Serum concentration of hyaluronic acid in healthy populations and patients with rheumatoid arthritis--relationship to clinical disease activity of RA

With the sandwich binding protein assay utilizing hyaluronic acid binding protein, we measured serum concentration of hyaluronic acid in 458 healthy persons, 71 patients with rheumatoid arthritis (RA) and 51 patients with various rheumatic diseases such as osteoarthritis (OA), progressive systemic sclerosis (PSS), systemic lupus erythematosus (SLE) and gout. The mean concentration +/- standard deviation (SD) of healthy persons whose age ranged 2 to 92 years old was 38.5 +/- 35.7ng/ml, and those with over 50 years old had apparently higher concentrations (51.9 +/- 40.5ng/ml) than those with below 50 of age (20.6 +/- 14.8ng/ml). When the upper limit of normal range was set up at 130 ng/ml, abnormal percentages were 62.0% (44/71) in RA, 0% (0/18) in OA, 6.3% (1/16) in PSS, 18.2% (2/11) in SLE and 0% (0/6) in gout. Patients who apparently had arthritis but not RA revealed normal or near to the upper limit in serum hyaluronic acid compared to RA patients having the mean +/- SD of 351.4 +/- 463.7ng/ml. When patients with RA were classified into stage I to IV with X ray of bone destruction, patients with more advanced X ray stage showed significantly higher serum concentrations of hyaluronic acid. Similarly, patients with lower activity of daily living revealed significantly higher serum concentrations of hyaluronic acid. In addition, serum hyaluronic acid level did correlate to concentration of serum CRP and sialic acid. Lansbury's index, strength of grip, joint score and erythrocyte sedimentation rate, but did not to duration of morning stiffness and titer of rheumatoid factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regulation of Fas-mediated apoptosis of rheumatoid synoviocytes by tumor necrosis factor alpha and basic fibroblast growth factor is associated with the expression of apoptosis-related molecules

OBJECTIVE: Fas-mediated apoptosis is associated with the pathophysiology of rheumatoid arthritis (RA). However, the molecular mechanisms of this process remain to be elucidated in rheumatoid synovium. We investigated the behavior of intracellular signaling molecules that regulate Fas-mediated apoptosis in RA synoviocytes. METHODS: Anti-Fas monoclonal antibody (mAb) was added to RA synoviocytes after treatment with tumor necrosis factor alpha (TNFalpha) or basic fibroblast growth factor (bFGF) for 5 days. The cytotoxic activity was measured using a lactate dehydrogenase-release assay. The expression of apoptosis-related molecules in RA synoviocytes was examined by immunoblot analysis. The enzymatic activities of caspases 3 and 8 under Fas ligation were examined. Transfer of the FADD (Fas-associated death domain) protein and the FLIP(L) (long form of the FLICE [FADD-like interleukin-1beta-converting enzyme]-inhibitory protein) gene into RA synoviocytes was performed using adenoviral vectors. RESULTS: Following a 5-day treatment with TNFalpha or bFGF, Fas ligation with its agonistic mAb induced apoptosis of almost all TNFalpha-treated RA synoviocytes but only showed a weak apoptotic activity in bFGF-treated synoviocytes. Although there was no correlation between the induction of Fas-mediated apoptosis and the expression of apoptosis-related molecules among these cells, a high enzymatic activity of caspases 3 and 8 was observed only in the TNFalpha-treated RA synoviocytes after Fas ligation. The bFGF-treated RA synoviocytes were relatively resistant to apoptosis induced by FADD gene transfection, as compared with the TNFalpha-treated synoviocytes. In addition, the expression of FLIP(L), an inhibitory molecule of Fas-mediated apoptosis, was reduced in TNFalpha-treated RA synoviocytes, and the expression of FLIP43 was augmented in bFGF-treated RA synoviocytes. Moreover, Fas-mediated apoptosis in TNFalpha-treated RA synoviocytes was partially inhibited by FLIP(L) gene transfection. CONCLUSION: Our results suggest that Fas-mediated apoptosis of RA synoviocytes is differentially regulated by TNFalpha and bFGF. In addition, the regulatory mechanisms of apoptosis involve the formation of the death-inducing signaling complex, especially at the level of caspase 8 activation, and this process may be partly associated with FLIP expression.     

A clinical and epidemiologic study of 292 cases of lance-headed viper bite in a Brazilian teaching hospital.

