Predictors of failure to detect early hepatocellular carcinoma in patients with chronic hepatitis B who received regular surveillance.

BACKGROUND: A proportion of chronic hepatitis B (CHB) patients are diagnosed with advanced hepatocellular carcinoma (HCC) despite regular surveillance. AIMS: To determine predictors for HCC detection failure in CHB patients who underwent regular surveillance. METHODS: CHB patients with well-preserved liver function, who underwent ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, were enrolled. Cox regression analysis was used to identify predictors for detection failure, defined as HCC initially diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C. RESULTS: Of the 4590 CHB patients (mean age, 52.1 years; men, 61.6%), 169 patients were diagnosed with HCC (3.68%) and 35 (20.7%) HCC patients were initially diagnosed with HCC BCLC stage B or C. The cumulative incidence of HCC detection failure was 0.2% at year 1 and 1.3% at year 5. Multivariate analyses indicated that cirrhosis (hazard ratio [HR], 3.078; 95% CI, 1.389-6.821; P = 0.006), AFP levels ≥9 ng/mL (HR, 5.235; 95% CI, 2.307-11.957; P = 0.010), and diabetes mellitus (HR, 3.336; 95% CI, 1.341-8.296; P = 0.010) were independent predictors of HCC detection failure. Another model that incorporated liver stiffness (LS) values identified LS values ≥11.7 kPa (HR, 11.045; 95% CI, 2.066-59.037; P = 0.005) and AFP levels ≥9 ng/mL (HR, 4.802; 95% CI, 1.613-14.297; P = 0.005) as predictors of detection failure. CONCLUSIONS: In CHB patients undergoing regular surveillance with ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, the HCC detection failure rate was not high (0.8% per person; 0.1% per test). However, careful attention should be paid in patients with advanced liver fibrosis (clinical cirrhosis or LS value >11.7 kPa), high AFP levels, or diabetes mellitus, who are prone to surveillance failure.

Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. RESULTS: A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION: These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

[A case of stage IV gastric cancer with multiple liver metastases and carcinomatous ascites responding to TS-1 for six months before progression].

We report the case of a 72-year-old male with Stage IV gastric cancer accompanied by multiple liver metastases and carcinomatous ascites which responded to chemotherapy using TS-1. Treatment of the patient with daily oral administration of 120 mg TS-1 for 4 weeks resulted in complete regression of the liver metastases and ascites, as well as a 35% reduction in the size of the primary lesion. After 2 cycles, the primary tumor size was reduced to 55% and serum CA19-9 and CA125 levels were decreased to the normal ranges. This regimen was effective without any adverse effects, and improved the patient's QOL, for 6 months before progression of liver lesions. The patient received chemotherapy at our outpatient clinic for 10 months after the first treatment, after which he died of peritonitis carcinomatosa. The current case suggests that TS-1 may have a potent therapeutic efficacy in advanced gastric cancer patients.

Existence of two L photointermediates of halorhodopsin from Halobacterium salinarium, differing in their protein and water FTIR bands.

FTIR difference spectra were recorded for the photoreactions of halorhodopsin from Halobacterium salinarium at 170 and 250 K. Obvious differences at the two temperatures were noted in neither the visible spectra nor the FTIR bands of the chromophore. However, perturbation of Asp141 is observed in the L intermediate at 250 K but not at 170 K. We named these photoproducts La (at 170 K) and Lb (at 250 K). The spectrum of Lb is distinct from that of La also in the different shifts of water O-H stretching bands, and larger changes in the bands from the protein backbone with different sensitivities to varying the halide. These results suggest that the photocycle of halorhodopsin contains two L states, La and Lb, in which the structure of protein and internal water molecules is different but chloride stays at the same site close to the Schiff base.

Intramembrane signaling mediated by hydrogen-bonding of water and carboxyl groups in bacteriorhodopsin and rhodopsin.

The light-induced mechanism for proton pumping of bacteriorhodopsin was studied by Fourier transform infrared spectroscopy of the discrete sequential intermediate states, L, M, and N. Attention is focused on L in the early microsecond time range, as a transition state in which the Schiff base forms strong H-bonding with a water molecule coordinated with Asp85. This structure leads to transfer of the Schiff base proton to Asp85 in the L-to-M process, which then triggers proton release from Glu204 to the extracellular surface. H-bonding of Arg82 and water molecules are involved in this process. Chloride can replace Asp85 in the D85T mutant, and this anion will be then transported instead of a proton. In L, structural perturbations are induced also around Asp96, through a string of H-bonding mediated by internal water molecules and peptide carbonyls in helices B and C, and Trp182 in helix F. These may cause the structural changes that occur later in the M-to-N process. Similar interactions, through internal water molecules and the peptide bonds in helices B and C, take place in bovine rhodopsin. They transduce changes across the membrane from the Schiff base to the cytoplasmic surface, where the activation of the transducin occurs.

