GSK2878175, a pan-genotypic non-nucleoside NS5B polymerase inhibitor, in healthy and treatment-naïve chronic hepatitis C subjects.

GSK2878175 is a potent, pan-genotypic, non-nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment-naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log10 IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens.

Longitudinal assessment of hepatitis C fibrosis progression by collagen and smooth muscle actin morphometry in comparison to serum markers.

BACKGROUND: Assessment of fibrosis progression in chronic liver disease relies upon non-invasive tools and changes in semi-quantitative histopathology scores that may not be reliable. AIM: To assess the diagnostic performance of the FibroSURE (FS) index and collagen/alpha smooth muscle actin (α-SMA) morphometry in relation to longitudinal changes in fibrosis on paired biopsies. METHODS: The study cohort included 201 chronic hepatitis C (CHC) nonresponders enrolled in a prior phase II anti-fibrotic study. Serum FS and paired biopsies, with both collagen and α-SMA morphometry, were evaluated at baseline and week 52. RESULTS: Study patients were mostly male (67%) and Caucasian (77%), with Ishak stages 2 (n = 79), 3 (n = 88) and 4 (n = 30), excluded (n = 4 stage 1 or 5). Mean biopsy length was 22.9 mm. For baseline Ishak 2/3 vs. 4, there were no significant differences in AUROCs for collagen (0.71), SMA (0.66) or FS (0.70). At week 52, 62% of patients had no change in Ishak stage, but collagen/α-SMA increased by 34-51% (P < 0.0001), and FS decreased by 5% (P = 0.008). Among the 33% of patients with +/-1 Ishak stage change, FS changes were not significant, but α-SMA increased 29-72%, and collagen increased by 12-38% (P = 0.01 for +1 only). CONCLUSIONS: Longitudinal changes in collagen and α-SMA morphometry are apparent prior to change in histological stage or FibroSURE in CHC nonresponders with intermediate fibrosis. This likely reflects quantitative morphological differences that are not detected by routine histological staging or serum markers such as FibroSURE.

Late-onset hemorrhagic cystitis associated with urinary excretion of polyomaviruses after bone marrow transplantation.

Hemorrhagic cystitis is a well known complication of allogeneic bone marrow transplantation (BMT) and is normally attributed to the use of high-dose cyclophosphamide in the preparative regimen. Hemorrhagic cystitis occurring late after BMT is unlikely to be due to the effects of this conditioning, and probably has an infective etiology. Three patients undergoing BMT for chronic granulocytic leukemia (CGL) developed terminal dysuria and hematuria at 38, 56, and 149 days post-BMT. Electron microscopy (EM) of urine voided at these times revealed large numbers of papovavirions, which were subsequently identified as BK virus. Urine samples inoculated onto human embryonic lung fibroblasts induced infection of the cells and replication of the virus as detected by EM of tissue culture fluid. Urine from one of these patients was examined by standard cytological techniques, and EM of urothelial cells showed nuclear inclusions consisting of nonencapsulated virus particles of diameter 40 nm, consistent with papovavirus. Five further patients were found to be excreting BK virus without symptoms of cystitis, although one of these patients did experience abnormalities of liver function that were otherwise unexplained. BK virus has already been implicated in hepatic dysfunction posttransplant, and in cystitis in nonimmunosuppressed children. We postulate that it may also be involved in the etiology of late hemorrhagic cystitis after BMT.

Prospective study of the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients.

Forty eight renal transplant recipients were investigated prospectively for evidence of infection with the polyomaviruses BK and JC and cytomegalovirus. An active polyomavirus infection was shown in 31 patients (65%) and cytomegalovirus in 30 (62.5%). Half of the BK and JC virus infections occurred within the first three months after transplantation compared with 93% of the cytomegalovirus infections. Very late polyomavirus infections two or more years after the transplant were also shown. Cytology was useful in identifying polyomavirus but not cytomegalovirus infections, and 21 (68%) of the 31 polyomavirus infected patients excreted inclusion-bearing cells. Only three patients had symptoms possibly associated with the polyomavirus infection. One patient with BK virus infection developed ureteric stenosis and a second patient had malaise and vomiting. One patient with JC virus infection developed pericarditis and effusion. Renal function became impaired at the time of the polyomavius infection in eight patients (26%) and ureteric obstruction and pericarditis developed in two patients treated with methyl prednisolone for possible rejection. At the end of the study 25 of the 31 polyomavirus infected patients (81%) had functioning renal grafts. The detection of polyomavirus infection is important as increased immunosuppression needs to be avoided to prevent possible complications such as ureteric stenosis in transplant recipients.

Identity of a newly isolated human polyomavirus from a patient with progressive multifocal leucoencephalopathy.

Isolation of a strain of polyomavirus, designated COL, from the brain of a patient with progressive multifocal leucoencephalopathy is described. The COL strain is antigenically similar to JC polyomavirus, previously isolated from a brain affected by progressive multifocal leucoencephalopathy and is unrelated to BK, another human polyomavirus isolated from urine. Immunological cross testing of viruses in the Polyomavirus genus shows that there are at least six antigenic types in this group.

Occurrence of IgM antibodies against BK and JC polyomaviruses during pregnancy.

In a serological survey of 430 pregnant women 45 had high or rising titres of BK-virus haemagglutination-inhibiting antibodies. The presence of BK-virus-specific IgM was confirmed in 10 of these women. No BK-virus-specific IgM was detected in the samples of cord blood from the babies born to these women. The sera from 40 women known to be excreting inclusion-bearing cells during pregnancy were tested for the presence of BK-virus and JC-virus-specific IgM and IgG. The presence of BK-virus-specific IgM was confirmed in three cases and JC-virus-specific IgM in seven cases. Specific IgM persisted for several months in some pregnant women. No Bk-virus-specific IgM was detected in any of the samples of cord blood from the babies born to these women with evidence of polyomavirus infection. No JC-virus-specific IgM was detected in 36 out of 37 of the cord bloods; however, in one it is possible that minute amounts of JC-virus-specific IgM were present.

Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients.

Human polyomavirus (BK) was detected in two renal allograft recipients as a result of routine examination of Papanicolaou-stained smears of urinary sediment in the light microscope. Infection with this recently identified virus was confirmed by virus isolation and electron microscopy. The cytological, histological, and ultrastructural changes due to the virus are described, and virus excretion is correlated with the clinical progress of the patients and the pathological findings. The transplant ureters in both patients were found to be ulcerated and stenosed, and virus-infected cells were observed in the ureteric epithelium. We suggest that the administration of high-dose steroids in transplantation may permit active infection with human polyomavirus to occur in ureteric epithelium which has been damaged by ischaemia or inflammation.

An indirect immunofluorescence method for detection of infectious BK virus in urine.

An indirect immunofluorescence (IF) method is described for the detection of infectious BK virus in urine within seven days in contrast to up to three months or longer using routine tissue culture. Virus is pelleted from the urine, inoculated onto pre-formed monolayers of human embryo lung (HEL) fibroblasts, and infected cells are detected in an indirect fluorescent antibody test using a human serum. The sensitivity of the IF method is 91%. Positive isolates may be confirmed as BK virus using specific rabbit antisera on the original inoculated cultures. Furthermore, a virus stock may be grown up by passage from the original culture fluids for further studies such as DNA analysis. As a broadly-reactive human serum is used for screening the cultures, other viruses which grow in HEL cells, such as CMV, may also be detected.

Progressive multifocal leucoencephalopathy and viral antibody titres.

Progressive multifocal leucoencephalopathy (PML) is caused by a papovavirus but serum antibody titres are generally considered unhelpful in clinical diagnosis because antibodies to the commonest causal agent (JC virus) are frequently found in normal adults. There is little published information about CSF titres but usually they have not been useful. Two cases of PML, confirmed by autopsy, are described where CSF antibody to JC virus was measured. In one case the JC antibody titre was significantly higher in the CSF than the serum and we suggest that this finding is diagnostically useful. In this case there was a transient stabilization of the disease following treatment with cytarabine with a change in antibody titres suggestive of reduced viral replication in the central nervous system and a host response to the infection. In the other case, which was untreated, rising serum antibody levels indicated active infection with a host response.

Progressive multifocal leukoencephalopathy-remission with cytarabine.

A 51-year-old woman who was in complete remission from non-Hodgkin's lymphoma, developed a rapidly progressive dementia. Progressive multifocal leukoencephalopathy (PML) was diagnosed on the basis of a rising antibody titre to JC polyomavirus in cerebro-spinal fluid and serum and the presence of diffuse white matter changes on magnetic resonance imaging. She was treated initially with intravenous cytarabine and showed minimal improvement. Rapid improvement occurred when intrathecal cytarabine was added and the patient is in complete remission from both lymphoma and PML 20 months later.

The use of the restriction endonuclease DdeI for mapping relataed DNAs.

Restriction endonuclease mapping of BK virus strain GS using DdeI has allowed us to correct and extend the previously published map.

Increased leaf area expansion of hybrid poplar in elevated CO2. From controlled environments to open-top chambers and to FACE.

We examined the response of hybrid poplar to elevated CO2 in contrasting growth environments: controlled environment chamber (CE). open-top chamber (OTC) and poplar free air CO2 enrichment (POPFACE) in order to compare short versus long-term effects and to determine whether generalisations in response are possible for this fast growing tree. Leaf growth, which for poplar is an important determinant of stemwood productivity was followed in all environments, as were the determinants of leaf growth-cell expansion and cell production. Elevated CO2 (550-700 micromol mol(-1), depending on environment) resulted in an increase in final leaf size for Populus trichocarpa x Populus deltoides (Populus x interamericana) and P. deltoides x Populus nigra (Populus x euramericana), irrespective of whether plants were exposed during a short-term CE glasshouse study (90 days), a long-term OTC experiment (3 years) or during the first year of a POPFACE experiment. An exception was observed in the closed canopy POPFACE experiment, where final leaf size remained unaltered by CO2. Increased leaf extension rate was observed in elevated CO2 in all experiments, at some point during leaf development, as determined by leaf length. Again the exception were the POPFACE experiment, where effects were not statistically significant. Leaf production and specific leaf area (SLA) were increased and decreased, respectively, on five out of six occasions, although both were only statistically significant on two occasions and interestingly for SLA never in the FACE experiment. Although both cell expansion and cell production were sensitive to CO2 concentration, effects appeared highly dependent on growth environment and genotype. However, increased leaf cell expansion in elevated CO2 was often associated with changes in the biophysical properties of the cell wall, usually increased cell wall plasticity. This research has shown that enhanced leaf area development was a consistent response to elevated CO2 but that the magnitude of this response is likely to decline, in long-term exposure to elevated CO2. Effects on SLA and leaf production suggest that CE and OTC experiments may not always provide good predictors of the 'qualitative' effects of elevated CO2 in long-term ecosystem experiments.

The history of pregnancies that occur following female sterilization.

Data on 208 pregnancies occurring among 20,749 women following sterilization were collected by the International Fertility Research Program and the histories of these pregnancies from conception to termination were analyzed. In the laparoscopic series, the operator's failure to interrupt the tube by electrocoagulation or a tubal occlusion device was the major reason reported for sterilization failure. In the culdoscopic series, operator error or device deficiency were the major reasons for failure. About three quarters of pregnancies in this study were conceived within the first year following sterilization and were confirmed during the first trimester. The rate of ectopic pregnancy occurring in this series was higher than the rate reported for nonsterilized women and was especially high when electrocoagulation was used.

PIP: The International Fertility Research Program collected data on 208 pregnancies occurring among 20,749 women following sterilization. The histories of these pregnancies were analyzed from conception to termination. The operator's failure to interrupt the tube by electrocoagulation or a tubal occlusion device was the major reason for sterilization failure in the laparoscopic series. Operator error or device deficiency were the causes for failure in the culdoscopic series. Three quarters of pregnancies in this study were conceived within the first year following sterilization and were confirmed during the first trimester. The rate of ectopic pregnancy occurring in this series was higher than the rate for nonsterilized women. It was especially high when electrocoagulation was used. From 1972 to August 1978, the pregnancies were reported to the Program. More than half the pregnancies were diagnosed by a test alone or a pelvic examination. In 38%, the reasons for failures were not reported. 123 of the 159 failures were terminated; the remainder were being continued at last follow-up. 15.7% of pregnancies were confirmed during the second trimester; 3.8% were diagnosed beyond the 25th week.

Comparison of laparoscopic sterilization via spring-loaded clip and tubal ring.

The spring-loaded clip and tubal ring techniques of laparoscopic female sterilization were compared for ease of performance, safety and effectiveness at the Asociación Demográfica Salvadoreña in San Salvador, where they were randomly assigned to a total of 299 patients. Rates of technical/equipment difficulties and procedural difficulties during laparoscopy were similar for both techniques. Procedure-related surgical complications occurred in three ring patients as a result of tubal transection. Pain during the procedure was more severe for tubal ring patients. Results suggest that both techniques can be safely and effectively used for laparoscopic sterilization.

PIP: A study was conducted to assess the relative ease of performance, ring techniques of laparoscopic female sterilization. 299 randomly-assigned female clients at the Asociacion Demografica Salvadorena in San Salvador were used in the study. Demographic characteristics of the 2 patient groups, operative procedures, and resultant side effects and complications from the 2 procedures are discussed and tabulated. Rates of technical/equipment difficulties and procedureal difficulties during the laparoscopy were similar for the 2 methods. Pain during the procedure was more severe for the tubal ring patients; this difference did not continue into the recovery or early follow-up periods. 1 of each group of patients was considered a technical failure. Mean surgical time for both groups was under 8 minutes. Follow up at 6, 12, and 24 months showed very low failure (i.e., pregnancy) rates in both groups. It is concluded that both procedures can be safely performed on an outpatient basis, using only local anesthetics plus analgesics. Both are very effective.

Menstrual pattern changes in laparoscopic sterilization patients whose last pregnancy was terminated by therapeutic abortion. A two-year follow-up study.

