Decreased arteriovenous flow resistance in the left gastric venous area in cirrhotic patients

Abstract. To assess the relationship between the fluid mechanics in the left gastric venous area and the portal trunk, manometric measurements were made in patients with or without cirrhosis of the liver. In ten normal subjects, temporary portal vein occlusion produced comparable elevation in both the occluded left gastric venous pressure (OLGP) and the portal vein pressure (PVP); 152–4129 mm of water in OLGP and 115–452 mm of water in PVP. In sixty cirrhotic patients, however, the portal vein occlusion resulted in far less increase in OLGP than that in PVP; 281–365 mm of water in OLGP and 281–540 mm of water in PVP. In other words, regarding pressure measurements, the relationship was 'separated' in cirrhotics, but 'continuous' in normal subjects. Mathematical analysis of the data using a modification of Wheat-stone bridge model suggested that the arteriovenous flow resistance in the left gastric venous area of cirrhotics was reduced to less than one fifth of that in the controls. It would appear that the increased flow capacity as a result of a reduced arteriovenous flow resistance is responsible for the functional 'separation' from the portal trunk.     

Establishment of embryonic stem cells secreting human factor VIII for cell-based treatment of hemophilia A

Summary.  Background:  Hemophilia A is an X-chromosome-linked recessive bleeding disorder resulting from an F8 gene abnormality. Although various gene therapies have been attempted with the aim of eliminating the need for factor VIII replacement therapy, obstacles to their clinical application remain. Objectives:  We evaluated whether embryonic stem (ES) cells with a tetracycline-inducible system could secrete human FVIII. Methods and results:  We found that embryoid bodies (EBs) developed under conditions promoting liver differentiation efficiently secreted human FVIII after doxycycline induction. Moreover, use of a B-domain variant F8 cDNA (226aa/N6) dramatically enhanced FVIII secretion. Sorting based on green fluorescent protein (GFP)–brachyury (Bry) and c-kit revealed that GFP–Bry⁺/c-kit⁺ cells during EB differentiation with serum contain an endoderm progenitor population. When GFP–Bry⁺/c-kit⁺ cells were cultured under the liver cell-promoting conditions, these cells secreted FVIII more efficiently than other populations tested. Conclusion:  Our findings suggest the potential for future development of an effective ES cell-based approach to treating hemophilia A.     

Prediction of interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C

To predict interferon-alpha (IFN-α)-induced thyroid dysfunction, anti-thyroglobulin (anti-TgAb) and anti-thyroid peroxidase antibodies (anti-TPOAb) were determined by radio-immunoassay (RIA) before IFN-α treatment in 30 patients with chronic hepatitis C in whom the conventional haemagglutination test had failed to detect anti-thyroid auto-antibodies. Seven patients developed thyroid dysfunction during IFN-α treatment (transient thyrotoxicosis in four patients, transient hypothyroidism in two, and Graves’ disease in one). Anti-TgAb and/or anti-TPOAb were detectable before IFN-α treatment in six of these seven patients, while these antibodies were detected before treatment in only four of 23 patients who did not develop any thyroid dysfunction. The prevalence of these antibodies was significantly higher (P= 0.002) in the former group of patients than in the latter. In four patients with detectable anti-TgAb before treatment but no subsequent thyroid dysfunction, the antibody disappeared during IFN-α treatment. Haemagglutination tests for anti-thyroid microsomal antibodies have previously been reported to be a useful predictive marker of IFN-α-induced thyroid dysfunction. In conclusion, sensitive detection of anti-thyroid auto-antibodies using RIA may also be useful for the prediction of IFN-α-induced thyroid dysfunction in patients with a negative haemagglutination test.     

Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines

The chemotaxis of human malignant plasma cells is promoted by two extracellular matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds, OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the expression of β1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1 cells showed chemotaxis promoted by FN (Ch^FN) and LN (Ch^LN). ARH-77 cells showed Ch^FN but not Ch^LN. RPMI-8226 cells did not show either Ch^FN or Ch^LN. The supernatant from KM-101 cells inhibited the chemotaxis of each of these cell lines regardless of whether the chemotaxis was promoted by FN or LN. Among the cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6 receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6) also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is probably transduced via the signal transducing receptor component, gp130. The chemotaxis-regulatory effect is another previously unrecognized function of this pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow microenvironment of patients with multiple myeloma appears to be favourable for the localization of myeloma cells there.     

Midline extraperitoneal approach to upper urinary tract surgery: Anatomical basis of surgical technique

Aim: To overcome the disadvantages inherent in the standard surgical approach to the kidney, we introduced a novel surgical technique via a midline extraperitoneal approach. The surgical technique is not substantially different from that of the standard midline transperitoneal approach, except no entry is made into the peritoneal cavity. Although the peritoneum itself is extremely thin and fragile, the peritoneum together with underlying subperitoneal fascia can be dissected readily as a substantial layer, if the proper plane is dissected. Further medial mobilization of the peritoneal sac en bloc by pursuing the fusion fascia plane allows full exposure of the kidney, ureter and great vessels. This approach was adopted for consecutive 51 patients during a 10-month period in 2003. All operations, including 33 radical nephrectomies and 11 nephroureterectomies were completed successfully without significant technical difficulties and differences in operation time and estimated blood loss compared to the transperitoneal approach. No intra- or perioperative complication occurred. All patients did seem to have a much more comfortable postoperative period with minor pain and few abdominal complaint, and the clinical impression was that they resumed the physical activity and oral intake earlier than those after the transperitoneal approach (P = 0.056). There are no operation-related problems such as intra-abdominal adhesion or abdominal muscle weakness resulting in some deformity at 2-year or more follow up. This approach combines the advantages of the transperitoneal midline and extraperitoneal flank approach. Its use will undoubtedly reduce the complications inherent in the transperitoneal approach or the flank approach.     

