administration of mycobacterial heat shock protein 65 and peptide p277 on the development of diabetes in NOD mice: caution required in vaccination studies.

Heat shock protein 65 (hsp65) and a derived peptide, p277, are autoantigens reported in IDDM. I.p. injection of hsp65 reduced diabetes incidence in NOD mice and administration of p277 cured already diabetic mice. Also, intrathymic (i.t.) administration of whole islets or GAD65 prevented diabetes in NOD mice. The aim of this study was to evaluate whether i.t. injection of mycobacterial hsp65 or p277 can prevent diabetes in NOD mice. Three-week-old NOD female mice were injected intrathymically with 50 microg of hsp65 (n=30), 5 microg of p277 (n=30), and PBS (n=29). Diabetes incidence was observed for the following 300 days. Pancreas was then used for histological and immunohistological evaluation. No significant differences in diabetes incidence were observed among the three groups of mice. Interestingly, hsp65-treated mice developed diabetes slightly faster at 177+/-6 days compared to 202+/-8 days (p=0.015) for the p277-treated group and 197+/-7 days (p=0.033) for controls. The insulitis score and average islet size did not differ significantly among the three groups of diabetic mice. Scattered TCR-gamma/delta positive cells were found in the pancreas of all groups of mice. In contrast, a huge infiltrate of TCR-gamma/delta positive cells was detected in four out of eight (50%) p277-diabetic NOD mice. Thus, our data show an earlier onset of diabetes in hsp65-treated mice and no improvement in the incidence with either hsp65 or p277, suggesting that hsp65 acts in a different way from what was reported with GAD65. Caution is advised in future vaccination studies as hsp65 poses a potential danger.

Cytokine production in NOD mice on prophylactic insulin therapy.

We investigated whether cytokines produced primarily by monocytes/macrophages (IL-1alpha), Th1-lymphocytes (IFNgamma), or Th2-lymphocytes (IL-4) are modulated in diabetes-prone NOD mice by insulin treatment as used in prophylaxis studies. The cytokines were measured by ELISA in plasma and in supernatants of spleen cells activated ex vivo by lipopolysaccharide plus phytohemagglutinin. Insulin, 0.25-0.50 IU/day, was given subcutaneously for 8 weeks starting in 4-week-old female mice. The insulin-treated and control NOD mice showed similar weight gains and, by the end of the study, both groups exhibited cell infiltration in about 25% of their islets. IL-1alpha, IFNgamma and IL-4 were generally below detection in plasma of prediabetic animals and controls. Diabetic NOD mice, aged 28-45 weeks, had significantly elevated plasma IL-1alpha: 154+/-39 pg/ml (mean+/-SEM, p<0.0001). While ex vivo activated NOD splenocytes released similar amounts of IL-1alpha, insulin therapy increased the levels from 99+/-17 to 155+/-19 pg/10(6) cells (p<0.05). Supernatants of activated splenocytes from prediabetic NOD mice had lower levels of IL-4 (<15 pg/10(6) cells) compared with those from BALB/c mice (88+/-22 pg/10(6) cells; p<0.01), and this deficiency was partially compensated for when the NOD mice were given insulin (27+/-8; p<0.01). The levels of IFNgamma were comparable and largely unaffected by insulin treatment. Hence, insulin therapy appears to partially normalize an otherwise deficient Th2 response in NOD mice.

Anaerobic and aerobic skin bacteria before and after skin-disinfection with chlorhexidine: an experimental study in volunteers.

The amount, composition, and localization of anaerobic and aerobic bacteria in the normal skin before and after disinfection were the subject of a volunteer study. The superficial bacterial flora were sampled by velvet pad imprints, and the deep flora were determined from whole skin biopsies. Only one anaerobic species, Propionebacterium acnes, was encountered even though other and more strict anaerobic bacteria could have been grown with the anaerobic technique employed. Staphylococcus albus dominated among the aerobic superficial bacteria, while diphtheroids, Micrococcus spp., and lactobacilli occurred sporadically. The deep aerobic bacteria were present in a significantly greater amount than the anaerobic. A two-step cleansing/disinfection procedure was evaluated in vivo in volunteers as well as in surgical patients, and aqueous cetrimide/chlorhexidine (Savlon) followed by chlorhexidine in alcohol (Hibitane) almost eradicated both the superficial and deep anaerobic and aerobic skin flora.

Basal hyposecretion of gastric inhibitory polypeptide after Roux-Y hepaticojejunostomy in man.

We previously showed that basal and pentagastrin-stimulated gastric acid secretion, gastrin in serum and gastrin in antral mucosa were significantly greater in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodenostomy. These findings prompted investigation of basal secretion of gastric inhibitory polypeptide (a peptide with an enterogastrone as well as an insulinogenic effect), insulin and glucose in the same patients. Basal gastric inhibitory polypeptide was significantly lower in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodensotomy, whereas glucose and insulin did not differ in the two groups. No correlation could be demonstrated between gastric inhibitory polypeptide, gastric acid secretion and gastrin, suggesting that hyposecretion of gastric inhibitory polypeptide is not a pathogenetic factor for the hypersecretion of gastric acid secretion in patients with Roux-Y hepaticojejunostomy. Hyposecretion of gastric inhibitory polypeptide and gastric acid hypersecretion in patients with bile diversion seem to be two independent phenomena.

Cytopathology laboratory improvement programs of the College of American Pathologists: Laboratory Accreditation Program (CAP LAP) and Performance Improvement Program in Cervicovaginal Cytology (CAP PAP).

Major programs of the College of American Pathologists (CAP) are directed toward improvement of laboratory practices through peer review, interlaboratory comparison, education, and development of practice standards and guidelines. Two programs provided to cytopathology laboratories, the Laboratory Accreditation Program and the Interlaboratory Comparison Program in Cervicovaginal Cytology, are dedicated to these laboratory improvement principles. In 1996, each of these programs served over 2100 laboratories that provide cytopathology services. This paper reviews the peer development, structure, and administration of the Laboratory Accreditation Program and the Interlaboratory Comparison Program in Cervicovaginal Cytology, focusing on recent and ongoing initiatives to enhance their contribution to continued improvement of gynecologic cytopathology laboratory practices.