The records of 292 patients who were admitted to a teaching hospital from 1984 to 1990 in Uberlandia in southeastern Brazil after being bitten by snakes of the genus Bothrops were retrospectively surveyed. The patients were from 42 municipalities in three states of Brazil. Most (42%) bites occurred between 4:00 PM and 10:00 PM. Fourteen percent of the bites occurred in the month of April. In 54 (18%) of the cases, the snakes were captured and identified as belonging to the following species: B. moojeni (29), B. neuwiedi (18), and Bothrops species (7). A diagnosis was made based on clinical findings in 238 (82%) cases. The lower limbs were the commonest site of bite (74%). The median time interval between bite and admission to the hospital was 3 hr. Fang marks were recorded in 58% of the cases and swelling was recorded in 82%. Clotting time was greater than 15 min in (142 of 264) 54% of the cases. A tourniquet was used on 44 cases. The mean +/- SD dose of specific antivenom used was 187.48 +/- 93.44 mg. The complications that occurred included abscess formation in 18% of the cases, necrosis in 16%, and renal failure in 5%. Amputation was performed in three (1%) cases. The case fatality rate was also 1% (three cases). When all cases were analyzed, the chi-square test for trend showed an increased susceptibility of renal failure with age (P < 0.04). Clotting time greater than 15 min was associated with the development of abscesses (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma levels of activated protein C-protein C inhibitor complex in patients with hypercoagulable states

Plasma levels of activated protein C (APC)-protein C inhibitor (PCI) were significantly increased in patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), acute myocardial infarction (AMI), pulmonary embolism (PE), or deep vein thrombosis (DVT) and in patients undergoing hemodialysis (HD). Plasma levels of APC-alpha(1)-antitrypsin (AT) complex were significantly increased in patients with DIC and in those with TTP. Plasma levels of PCI were significantly decreased in patients with DIC, non-DIC, or TTP and in those undergoing HD. In the pre-DIC stage, the plasma levels of APC-PCI complex were significantly increased but not those of APC-alpha(1)-AT complex. These data suggest that measurements of APC-PCI complex and APC-alpha(1)-AT complex may be useful for the diagnosis of DIC. After treatment of DIC, the plasma levels of APC-PCI complex and APC-alpha(1)-AT complex were significantly decreased, but not those of PCI. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-alpha(2)-plasmin complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were markedly increased in patients with DIC or pre-DIC and were moderately increased in patients with non-DIC, TTP, AMI, PE, or DVT and in those undergoing HD. The receiving operating characteristic (ROC) analysis showed that SFM and the APC-PCT complex are useful markers for diagnosis of DIC. The specificity of plasma TAT and PPIC levels was low. The positive rate of APC-PCI complex was higher than 90% with DIC, TTP, AMI, PE, and it was higher than 60% with DVT and HD. Since the APC-PCI complex was elevated not only in patients with venous thrombosis but also in those with arterial thrombosis, components of the protein C pathway might be useful markers for the diagnosis of arterial thrombosis.     

Evaluation of aggressive surgical treatment for advanced carcinoma of the gallbladder

Background/Purpose. An aggressive approach is required to resect advanced carcinoma of the gallbladder. Therefore, an extended surgical procedure often brings about a poor surgical outcome. To test whether an aggressive surgical treatment can improve the survival rate for primary advanced carcinoma of the gallbladder, 59 patients with stage IV primary gallbladder carcinoma were studied. Methods. Patients were divided into three treatment groups for the survival analysis: group A (resectional surgery, n = 29), group B (low-dose cis-diamminedichloroplatinum-II and 5-fluorouracil therapy, n = 10), and group C (exploratory laparotomy, other treatment modalities, or no treatment, n = 20). Results. The prognosis of group A patients was significantly better than that of group B (P = 0.018) or group C (P = 0.0009). Furthermore, group A patients were divided into subgroups. The prognosis of patients resected with no distant metastasis (group A1) was significantly better than that of patients resected with distant metastases of the distant lymph nodes and the liver (group A2) (P = 0.0004). Also, there was no significant difference in the survival rate between the patients resected with distant metastasis (group A2) and chemotherapy cases (group B). Conclusions. These results indicated that radical surgery should be performed for patients with no distant metastasis, and that chemotherapy might be a useful alternative treatment for patients with distant metastasis in advanced carcinoma of the gallbladder.     

