Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma.

BACKGROUND: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. METHODS: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. RESULTS: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. CONCLUSIONS: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC.

Ethnic variation in maternity care: a comparison of Polish and Scottish women delivering in Scotland 2004-2009.

OBJECTIVES: Birth outcomes in migrants vary, but the relative explanatory influence of obstetric practice in origin and destination countries has been under-investigated. To explore this, birth outcomes of Scots and Polish migrants to Scotland were compared with Polish obstetric data. Poles are the largest group of migrants to Scotland, and Poland has significantly more medicalized maternity care than Scotland. STUDY DESIGN: A population-based epidemiological study of linked maternal country of birth, maternity and birth outcomes. METHODS: Scottish maternity and neonatal records linked to birth registrations were analysed for differences in modes of delivery and pregnancy outcomes between Polish migrants and Scots, and compared with Polish Health Fund and survey data. RESULTS: 119,698 Scottish and 3105 Polish births to primiparous women in Scotland 2004-9 were analysed. Poles were less likely than Scots to have a Caesarean section and more likely to have a spontaneous vaginal or instrumental delivery. The Caesarean section rate in Poland is significantly higher and instrumental delivery rate lower than for either group of women in Scotland. CONCLUSIONS: Methodologically, comparing a large group of migrants from one country with the host population has advantages over grouping migrants from several countries into a single category, and allows more informed analysis of the effect of health services. Polish mothers' being slightly healthier explains some of their lower Caesarean section rate compared to Scots in Scotland. However, dominant models of obstetrics in the two countries seem likely to influence the differences between Poles delivering in Poland and Scotland. Further investigation of both is required.

Screening for gestational diabetes mellitus: cost-utility of different screening strategies based on a woman's individual risk of disease.

AIMS/HYPOTHESIS: The cost-effectiveness of eight strategies for screening for gestational diabetes (including no screening) was estimated with respect to the level of individual patient risk. METHODS: Cost-utility analysis using a decision analytic model populated with efficacy evidence pooled from recent randomised controlled trials, from the funding perspective of the National Health Service in England and Wales. Seven screening strategies using various combinations of screening and diagnostic tests were tested in addition to no screening. The primary outcome measure was the incremental cost per quality-adjusted life-year (QALY) over a lifetime. RESULTS: The strategy that has the greatest likelihood of being cost-effective is dependent on the risk of gestational diabetes mellitus for each individual woman. When gestational diabetes mellitus risk is <1% then the no screening/treatment strategy is cost-effective; where risk is between 1.0% and 4.2% fasting plasma glucose followed by OGTT is most likely to be cost-effective; and where risk is >4.2%, universal OGTT is most likely to be cost-effective. However, acceptability of the test alters the most cost-effective strategy. CONCLUSIONS/INTERPRETATION: Screening for gestational diabetes can be cost-effective. The best strategy is dependent on the underlying risk of each individual and the acceptability of the tests used. The current study suggests that if a woman's individual risk of gestational diabetes could be accurately predicted, then healthcare resource allocation could be improved by providing an individualised screening strategy.

Didemnins: antiviral and antitumor depsipeptides from a caribbean tunicate.

Extracts of samples of a Caribbean tunicate (ascidian, sea squirt) of the family Didemnidae inhibit in vitro at low concentrations the growth of DNA and RNA viruses as well as L1210 leukemic cells. The active compounds isolated from the tunicate, didemnins A, B, and C, are depsipeptides, and didemnin B (a derivative of didemnin A) is the component active at the lowest concentration in inhibiting viral replication in vitro and P388 leukemia in vivo.

Seagrass wasting disease: Nitrate enrichment and exposure to a herbicide (Diuron) increases susceptibility of Zostera marina to infection.

Seagrass meadows suffered large-scale declines in the past century. The 'wasting disease', pathognomonically associated with Labyrinthula zosterae, reduced populations of Zostera marina on both sides of the North Atlantic in, and since, the 1930s, coinciding with intensive agricultural use of artificial fertilizers and herbicides. This study tests the long-standing hypothesis that nutrient enrichment and a herbicide increases vulnerability to pathogens. Z. marina shoots from the Thames Estuary grown in elevated nitrate concentrations had significantly higher rates of infection by L. zosterae than controls, but not by Aplanochytrium sp., another slime-mould like protist. Z. marina shoots grown in 2µg·l-1 Diuron solutions and infected separately by L. zosterae and Aplanochytrium sp. had significantly higher wasting indices than controls. The results identified Aplanochytrium sp. as another opportunistic pathogen causing a seagrass wasting-type disease and support the hypothesis that pollution by herbicides and nitrate increases the susceptibility of Z. marina to infections.

Identification and characterization of functional genes encoding the mouse major urinary proteins.

Mouse Ltk- cells were stably transfected with cloned genes encoding the mouse major urinary proteins (MUPs). C57BL/6J MUP genomic clones encoding MUP 2 (BL6-25 and BL6-51), MUP 3 (BL6-11 and BL6-3), and MUP 4 (BL6-42) have been identified. In C57BL/6J mice, MUP 2 and MUP 4 are known to be synthesized in male, but not female, liver, and MUP 3 is known to be synthesized in both male and female liver and mammary gland. A BALB/c genomic clone (BJ-31) was shown to encode a MUP that is slightly more basic than MUP 2 and was previously shown to be synthesized in both male and female liver of BALB/c but not C57BL/6 mice. Comigration on two-dimensional polyacrylamide gels of the MUPs encoded by the transfecting gene provides a basis for tentative identification of the tissue specificity and mode of regulation of each gene. DNA sequence analysis of the 5' flanking region indicates that the different MUP genes are highly homologous (0.20 to 2.40% divergence) within the 879 base pairs analyzed. The most prominent differences in sequence occur within an A-rich region just 5' of the TATA box. This region (from -47 to -93) contains primarily A or C(A)N nucleotides and varies from 15 to 46 nucleotides in length in the different clones.

The effect of sewage pollution on the feeding behaviour and diet of Hediste (Nereis diversicolor (O.F. Müller, 1776)) in three estuaries in south-east England, with implications for saltmarsh erosion.

Stable isotope analyses of the abundant infaunal polychaete Hediste diversicolor, recognised as an indicator of sewage pollution, support the hypothesis that nutrient enrichment promotes surface deposit feeding, over suspension feeding and predation. At sewage-polluted sites in three estuaries in SE England Hediste mainly consumed microphytobenthos, sediment organic matter and filamentous macroalgae Ulva spp. At cleaner sites Hediste relied more on suspension feeding and consumption of Spartina anglica. There were no consistent differences in Hediste densities between the polluted and cleaner sites, probably because of increased densities at the cleaner sites too, facilitated by the planting of Spartina and nitrogen enrichment there too, including from agricultural run-off. Increased nutrient enrichment and the artificial availability of Spartina have probably increased densities of, and deposit-feeding by, Hediste in the past half-century and contributed indirectly to saltmarsh losses, since deposit-feeding by Hediste has been implicated in recent saltmarsh erosion in SE England.

Synthesis and biological effects of acyclic pyrimidine nucleoside analogues.

A series of nucleoside analogues has been prepared, wherein the cyclic carbohydrate moiety is replaced by aliphatic side chains attached to cytosine, thymine, uracil, and 5-fluorouracil. The 1-[(2-hydroxyethoxy)methyl] derivatives of these heterocycles were synthesized by reacting the silylated bases with 2-(chloromethoxy)ethyl benzoate, followed by removal of the protecting groups with methanolic ammonia. The hydroxy groups of a number of these derivatives was subsequently replaced by an azido, amino, or carbamoyloxy moiety. The 1-(2-oxo-3-butyl) and 1-(2-oxo-3-nonyl) derivatives of cytosine were also prepared, their synthesis being accomplished by condensation of the silylated heterocycle with the appropriate alpha-halo ketone. At 10(-4) M concentrations, the newly prepared compounds were inactive against leukemia L-1210 cells in culture. However, a number of the agents inhibited the in vitro growth of Escherichia coli K-12, the most potent among these, 1-[(2-hydroxyethoxy)methyl]-5-fluorouracil being active at an IC50 of 1.2 micro M. This compound was equally active in preventing the growth of a 5-fluorouracil resistant strain of E. coli. Some of the analogues were also found to selectively interfere with herpes simplex virus replication in vitro. None of the cytosine derivatives tested served as either substrates or inhibitors of human liver cytosine nucleoside deaminase.

Acetylenic nucleosides. 3. Synthesis and biological activities of some 5-ethynylpyrimidine nucleosides.

Iodination of 1-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)uracil furnished the 5-iodo derivative (Ib), which, on treatment with (trimethylsilyl)acetylene in the presence of catalytic amounts of (Ph3P)2PdCl2/CuI and subsequent deblocking, afforded 1-beta-D-arabinofuranosyl-5-ethynyluracil (Ie). Condensation of the trimethylsilyl derivative of 5-(dibromovinyl)uracil with 3-O-acetyl-5-O-benzoyl-2-deoxy-2-azido-D-arabinofuranosyl chloride, followed by treatment with phenyllithium, gave 1-(2-deoxy-2-azido-beta-D-arabinofuranosyl)-5-ethynyluracil (IIb). Condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide with the trimethylsilyl derivative of 5-ethynylcytosine and subsequent removal of the protecting groups furnished 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethynylcytosine (IIIb). The structural assignment for IIb and IIIb was made by NMR and ORD spectra. Compounds Ie and IIIb inhibited the growth of leukemia L-1210 cells in culture by 50% at concentrations of 1.7 X 10(-5) and 6 X 10(-5) M, respectively. In addition, Ie and IIIb inhibited the replication of herpes simplex virus type I by 90% at concentrations of 2.8 X 10(-5) and 5 X 10(-5) M, respectively. Compound IIb did not show any antileukemic or antiherpes activity.

Structure--activity relationships of the didemnins.

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Selectivity of antitemplates as inhibitors of deoxyribonucleic acid polymerases.

DNA polymerase alpha from calf thymus was relatively insensitive to the action of partially thiolated polycytidylic acid (MPC) which had been shown previously to be a potent inhibitor of the corresponding enzyme from regenerating rat liver, competitive with the activated DNA template. In contrast, partially thiolated polyuridylic acid (MPU) strongly inhibited the calf thymus enzyme as well, but showed non-competitive kinetics with respect to the activated DNA template. The much more potent inhibitory activity of MPU compared to MPC was attributed to the less rigid conformation of the former. Methyl substitution on the 5-mercapto groups of MPU substantially decreased but did not abolish its inhibitory activity. MPU was also a potent inhibitor of the herpes virus (HSV-1) induced DNA polymerase which, too, showed little sensitivity toward MPC; in this case, the inhibition by MPU was uncompetitive with respect to the DNA template. In preliminary experiments, MPU showed significant (61%) inhibition of the replication of HSV-1, while MPC was inactive. The results demonstrate that the inhibitory activity of partially thiolated synthetic polynucleotides toward certain DNA polymerases is dependent on the base composition.

Expression of major histocompatibility class II antigens by Langerhans' cells in cervical intraepithelial neoplasia.

Cervical biopsy samples from 67 patients who had various grades of cervical intraepithelial neoplasia (CIN) or who showed evidence, in the form of koilocytosis, of human papillomavirus (HPV) infection of the uterine cervix, and from 10 women with normal cervices were examined. Cryostat sections from the biopsy samples were stained using monoclonal antibodies to T6, a Langerhans' cell marker, and to major histocompatibility complex (MHC) class II antigens (HLA-DP, DQ, and DR). Epithelial Langerhans' cells were reduced in number and showed changed morphology and distribution in koilocytic lesions and in all grades of CIN (p less than 0.01) except CIN I. HLA-DR expression by Langerhans' cells was significantly increased in koilocytic lesions and in CIN grades I and II (p less than 0.05); HLA-DQ expression was significantly increased in all grades of CIN (p less than 0.05) with the increase being most pronounced in CIN I (p less than 0.01). Columnar epithelium expressed MHC class II antigens in all samples tested and squamous epithelium in four of 29 cases of CIN III. These findings support the view that there is a localised disturbance of immune function in both neoplastic cervical epithelium and that infected with papillomavirus.

Papillomavirus and c-myc antigen expression in normal and neoplastic cervical epithelium.

Cervical punch biopsy specimens or brushings were collected from 33 patients with cervical human papilloma virus (HPV) infection, cervical intraepithelial neoplasia (CIN), or invasive cervical carcinoma, and from eight control patients with recent normal cervical cytology. Prostatic chippings obtained from six men with benign prostatic hypertrophy were used as further controls. Biopsy specimens and brushings were assayed by flow cytometry for c-myc oncogene antigen and papillomavirus antigen expression and rate of cell division (by measuring DNA content). Results obtained from analysis of specimens and brushings were similar in terms of c-myc antigen and total DNA content, but when the percentages of nuclei from biopsy and brush specimens staining positively with antibody to papilloma viral antigens were compared, brush specimens gave consistently higher percentages than biopsy specimens. More specimens from normal epithelium were c-myc antigen positive (five of eight, (63%) than specimens from CIN II or III (two of 10, 20%), or invasive carcinoma (0%). No association was found between c-myc antigen expression and cell division. HPV antigen positive specimens were found to contain more dividing cells than negative specimens.

Tracking consumers' reactions to the changing health care system: early indicators.

A survey in fifteen communities and nationwide of consumers' opinions about changes in their local health care system reveals that Americans are surprisingly positive about recent changes in their personal access to and quality of care and consistently negative about changes in the cost of care. Although many consumers think that changes in the system are making things worse, they are optimistic about the trend toward managed care. Subgroup analysis shows that uninsured persons and persons with health problems reported high rates of concern about many of the health system issues we explored, while Medicaid recipients, Hispanics, and African Americans reported positive changes in their access to and quality of care.

Inequality in America: the contribution of health centers in reducing and eliminating disparities in access to care.

Reducing and eliminating health status disparities by providing access to appropriate health care is a goal of the nation's health care delivery system. This article reviews the literature that demonstrates a relationship between access to appropriate health care and reductions in health status disparities. Using comprehensive site-level data, patient surveys, and medical record reviews, the authors present an evaluation of the ability of health centers to provide such access. Access to a regular and usual source of care alone can mitigate health status disparities. The safety net health center network has reduced racial/ethnic, income, and insurance status disparities in access to primary care and important preventive screening procedures. In addition, the network has reduced low birth weight disparities for African American infants. Evidence suggests that health centers are successful in reducing and eliminating health access disparities by establishing themselves as their patients' usual and regular source of care. This relationship portends well for reducing and eliminating health status disparities.

Racial and ethnic differences in access to medical care in managed care plans.

OBJECTIVE: To examine the extent to which access differences between racial/ethnic minorities and whites in managed care plans are greater than such differences in other types of health plans. DATA SOURCE: A nationally representative sample of 4,811 African American, 3,379 Hispanic, and 33,737 white nonelderly persons with public or private health insurance. STUDY DESIGN/DATA COLLECTION: A cross-sectional survey of households was conducted during 1996 and 1997. Commonly used measures of access to and utilization of medical care were constructed for individuals: (1) percentage of visits with a usual provider, (2) percentage with a regular provider, (3) visit with a physician in the past year, (4) hospital ER use, (5) last visit was to a specialist. PRINCIPAL FINDINGS: Fewer than 74 percent of Hispanics and African Americans had a regular provider compared to more than 78 percent of white Americans. Hispanics were least likely to have had their last doctor visit with a specialist (22 percent) compared to African Americans (26 percent) and whites (28 percent). Differences between ethnic/racial minorities and whites in managed care plans are similar to differences observed in non-managed care plans. Americans of all racial and ethnic backgrounds in managed care plans with gatekeeping are more likely to have a usual source of care, a regular provider, and lower use of specialists compared to persons in plans without gatekeeping. CONCLUSION: Although greater access to primary care was shown among African Americans and Hispanics in managed care plans, the extent of the disparities between racial/ethnic minorities and whites in managed care is similar to disparities in other types of health plans.

Effect of 50 percent distal small bowel bypass on gastric secretory function in rhesus monkeys.

Six rhesus monkeys had basal acid output and histamine-stimulated maximal acid output measured before and at 10 weeks and 6 months after 50 percent distal small bowel bypass. At each stage fasting serum gastrin was measured in all animals and fasting serum gastric inhibitory polypeptide in two animals. No change in basal or maximal acid output occurred after a sham operation carried out in two of the animals. The mean preoperative basal acid output (0.17 +/- 0.02) increased to 0.49 +/- 0.04 at 10 weeks after bypass (p less than 0.001) and then decreased significantly to 0.33 +/- 0.03 mEq/kg/hour at 6 months (p less than 0.001). Preoperative maximal acid output (0.43 +/- 0.06) increased to 0.76 +/- 0.10 mEq/kg/hour at 10 weeks (p less than 0.001) and remained at that level at 6 months. Small bowel biopsy specimens at 6 months showed characteristic changes in both proximal and distal small bowel segments. Fasting gastrin and gastric inhibitory polypeptide levels did not change significantly during the study. A comparison of these results with those obtained after 50 percent distal small bowel resection in a previous study revealed a similar proportional increase in maximal acid output in both early (resection, 78 +/- 20 percent; bypass, 77 +/- 23 percent) and late postoperative studies (resection, 57 +/- 14 percent; bypass, 74 +/- 19 percent). However, the early increase in basal acid output after resection (370 +/- 50 percent) was sustained and was significantly greater (p less than 0.005) than the early ill-sustained increase (188 +/- 24 percent) after bypass.

Pancreatic cancer screening. Analysis of the problem and the role of radionuclide imaging.

The clinical, surgical, and pathologic findings in a five year prospective study of 192 patients referred with a high probability of pancreatic cancer are reported. We have defined the requirements of any pancreatic imaging procedure as its ability to distinguish a normal pancreas from pancreatic cancer or chronic pancreatitis and the capability of detecting tumors less than 5 cm in diameter. There was a 47 percent incidence of pancreatic disease (27 percent pancreatic cancer and 20 percent chronic pancreatitis). Prospective radionuclide imaging as routinely performed was found to be of little clinical value in this patient population; it was neither specific nor sensitive to pancreatic cancer or chronic pancreatitis. Preliminary data with longitudinal multiplane emission tomography show an improved diagnostic accuracy and the ability to detect resectable tumors, but its efficacy needs to be prospectively compared with other screening tests on a carefully defined patient population.

The food-service industry, dietary guidelines and change.

The influence of the food-service industry on compliance with the Australian dietary guidelines was investigated through three separate methods of data collection and analysis: a telephone survey of 1683 randomly selected Brisbane residents; telephone interviews with 69 food-service-industry operators and 10 face-to-face interviews with key stakeholders in industry and government. Nearly 40 per cent of respondents had consumed foods prepared by the food-service industry at least once on the day before the interview, mainly from restaurants, cafes and takeaway shops, in the form of fast-food or snacks. Consumption of these foods declined with age. Those consuming foods prepared by the food-service industry ate significantly less fruit, vegetables and dairy food and were therefore less likely to comply with the dietary guidelines. Outcomes from interviews with operators in the food-service industry show that food choices offered to consumers were the result of a dynamic interaction between consumer demand and operators' own tastes and perceptions of food quality. Key informant interviews show that public health nutrition programs will have limited effect without supportive environmental changes in the food-service industry supply. An effective means of increasing the likelihood of compliance with the Australian dietary guidelines will be to encourage food suppliers in ways that address their core business concerns simultaneously with the goals of health professionals.

An unusual late complication of superior mesenteric embolectomy.

Few complications of superior mesenteric artery embolectomy have now been reported. We present the case history of a patient who developed duodenal obstruction due to a haematoma forming in the root of the mesentery following successful superior mesenteric embolectomy. The aetiology is discussed and a method of avoiding this complication suggested.