Women were used as their own controls in the comparison of presterilization and poststerilization menstrual patterns. Five parameters were studied: regularity of cycle length, duration and amount of flow and incidence of dysmenorrhea and intermenstrual bleeding. Three parameters in the electrocoagulation group (regularity of cycle length and duration and amount of flow) and one parameter in the tubal ring group(duration of flow) showed significant changes after sterilization. However, by controlling for the effect of previous contraceptive methods used, no significant menstrual pattern changes following sterilization were discerned in either technique group.

PIP: Between 1973 and 1975, 2501 women were sterilized by laparoscopy at the Yonsei University College of Medicine in Seoul, Korea. The women were used as their own controls in a follow-up study of the changes in menstrual patterns following sterilization. Tables present the results of the study. In the electrocoagulation group, twice as many patients changed from regular to irregular cycles than the other way; there was no such difference among the tubal occlusion group. More patients in both groups experienced a decline in menstrual flow. The aging of the patients and the fact that some had had therapeutic abortions prior to or concurrent with the sterilization procedure did not have any effect on the observed changes in menstrual cycles. Changes in menstrual cycle length, duration, and amount seemed to be associated with the type of contraceptive used previously. Controlling for prior contraceptive usage caused the observed differences in menstrual cycles to disappear.

Pregnancy risk following laparoscopic sterilization in nongravid and gravid women.

A multicenter data set was analyzed to compare incidences of poststerilization pregnancies between women who were not pregnant and those who were pregnant at admission of laparoscopic sterilization. The 12-month life-table poststerilization pregnancy rate was 6.0 per 1,000 procedures for the 7,696 nongravid and 32.8 for the 1,703 gravid women, for a fivefold difference. The crude pregnancy rates were consistently higher for the gravid women when data were classified by tubal occlusion technique and by patients' sociodemographic characteristics. The difference in pregnancy rates between the two groups was reduced to 2.4-fold when analysis was limited to data sets from centers that admitted both groups of women and that performed sterilization by the same technique. Results of this analysis support previous studies suggesting that gravid women, especially postpartum patients, carry a higher pregnancy risk following sterilization.

PIP: A multicenter data set was analyzed, which consisted of women sterilized via laparoscopy, to determine the difference in risk of poststerilization pregnancy between interval and combined procedures. 9399 women were sterilized by laparoscopy between 1972 and 1978 and followed for at least 6 months in this data set reported to IFRP (from 33 centers in 19 countries). In this series 7696 women were not pregnant when admitted for sterilization (nongravid group) and 1703 were (gravid group). 1201 of the 1703 were postabortion patients and 502 were postpartum patients. Using this data to create a 12-month life-table poststerilization pregnancy rate per 1000 women, the nongravid group's rate was 6 and the gravid group's was 32.8--a fivefold difference. 3 tubal occlusion techniques were used (electrocoagulation, tubal ring, or prototype spring-loaded clip), and when the crude pregnancy rates were calculated by occlusion technique the gravid group's rates were consistently higher. When the data were calculated by sociodemographic factors, the gravid group still had a much higher poststerilization pregnancy rate. Even a 24-month life table showed gravid women with higher pregnancy rates (2.4 times higher) than nongravids. 2 reasons for greater pregnancy rate among gravid women are offered: 1) gravid women may be inherently more fecund; and 2) pregnancy may cause unfavorable pelvic changes that increase technical problems during sterilization procedures.

Posttreatment and postretention changes following orthodontic therapy.

This investigation was performed to determine the changes which occurred in treated orthodontic cases out of retention. The material consisted of 103 cases, of which 74 cases were treated nonextraction and 29 were treated with the extraction of four first premolars. The treatment was accomplished by the full-banded edgewise bioprogressive technique. Five measurements were taken: intercanine, inter-first premolar, intersecond premolar and inter-first molar widths, and incisor to molar distance. The measurements were made on the mandibular arch of the pretreatment, posttreatment, and prostretention casts. The postretention model was obtained a minimum of one year after all retaining devices were removed with an average of 5.2 years. The following conclusions were drawn from the changes in dimensions: 1. The intercanine width was expanded during treatment, but had a strong tendency to return to or close to its original pretreatment width in both nonextraction and extraction cases. 2. The inter-first premolar width showed the greatest treatment increase in width with only a minimal amount of postretention decrease. 3. The second premolar width for nonextraction cases showed a significant amount of increase with a slight tendency for postretention decrease. 4. The second premolar width for extraction cases showed a decrease with treatment and a slight continued decrease postretention. 5. The intermolar width of nonextraction cases showed a significant increase in width with treatment. The extraction cases showed a significant decrease with treatment. However, there were no changes in either extraction or nonextraction cases postretention. 6. The incisor to molar distance decreased with treatment and had a slight tendency to continue to decrease postretention.