Sudden Cardiac Death: Future Approaches Based on Identification and Control of Transient Risk Factors

Sudden Cardiac Death . Future progress in the ability to control the problem of sudden cardiac death will require new approaches in applied epidemiology, methods of accurately evaluating therapeutic outcome, and techniques to identify and control those transient risk factors that are responsible for the initiation of fatal arrhythmias. In regard to the latter, transient risk factors are distinguished from classical risk factors in two ways: (1) they are not present continuously over time, thus confounding sampling techniques among a population; and (2) their dynamic nature suggests a proximate role in the initiation of potentially fatal arrhythmias in contrast to the role of classical risk factors in the genesis of the underlying diseases. Transient risk factors derive from the structure/function model of sudden cardiac death, which places structural abnormalities in a conditioning role, establishing the sensitivity to a transient destabilizing influence. In contrast, functional abnormalities are those conditions immediately responsible for destabilizing the system, establishing vulnerability to potentially fatal arrhythmias. They include four categories of risk: (1) transient ischemia and reperfusion; (2) systemic abnormalities, such as hemodynamic dysfunction and fluid and electrolyte imbalance; (3) autonomic fluctuations, both central and cardiac; and (4) cardiac toxic states, including proarrhythmic effects of antiarrhythmic drugs and arrhythmogenic effects of other substances. Sudden cardiac death is a dynamic problem, and its pathogenesis contains dynamic features. The ability to identify transient risk factors and to control them before they exert their influence on a conditioned electrophysiologic system will provide new inroads into the problem of sudden cardiac death.     

Evaluation of proximal tubular function in preterm infants by urinary α1-microglobulin

α₁-Microglobulin is a low molecular weight protein that is relatively stable in urine of low pH. There have been few reports on urinary α₁-microglobulin (U-A₁M) excretion in preterm infants. This study was designed to establish the ranges for U-A₁M in clinically stable preterm infants and to investigate changes observed in sick preterm infants. We measured U-A₁M and urinary β₂-microglobulin (U-B₂M) levels at 1, 4, 7, 14, 28 and 90 days after birth in stable preterm infants (Group 1) and sick preterm infants who were depressed at birth and required immediate resuscitation (Group 2). In Group 1 infants, both parameters were high during the first 28 days and appeared to decline thereafter. U-A₁M in Group 2 infants was only significantly increased compared with Group 1 on day 1, as was U-B₂M. On each day of the study, U-A₁M had significant positive correlations with U-B₂M for all the infants studied. The changes of the two parameters observed in Group 1 probably reflect postnatal evolution of proximal tubular function in stable preterm infants. A comparison of groups 1 and 2 shows a high prevalence of acute tubular injury at birth in sick infants and also suggests that U-A₁M as well as U-B₂M may be a sensitive index for detecting acute tubular damage and for following its course in preterm infants.     

CUTANEOUS B-CELL LYMPHOMA CONSISTING OF LARGE CLEAVED CELLS WITH MULTILOBATED NUCLEI

A 65-year-old man was seen at the Ushioda Hospital in Au-gust 1989, because of a 1-month history of a tumor on the scalp. The tumor was excised and the diagnosis was malig-nant lymphoma. The patient was then referred to our de-partment in September 1989. Several nut-sized lymph nodes wvepa-b and m-fepa for 2 months. Since then, the patient has been free of disease up to the time of writing, July 1992, a period of 2.5 years. Biopsy samples taken from the tumor on the scalp showed a monomorphous infiltrate of large lymphoid cells throughout the entire dermis and subcutis, with a definite clear zone (Fig.1). A high-power view showed diffuse large lymphoid cell infiltration. Numerous mitotic figures were also seen. The lymphoid cells had multilobated nuclei and distinct nucleoli (Fig. 2). Monoclonal antibodies such as Leui (CD5), Leu2a (CD8), Leu3a (CD4), Leu4 (CD3), MT-1 (CD43), Leu14 (CD22), LN1 (CDw75), and Leu26 (CD20), and polyclonal antibodies such as anti-kappa, anti-lambda, anti-IgG, anti-lgA, anti-IgM, and anti-lgD were purchased from commercial sources. Optimal dilutions of the monoclonal antibodies and heteroantisera were assessed beforehand by titration on suitable tissue samples. The antigens recognized by the monoclonal anti-bodies and heteroantisera were investigated by either the avidin-biotin peroxidase complex (ABC) method on cryostat sections or the peroxidase-antiperoxidase complex (PAP) method on paraffin sections, as described elsewhere.¹ The immunologic properties of the infiltrating cells were determined using skin biopsied in August 1989, and October 1989. Large lymphoid cells, which formed the major popu-lation of infiltrating cells, were positive for CD20, CD22, and HLA-DR and negative for CD3, CD4, CD43, and CD45RO. From these findings the patient was diagnosed as hav-ing primary cutaneous B-cell lymphoma, diffuse large non-cleaved cell type, as classified by the Working Formulation.²     

Solid-phase synthesis of human osteocalcin by using a γ-carboxyglutamic acid derivative

Human osteocalcin, also called bone Gla protein (BGP), consisting of 49 amino acids with two to three γ-carboxyglutamate residues, was chemically synthesized for the first time by a novel solid-phase peptide synthesis. An l -enantiomer of N-tert-butyloxycarbonyl-γ,γ′-dicyclohexyl-γ-carboxyglutaniic acid was designed, prepared and utilized as a monomeric compound and proven to be useful for the solid-phase peptide synthesis of human osteocalcin. The synthesis and optical resolution of the γ-carboxyglutamic acid (Gla) derivative are first described, followed by the synthesis and characterization of Gla¹⁷-human osteocalcin.