Somatostatin-like immunoreactivity in the pituitary and brain of three teleost fish species: somatostatin as a potential regulator of prolactin cell function

Somatostatin-like immunofluorescence occurs in the hypothalamus and neurohypophysis of three euryhaline teleosts: tilapia, killifish, and mudsucker. This immunofluorescence was eliminated by incubating the primary antibody with excess somatostatin or somatostatin-28 but not with urotensin II, a partial analogue of somatostatin. In all three fishes, the strongest reaction was seen in the proximal pars distalis and parts of the pars intermedia. Strongly fluorescing processes from cells of the preoptic nucleus extend toward the pituitary. Distinct fluorescence was also associated with the neurohypophysis penetrating into the rostral pars distalis in the tilapia but not in the killifish or mudsucker. In the tilapia, an extensive network of immunofluorescent fibers and small cells were present in the anterior dorsolateral telencephalon, in addition to a moderately fluorescing group of cells anterolateral to the preoptic nucleus. A small area of diffuse fluorescence was also seen in the anterior dorsolateral midbrain tegmentum. Previous physiological studies have implicated somatostatin as a regulator of prolactin cell activity in tilapia. The present study demonstrates the route by which somatostatin may be delivered to the rostral pars distalis to inhibit prolactin secretion.     

Duodenal erosions after eradication of Helicobacter pylori infection

BACKGROUND: There is interest in the development of GERD after Helicobacter pylori eradication. In contrast, the development of duodenal erosions after therapy has received scant attention. Patients were examined after eradication of H pylori infection to determine the frequency of post-therapy duodenal erosions (primary outcome) and whether there was a relation between development of duodenal and esophageal erosions. Additionally, factors were searched for that would identify patients at increased risk for duodenal erosions. METHODS: A single-center, endoscopist-blinded, observational study was conducted of 196 patients in whom H pylori was eradicated. The presence of esophageal or duodenal erosions was evaluated 4 weeks and 6 months after eradication. Serum gastrin and pepsinogen I (PG I) and II (PG II) levels were also determined for 83 patients entering the study during its final year. RESULTS: Multiple small duodenal erosions developed in 8.6% of patients after H pylori eradication and were more common in patients with pre-eradication duodenal ulcer (27.8%) compared with those with gastric ulcer (6.7%) or atrophic gastritis (1.4%) (p < 0.05). Duodenal erosions were associated with high levels of PG I before and after eradication. The frequency of duodenal erosions decreased over time (3.1% by 6 months). CONCLUSION: Duodenal erosions occur after H pylori eradication and appear to be related to duodenal ulcer and increased PG I levels, both of which are associated with increased acid secretion. Measurement of PG I may help to identify patients who have duodenal erosions develop after H pylori therapy for studies of the pathogenesis of these lesions.     

Noninvasive transcutaneous low frequency ultrasound enhances thrombolysis in peripheral and coronary arteries

Previous studies have shown that external ultrasound with low frequencies and high intensities can enhance thrombolytic drug-induced clot dissolution during in vitro experiments. In this series of studies, we evaluated the efficacy of peripheral and coronary thrombolysis in vivo in animals by using noninvasive transcutaneous ultrasound combined with thrombolytic drugs (streptokinase and tPA) and/or microbubbles agents (dodecafluoropentane [DDFP] and perfluorocarbon-exposed sonicated dextrose albumin [PESDA]). Thrombotic occlusions were induced in 74 rabbit iliofemoral arteries and 24 canine left anterior descending (LAD) coronary arteries in this in vivo study. By using the combination of transcutaneous ultrasound and streptokinase, the angiographic patency rate in rabbit iliofemoral arteries was higher (56%-100%) than with ultrasound (6%; P < or = 0.0036) and streptokinase alone (6%; P < or = 0.0012). Also, with transcutaneous ultrasound and microbubbles, the angiographic patency rates were 76%-100% as compared with ultrasound alone (0%, P < or = 0.0003) or microbubbles alone (9%, P < or = 0.0001). In the canine study of acute myocardial infarction, thrombolysis in myocardial infarction (TIMI) grade flow at 90 minutes in the tPA alone group was 0.92 +/- 1.4 as compared with 2.42 +/- 1.9 in the tPA plus transthoracic ultrasound group (P = 0.006). There was much improved reperfusion with tPA plus ultrasound as compared with tPA alone. In vivo animal studies demonstrate that noninvasive transcutaneous ultrasound can greatly enhance the effect of clot dissolution with thrombolytic drugs and/or microbubbles, and has the potential for clinical application as an adjunctive method to improve arterial thrombolysis.     

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR.