The response of the rat liver to alterations in total portal blood flow.

In attempting to isolate the various components involved in the stimulus induced by partial hepatectomy, the effect of sudden increased portal flow to the whole liver has been studied. The technique involved the construction of a portacaval anastomosis and after a week, reconstitution of the original portal vein, allowing resumption of portal blood flow. The effects of increased portal flow in this experiment were to induce hypertrophy of hepatocytes and a minor degree of DNA synthesis.     

Deiodination of thyroid hormones by the perfused rat liver

1. An investigation has been made into the deiodination of thyroid hormones by the perfused rat liver. The hormones were labelled with (125)I in the phenolic ring and the rate of deiodination was estimated by measuring the release of radio-iodide into the perfusate.2. At tracer concentrations, 0.98% of the liver thyroxine is deiodinated/5 min. The deiodination of tri-iodothyronine is considerably faster, 3.3%/5 min.3. Deiodination is very sensitive to changes in temperature.4. The reaction shows saturation kinetics typical of many enzymes, the reciprocal of the rate of deiodination being proportional to the reciprocal of the hormone concentration in the tissue. The maximum rate of deiodination of each hormone is about 1.5 mug/min for a whole liver preparation weighing 16 g.5. Tri-iodothyronine inhibits thyroxine deiodination and vice versa, suggesting that a single enzyme is responsible for both reactions.6. Propyl thiouracil (PTU) at high concentrations inhibits the deiodination of both hormones.7. An abnormally high rate of deiodination is associated with the actual injection of hormone into the preparation. This suggests that only the free (unbound) hormone in the tissue is directly available to the deiodinating enzyme.8. About half of the whole body deiodination of thyroxine is relatively insensitive to PTU. It is suggested that most of this type of deiodination is performed in the liver and that the process is one of inactivation.     

Clinical and pathologic findings of the liver in the acquired immune deficiency syndrome (AIDS)

Clinical data and histologic sections of the liver, including immunohistochemical studies for hepatitis B surface and core antigens, were reviewed in 42 autopsy cases of the acquired immune deficiency syndrome (AIDS). Hepatomegaly, elevation of serum transaminases, and mild elevation of alkaline phosphatase were commonly observed clinical and biochemical abnormalities. Mildly elevated alkaline phosphatase and normal bilirubin levels were present in patients with Mycobacterium avium-intracellulare (MAI) infection, cytomegalovirus (CMV) infection, and Kaposi's sarcoma (KS). Histologic sections demonstrated liver involvement by MAI in eight cases; KS in six cases; cryptococcus in three cases; and CMV in two cases. One case of MAI infection was associated with marked central vein sclerosis, a finding previously unreported. Thirty-two (76%) of 42 cases had serologic or pathologic evidence of hepatitis exposure. Two patients had histologic evidence of chronic active hepatitis. The pathologic processes involving the liver appeared to be secondary to the infections and neoplasms for which this population is susceptible and did not significantly contribute to morbidity or mortality. No findings specific or pathognomic for AIDS were identified in the liver.     

Hereditary tyrosinemia type I (chronic form): pathologic findings in the liver

Hereditary tyrosinemia type I presents with either acute hepatic failure in the neonatal period or later in infancy with progressive liver dysfunction secondary to cirrhosis. The inevitably fatal outcome in those children with the chronic form has been transformed with the advent of liver transplantation. Native livers from five children who received allografts were studied pathologically and compared with earlier hepatic biopsies in two of these patients that had been performed several years before transplantation. Our findings support the conclusion that a sequence of morphologic changes from the initial micronodular cirrhosis through an intermediate mixed cirrhotic pattern to macronodular cirrhosis occurs. The micronodular phase is transitory, over a period of only a few months, since mixed micronodular macronodular cirrhosis was already present in the livers of children who received transplants by 11 months of age. Focal hepatocellular dysplasia was present in one of the livers with mixed cirrhosis but was not identified in the other two cases. Macronodular cirrhosis accompanied two cases of hepatocellular carcinoma in this study. In order to preclude the latter complication, liver replacement is necessary before the age of 2 years.     

Genetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response

TPO autoantibodies, the hallmark of human autoimmune thyroid disease, are of IgG class and are associated with thyroid destruction and hypothyroidism. Using the immunoglobulin gene combinatorial library approach, a panel of human monoclonal TPO autoantibodies (expressed as Fab) has been generated from thyroid tissue-infiltrating B cells. TPO-specific Fab closely resemble patients' serum autoantibodies in terms of L chain type, IgG subclass, affinities for TPO as well as epitopes recognized by > 80% of TPO autoantibodies in an individual's serum. TPO autoantibody V region genes are not unique; H chain V genes are usually mutated, while L chain V genes are sometimes in germ-line conformation. The autoantibodies recognize an immunodominant region involving conformational, overlapping epitopes in domains A and B. Finally, TPO autoantibody epitopic fingerprints are distinctive for individual sera, are not associated with hypothyroidism, but are conserved over time (indicating a lack of B cell epitope spreading). Evidence for conservation as well as inheritance of the fingerprints in some families, together with V_H gene polymorphisms, may provide insight into the genetic basis of human autoimmune thyroid disease. Furthermore, monoclonal human TPO autoantibodies will be invaluable for B cell presentation of TPO to determine the T cell epitopes involved in TPO autoantibody production.     

The brain tissue response to biodegradable poly(methylidene malonate 2.1.2)-based microspheres in the rat

The aim of this study was to follow the in vivo biodegradation as well as to appreciate the brain tissue response to poly(methylidene malonate 2.1.2) (PMM 2.1.2)-based microspheres implanted into the rat brain. Ninety-three adult Sprague-Dawley female rats were engaged in the study in which 54 underwent stereotactic implantation of blank gamma-sterilized PMM 2.1.2-based microspheres, prepared by an emulsion-extraction method. Twelve rats were implanted with the same 5-fluorouracil (5-FU)-loaded microspheres. Seventeen controls received the suspension medium alone (carboxymethylcellulose aqueous solution). The animals were sacrificed on post-operative days 1, 2, 8 and months 1, 2, 3, 6, 9, 12, 15 and 18. The brains were dissected, frozen, cut in a freezing microtome, and the slides were processed for immunohistological evaluation and scanning electron microscopy. During the first few days, the moderate inflammatory response to blank or loaded PMM 2.1.2 microspheres was largely a consequence of the mechanical trauma that occurs during surgery. The macrophagous-microglial reaction was similar to the one typically found following any damage in the CNS. There were also no differences in GFAP reactivity between the implanted animals and the controls. Blank microspheres began to degrade between 3 and 6 months, while 5-FU microspheres degraded between 8 days and 1 month. The polymer degradation generated in both cases a pronounced inflammatory and immunological reaction, leading to an important cell loss, a cerebral atrophy and to the death of several animals. PMM 2.1.2 was thus shown to be inadequate for intracerebral drug delivery.     

The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB₄ receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7–16 times more potent than SC-41930 in LTB₄ receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB₄-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.     

Rat leucocyte response to the bites of rat fleas (Siphonaptera: Pulicidae)

The host response to bites of the oriental rat flea, Xenopyslla cheopis Rothschild, was investigated by examining rat blood leucocyte kinetics, histopathology, and the effect that the host response had upon subsequent flea feeding and longevity. Test rats were subjected to controlled exposures of fleas, and leucocyte data from test rats were compared to those of unexposed controls. Of the five leucocyte types examined, only the basophil appeared to play a role in the host blood response to flea bites. Significant increases in blood basophil levels occurred 2-3 d after exposure but subsided to control levels within a week. However, flea feeding did not produce histopathology at the flea feeding sites nor did the basophilic blood response of rats affect subsequent feeding or longevity of the fleas.     

Failure to obtain an autoimmune response following cryosurgery to the normal rat liver.

Smooth muscle antibody (SMA) and anti-liver-specific lipoprotein (anti-LSP) responses were investigated following five different freeze thaw regimes to the normal rat liver. The livers were examined histologically for evidence of autoimmune liver disease. No SMA or anti-LSP was found in any animal and on histological examination the unfrozen part of all livers was normal. It is concluded that cryosurgical damage to the liver is unlikely to provoke an autoimmune response.     

Long-term pathologic changes of alpha1-acid glycoprotein (orosomucoid) glycoforms in autoimmune thyroid disease

OBJECTIVE: We measured alpha1-acid-glycoprotein (AGP) in patients with autoimmune thyroid disease to study a possible relationship between microheterogeneity of the naturally occurring glycoforms of AGP and autoimmune thyroid disease. DESIGN, PATIENTS, MEASUREMENTS: In a group of 12 fasting thyrotoxic patients (11 females, mean age: 43 years) with newly diagnosed Graves' disease (subgroup 1), we measured serum concentrations of total AGP and its 3 glycoforms (micromol/l, crossed affinity immunoelectrophoresis with con A in the first dimension gel) as well as total thyroxine, total triiodothyronine, thyrotropine, thyroid peroxidase antibodies (anti-TPO), antibodies against the TSH receptor (TRAb, TRAK), at baseline and after 12 months of antithyroid drug therapy (ATD). For comparison, 4 subgroups of thyroid patients (patients with Graves' disease and thyroid associated ophthalmopathy (TAO) (subgroup 2, n = 10), radioiodine treated Graves' patients (subgroup 3, n = 7), Graves' patients without TAO (subgroup 4, n = 13), patients with Hashimoto's thyroiditis (subgroup 5, n = 8)) and 25 normal controls (17 females, mean age: 38 years) were studied. RESULTS: In subgroups of TRAb positive Graves patients' serum levels of glycoform 1, 2 or 3 increased significantly (p < 0.005) after 12 months of ATD as compared to both baseline of that person or normal controls. No significant changes were found in the TRAb negative Hashimoto subgroup. CONCLUSION: Patients with autoimmune Graves' disease changed their relationship to AGP, and thus a role of AGP and its 3 glycoforms is suggested in the pathogenesis of Graves' disease.