Hydration of the counterion of the Schiff base in the chloride-transporting mutant of bacteriorhodopsin: FTIR and FT-raman studies of the effects of anion binding when Asp85 is replaced with a neutral residue.

The chromophores of the D85T and D85N mutants of bacteriorhodopsin are blue but become purple like the wild type when chloride or bromide binds near the Schiff base. In D85T this occurs near neutral pH, but in D85N only at pH < 4. The structures of the L and the unphotolyzed states of these proteins were examined with Fourier transform infrared spectroscopy. The difference spectra of the purple forms, but not the blue forms in the absence of these anions, resembled the spectrum of the wild-type protein. Shift of the ethylenic band toward lower frequency upon replacing chloride by bromide confirmed the contribution of the negative charge of the anions to the Schiff base counterion. These anions restored the change of water, which is bound near the protonated Schiff base but is absent in the blue form of the D85N mutant, though with stronger H-bonding than in the wild type. The C = N stretching vibration of the Schiff base in H2O and 2H2O was detected by Fourier transform Raman spectroscopy. The H-bonding strength of the Schiff base in the unphotolyzed state was weaker when chloride or bromide was bound to the mutants than with Asp85 as the counterion in the wild type. Thus, although the geometry of the environment is different, there is at least one water molecule coordinated to the bound halide in these mutants, in a way similar to water bound to Asp85 in the wild type.

Conversion of bacteriorhodopsin into a chloride ion pump.

In the light-driven proton pump bacteriorhodopsin, proton transfer from the retinal Schiff base to aspartate-85 is the crucial reaction of the transport cycle. In halorhodopsin, a light-driven chloride ion pump, the equivalent of residue 85 is threonine. When aspartate-85 was replaced with threonine, the mutated bacteriorhodopsin became a chloride ion pump when expressed in Halobacterium salinarium and, like halorhodopsin, actively transported chloride ions in the direction opposite from the proton pump. Chloride was bound to it, as revealed by large shifts of the absorption maximum of the chromophore, and its photointermediates included a red-shifted state in the millisecond time domain, with its amplitude and decay rate dependent on chloride concentration. Bacteriorhodopsin and halorhodopsin thus share a common transport mechanism, and the interaction of residue 85 with the retinal Schiff base determines the ionic specificity.

Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy.

Intermittent calcitriol therapy is commonly used to treat secondary hyperparathyroidism in patients undergoing regular dialysis, but there is little available information about the histologic response of bone to this form of therapy. Accordingly, 14 children and adolescents with biopsy-proven secondary hyperparathyroidism were treated with intermittent oral or intraperitoneal doses of calcitriol for 12 months. Biochemical indices of mineral metabolism including serum intact PTH levels were measured monthly throughout the study, and bone biopsies were repeated at the end of treatment. Before treatment, 11 patients had osteitis fibrosa and three had mild lesions of secondary hyperparathyroidism. Histologic improvement was seen in 12 of 14 patients, and osteitis fibrosa resolved in 10 of 11 cases. Bone formation decreased in all patients during intermittent calcitriol therapy, falling from 861 +/- 380 to 150 +/- 170 microns2/mm2/day, P < 0.001. Bone formation decreased to normal in six patients, but six patients developed adynamic lesions of bone with subnormal bone formation rates. Serum PTH and alkaline phosphatase levels declined in those who developed adynamic bone, but values remained elevated in patients with normal rates of bone formation at follow-up evaluation. Neither the mean dose of calcitriol nor the average dose per kilogram body weight differed in patients with adynamic lesions. Thus, adynamic renal osteodystrophy develops in a substantial number of patients during intermittent calcitriol therapy. Although declining serum PTH and alkaline phosphatase levels suggest the development of the adynamic lesion, bone formation decreases in some patients despite persistently high serum PTH levels. Calcitriol may directly suppress osteoblastic activity in patients with secondary hyperparathyroidism when given in large doses to patients undergoing peritoneal dialysis.

The extent, time course, and fraction size dependence of mouse spinal cord recovery from radiation injury.

PURPOSE: This experiment was designed to assess: (a) the influence of fraction size and time interval between fractions on the tolerance of the spinal cord to high cumulative doses of radiation; and (b) the influence of the long-term recovery process on the tolerance of the spinal cord to reirradiation. METHODS AND MATERIALS: The T10-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily, a prolonged fractionated regimen of 1.2 Gy once daily, a hyperfractionated regimen of 1.2 Gy twice daily, or a single dose of 12 Gy followed 0-190 days later by a second dose of 5-20 Gy. Mice in the multifractionated regimen groups were given a single 15 Gy top-up dose 24 h after reaching a cumulative fractionated dose of 24-70 Gy. Hind limb strength was measured weekly for 2 years after the completion of irradiation. RESULTS: Paralysis occurred in a bimodal time distribution, with peaks at 5-10 months and 15-23 months after the completion of irradiation. The cumulative radiation dose was directly associated with the incidence of paralysis in each radiation schedule (p < 0.0001) and inversely associated with the time to onset of paralysis in the 1.2 Gy b.i.d. (p = 0.0001) and 2.0 Gy q.d. schedules (p = 0.03). The median latency of paralysis in each group was inversely associated with the incidence of paralysis in that group (p < 0.001). Decreasing the fraction size from 2.0 to 1.2 Gy once daily markedly increased the radiation tolerance of the spinal cord (p < 0.0001), consistent with a very small alpha-beta value of -0.30 Gy (approximately 95% confidence interval -0.72, +0.18) in the linear-quadratic model. Decreasing the time interval from 24 h to alternating 8 and 16 h periods produced an offsetting diminuation in cord tolerance (p < 0.0001). The 1.2 Gy once daily schedule resulted in ED20 and ED50 values that were approximately double those of the 2.0 Gy once daily and the 1.2 Gy twice daily schedules and a relative risk of paralysis from a given dose that was 0.03 times the risk associated with the other two regimens (p < 0.0001). There was no significant difference between the 2.0 Gy once daily and the 1.2 Gy twice daily dose-paralysis curves (p = 0.86). The residual from a single 12 Gy radiation dose was 17% after 190 days, leaving the retreatment ED50 only 10% below the ED50 of previously unirradiated spinal cord. The relative risk of paralysis after 12 Gy plus a second radiation dose decreased from 1.00 with no time interval between doses to 0.51-0.73 with a 0.25, 1 or 3 day interval, 0.32 with a 7 day interval, 0.11 with a 30 day interval, and 0.06 with a 190 day interval. CONCLUSION: The increased radiation tolerance of the murine spinal cord produced by decreasing the fraction size from 2.0 to 1.2 Gy was offset by the diminished tolerance produced by decreasing the time interval between fractions from 24 to 8-16 h, resulting in no significant difference in the dose-paralysis curves of conventional and hyperfractionated radiation schedules. The rodent spinal cord eliminates the majority of the occult radiation injury produced by a radiation dose equal to half the ED50 during the months following irradiation. This permits retreatment of previously irradiated spinal cord to high doses without the induction of myelopathy.

Smoothing grouped bivariate data to obtain the incubation period distribution of AIDS.

We use a penalized likelihood approach to obtain a smooth estimate of a bivariate distribution from grouped data where each observation consists of a region in a plane. The purpose of the analysis is to estimate the incubation period distribution of AIDS from the Multicenter AIDS Cohort Study, a prevalent cohort of homosexual men. In this article we illustrate the usefulness of the penalized likelihood approach. We also discuss the use of a cross-validation and a Bayesian scheme to choose the smoothing parameters and bootstrap samples to assess uncertainty.

Studies with FtsA-LacZ protein fusions reveal FtsA located inner-outer membrane junctions.

Four FtsA-LacZ translational gene fusions were constructed using a mini-Mu transposon (MudII 1734). FtsA-LacZ fusions and FtsA protein that were radioactively labelled using maxicell technique fractionated identically into membranes and cytoplasm. The FtsA-LacZ fusion proteins were also localized in wild type dividing cells using beta-galactosidase activity. Fractions from a modified sucrose equilibrium gradient exhibited beta-galactosidase activity in fractions corresponding to outer membrane-heavy (OMH) and outer membrane light (OML). The data are consistent with a model in which FtsA protein is incorporated into septal adhesion sites associated with cell division.

The value of graphic reconstructions--comparison with scanning electron microscopy.

Because knowledge of spatial morphology of the human embryonic heart mainly derives from serial microscopic sections and from reconstructions based on such series, it might be questioned whether the results obtained are comparable with animal studies in which scanning electron microscopy is used. Therefore, pig embryo hearts of the same developmental stage were processed for routine histological sectioning as well as for scanning electron microscopy. A graphic reconstruction was made of a right ventricular view, to be compared with a similar scanning micrograph. The two images, produced by much different techniques, were strikingly similar. In addition, the graphic reconstruction technique is complementary to scanning electron microscopy, because histological details can be introduced.

Significance of systemic vascular resistance in determining the hemodynamic effects of hydralazine on large ventricular septal defects.

The hemodynamic effects of hydralazine were studied in 17 infants and young children with ventricular septal defects to clarify the significance of systemic vascular resistance (SVR) in determining these effects. Patients with peak pulmonary arterial pressures greater than 75% of systemic pressure were placed in group I, which was further divided into group Ia (n = 6), consisting of those with a control SVR of 20 U.m2 or higher, and group Ib (n = 8), consisting of those with a lower SVR. Group II consisted of three patients with lower pulmonary arterial pressures. Intravenous injection of hydralazine (0.3 mg/kg) reduced SVR in all but two patients. The magnitude of reduction correlated with prehydralazine (control) SVR (r = .66, p less than .01). Systemic blood flow (Qs) increased from 3.7 +/- 0.7 to 5.0 +/- 0.8 l/min/m2 (p less than .005). The mean systemic arterial pressure for all patients decreased from 69 +/- 2 to 65 +/- 2 mm Hg (p less than .01) and the mean pulmonary arterial pressure decreased from the control value by 9 +/- 4% (p less than .01) in group I and by 17 +/- 1% in group II. Pulmonary blood flow (Qp) did not change significantly in either group. The Qp/Qs ratio was reduced from 3.6 +/- 0.4 to 2.4 +/- 0.2 (p less than .02) in group Ia. In sharp contrast, however, it increased from 2.6 +/- 0.3 to 3.3 +/- 0.5 (p = .06) in group Ib. The posthydralazine Qp/Qs ratio, expressed as percent of the control value, inversely correlated with the control SVR (r = -.61, p = .02) in group I. The response was not different in the group II patients. Thus, we conclude that control SVR is important for prediction of the hemodynamic effects of afterload reduction by hydralazine in infants and young children with large ventricular septal defects, and that this drug may be beneficial in patients with high control SVRs since a high SVR brings about a decrease in the Qp/Qs ratio.

Afterload reduction treatment for large ventricular septal defects. Dependence of haemodynamic effects of hydralazine on pretreatment systemic blood flow.

The haemodynamic effects of hydralazine were studied in seven infants and a child, each with a large ventricular septal defect. Hydralazine, 0.3 mg/kg, was administered intravenously. This caused a lowering of pulmonary arterial pressure from 57 +/- 4 mmHg to 49 +/- 4 mmHg, and a lowering of left atrial pressure from 12 +/- 1 mmHg to 10 +/- 1 mmHg. Systemic vascular resistance was reduced from 19.0 +/- 2.4 units/m2 to 15.1 +/- 0.9 units/m2. Pulmonary vascular resistance was reduced in six cases and increased in two. Systemic blood flow (Qs) increased in six cases and was unchanged in one. It decreased in one case where the pretreatment Qs was high, that is 6.4 l/min per m2. Pulmonary blood flow (Qp) increased in six cases while it decreased in two. These two cases had a pretreatment Qs less than 3.0 l/min per m2. The pulmonary to systemic blood flow ratio (Qp/Qs ratio) decreased only in three patients who had Qs less than 3.0 l/min per m2 before hydralazine. In contrast, the Qp/Qs ratio increased in the five cases with higher pretreatment Qs. Thus, this study has found that the pretreatment Qs alters the effect of hydralazine on the Qp/Qs ratio in large ventricular septal defects, thus indicating that afterload reduction treatment with hydralazine may be effective in the management of large ventricular septal defects by reducing the Qp/Qs ratio in the cases that are associated with a low systemic blood flow.

Pulmonary arteriography through patent ductus arteriosus with preformed catheters.

Selective pulmonary arteriography was performed successfully with new preformed catheters in eight consecutive patients with pulmonary atresia or severe stenosis and patent ductus arteriosus. The catheters were inserted percutaneously into the femoral artery and passed into the patent ductus arteriosus very easily within a few minutes. Pulmonary arteriography was performed with biplane cineangiography. All eight patients showed either stenosis or secondary atresia in the central pulmonary artery. The obstructive lesions occurred at the junction of either a patent ductus arteriosus or a surgically anastomosed subclavian artery.