Cholelithiasis prevalence and risk factors in individuals with severe or profound intellectual and motor disabilities.

BACKGROUND: The prevalence and risk factors of cholelithiasis in individuals with severe or profound intellectual and motor disabilities (SPIMD) are poorly characterised. Thus, we aimed to investigate the prevalence and risk determinants of cholelithiasis in a cohort with SPIMD under medical care in a residential facility. METHODS: We categorised 84 patients in a residential hospital for persons with SPIMD into groups: those with (Group CL) and without (Group N) cholelithiasis. Gallstones were detected via computed tomography, ultrasonography or both. We evaluated gastrostomy status, nutritional and respiratory support, constipation, and bladder and kidney stones. Data were significantly analysed using univariate and multivariate logistic regression analyses. RESULTS: The prevalence rate of cholelithiasis in our SPIMD cohort was 27%. There were no significant differences in sex, age, weight, height, or Gross Motor Function Classification System between the two groups. However, more patients received enteral nutrition (39.13% vs. 6.56%; P = 0.000751) and were on ventilator support (56.52% vs. 19.67%; P = 0.00249) in Group CL than in Group N. Enteral nutrition [odds ratio (OR) 10.4, 95% confidence interval (CI) 1.98-54.7] and ventilator support (OR 20.0, 95% CI 1.99-201.0) were identified as independent risk factors for the prevalence of cholelithiasis in patients with SPIMD. CONCLUSIONS: Patients with SPIMD demonstrated an increased prevalence of cholelithiasis, with a notable association between nutritional tonic use and respiratory support. Therefore, to emphasise the need for proactive screening, it is crucial to devise diagnostic and therapeutic strategies specific to patients with SPIMD. Further investigation is essential to validate our findings and explore causative factors.

[Concurrent chemoradiation therapy with nedaplatin for high-risk cervical cancer--clinical investigation of adverse events].

A clinical investigation of adverse events was conducted to confirm the safety of concurrent chemotherapy using nedaplatin (cisplatin derivative) and radiotherapy in the high-risk carcinoma of the uterine cervix. Seven patients who were treated with radical radiotherapy and 5 patients who were treated with adjunctive radiotherapy after radical hysterectomy and pelvic lymphadenectomy were eligible for the study. Nedaplatin was given intravenously at 70 mg/m2 on day 1 and day 29, and a total of 24 courses of nedaplatin administration were observed. None of the planned radiotherapy was postponed or discontinued due to side effects. Major adverse effects observed were gastrointestinal effects such as anorexia (66.7%), nausea and vomiting (33.3%) and diarrhea (66.7%). Grade 3 (in the 2nd course) and Grade 4 (in the 1st course) diarrhea was observed in one patient, which was easily relieved by antidiarrheal. Hematologic side effects were also major, including leukopenia (62.5%), neutropenia (75.0%), anemia (75.0%), and thrombocytopenia (33.3%). Hematologic effects were generally moderate; no Grade 4 (severe) effects were observed. Although these hematologic effects were lasting longer compared with radiation therapy alone, there were no significant differences in the seriousness of these side effects. Concurrent chemoradiation therapy with nedaplatin 70 mg/m2 every 4 weeks was safe and adverse effects were self-limited or resolved with medical management. Dose escalation in the phase III clinical study may be considered.

Structure-activity studies of analogues of blomhotin mediating contraction of rat fundus.

Blomhotin is a novel peptide (pGlu1-Gly2-Arg3-Pro4-Pro5-Gly6-Pro7-Pro8-Ile9-Pro10-Arg11) which has been isolated from the venom of Agkistrodon halys blomhoffii and exhibits contractile activity on rat stomach fundus. We carried out a structure-activity study of blomhotin and its related peptides, and the findings suggested that the N-terminal portion of blomhotin is mainly responsible for affinity for the blomhotin receptor, whereas the C-terminal portion of blomhotin, Pro-Ile-Pro-Arg, is responsible for complete activation of the blomhotin receptor in the rat stomach fundus. In particular, the amino acids at positions 9 and 11 of blomhotin appear to be essential for binding and intrinsic activity. Using knowledge gained from this structure-activity analysis, we have identified photoactive blomhotin analogues that have sufficient biological activity to probe the target molecule of blomhotin.

[Vascular anastomoses in free jejunal reconstruction to the neck vessels: an experience of consecutive 20 cases without using surgical microscope].

Twenty consecutive cases of pharyngoesophageal cancer who underwent free jejunal reconstruction were reported. The common carotid or external carotid artery was used for a feeder of the free graft. The internal jugular vein were served as a drainage vein. All anastomoses were performed in an end-to-side fashion without using surgical microscopes. Mean carotid artery clamping time was 16 minutes and no neurological complications were noticed postoperatively. Graft failure was occurred in 1 patient. The presenting technique, showing 95% success rate, is recommended as a simple option for vascular anastomosis in free jejunal reconstructive surgery.

Cytokine production in chorioamnionitis.

Lymphohematopoietic cytokines play a significant role in many biological mechanisms including a number of reproductive processes such as ovulation, implantation, placentation, cervical dilation and parturition. Recent experiments have suggested that cytokines play a crucial role in the mechanisms of preterm labor and delivery, which are the leading causes of perinatal morbidity and mortality. Growing evidence suggests that infection is deeply concerned in the pathogenesis of preterm labor and delivery. Chorioamnionitis, a subset of intrauterine infection, has been identified in 20-33% of women with preterm delivery, and the inflammatory and related cytokines, interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8), showed substantial increases in the amniotic fluid at women with intrauterine infection. Although the precise mechanism for chorioamnionitis-driven preterm labor mediated via cytokines is still unknown, both IL-1 and TNF-alpha along with IL-6 enhance prostaglandin production by human amnion cells, chorionic cells and decidual cells. Analysis of the regulatory sequences in the 5' upstream regions of receptor gene for human oxytocin, a potent uterotonic agent, suggests a close relationship between preterm labor and inflammatory cytokines through induction at the oxytocin receptor. Prompt identification of the patients with intra-amniotic infection may be useful in clinical practice. At present, the measurement of IL-8 in maternal serum or the measurement of IL-6 in cervical secretion may be helpful as a non-invasive screening for chorioamnionitis.

cDNA cloning of bradykinin-potentiating peptides-C-type natriuretic peptide precursor, and characterization of the novel peptide Leu3-blomhotin from the venom of Agkistrodon blomhoffi.

A cDNA clone, 1.8 kb long, was isolated from a venom gland cDNA library of Agkistrodon blomhoffi that encodes a large plurifunctional precursor composed of 263 amino-acid residues. Nucleotide sequence analysis of this clone revealed that sequences which code for blomhotin and a novel peptide Leu3-blomhotin are located in the N-terminal region of the precursor polypeptide, followed by four tandemly aligned sequences which code for three types of bradykinin-potentiating peptide. In the C-terminal region, the sequence for the C-type natriuretic peptide was located along with a preceding processing signal. The deduced amino-acid sequences for the four bradykinin-potentiating peptides coincided exactly with previously known sequences for potentiator B, potentiator C and potentiator E. The actual Leu3-blomhotin peptide was subsequently isolated from the venom of A. blomhoffi and characterized. Leu3-blomhotin possesses contractile activity in isolated rat stomach fundus smooth muscle in the same manner as blomhotin. Furthermore, it was shown that blomhotin and Leu3-blomhotin retained activity to inhibit the angiotensin-converting enzyme.

Amino acid sequence studies on cytolytic toxins from sea anemone Heteractis magnifica, Entacmaea quadricolor and Stichodactyla mertensii (Anthozoa).

The complete amino acid sequence of a cytolytic toxin, HmT, isolated from sea anemone Heteractis magnifica was determined. It is composed of 177 amino acid residues and lacks half-cystines. Partial N-terminal sequences of three other cytolysins from Entacmaea quadricolor (EnT) and Stichodactyla mertensii (SmT-1 and SmT-2) were also determined. Comparing these sequences with those of other sea anemone cytolysins, a high degree of homology was observed.

Transient thyrotoxicosis and hypothyroidism following administration of the GnRH agonist leuprolide acetate.

A 45-year-old women with chronic idiopathic thrombocytopenic purpura was given monthly injections of the GnRH agonist leuprolide acetate for the treatment of uterine leiomyoma. Two weeks after the fifth injection, she showed mild symptoms of thyrotoxicosis. At that time, serum thyroxin (T4) and triiodothyronine (T3) levels were elevated whereas TSH level was suppressed. Anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies were positive, whereas TSH binding inhibitory immunoglobulin (TBII) was undetectable. Two months later, serum T4 and T3 levels spontaneously decreased below the normal ranges. Five months after the onset of the disease, they returned to normal without any treatment. Anti-TPO and anti-Tg antibodies gradually decreased during the clinical course. Thus, the present case was indicated to be an instance wherein silent thyroiditis developed after leuprolide acetate administration. This is the first report to demonstrate the association of thyroid disorder with leuprolide injection.

Satisfaction of patients treated surgically for intractable aspiration.

STUDY OBJECTIVE: Impaired laryngeal protective function can result in intractable aspiration requiring surgical treatment. There are, however, few reports evaluating the satisfaction of patients and the efficacy of surgical therapy. The purpose of this study is to determine whether surgery for intractable aspiration is beneficial for alleviating depression and improving the mood of patients who have undergone surgical treatment and whether patients and their families are satisfied with the therapy. PATIENTS AND STUDY DESIGN: Seven patients with recurrent aspiration pneumonia that could not be controlled by appropriate medical therapies participated in the study. These patients had no hope of recovering laryngeal function. Six underwent laryngectomy and one underwent laryngotracheal separation. After surgery, we evaluated the efficacy of the therapy and the patients' satisfaction with the therapy. METHODS: The following clinical variables concerning surgical procedure were examined: operation time, time until oral intake, videofluorographic study, and surgical complications. The treatment methods including feeding status were also examined before and after surgery. In addition, the following markers were examined to evaluate the efficacy of the surgery: score of aspiration pneumonia, body mass index, total protein, albumin, hematocrit, WBC count, C-reactive protein, erythrocyte sedimentation rate, and the Barthel Index, an indicator of daily activity. Furthermore, the grade of depression and mood, and satisfaction of patients and their caretakers among family members were scored by the Zung self-rating depression scale, a 20-picture face scale, and the visual analog scale. RESULTS: After surgical therapy, we confirmed by videofluorography that aspiration was completely prevented. No surgical complications occurred. By 18 +/- 6 days, all seven patients were able to ingest a meal orally. The need for extensive medical care and repeated hospitalizations became unnecessary after surgery. The control of pneumonia and albumin improved significantly. The grade of depression and mood of patients and their families also improved significantly. Satisfaction scores of patients receiving therapy were very high. CONCLUSIONS: Our study shows that surgical therapy to prevent aspiration improves the depression and mood of patients and their families as well as feeding status and clinical outlook. Surgical therapy for patients with intractable aspiration is effective and beneficial.

Inhibition of lysoPAF acetyltransferase activity by components of licorice root.

Licorice root traditionally used as an anti-inflammatory drug exhibited an inhibitory effect on lysoPAF (platelet-activating factor) acetyltransferase in vitro: the ether soluble fraction of the crude drug produced a 27.3% inhibition at a concentration 10 microg/ml. From this fraction, licoricidin (1), 1-methoxyphaseollin (2), 6,8-diprenylgenistein (3) and 1-methoxyphaseollidin (4) were isolated as active components, whose IC50 values were 7.7, 57, 19 and 48 microM, respectively. Licoricidin (1) seems to be one of the most potent compounds of plant origin isolated so far.

Blomhotin: a novel peptide with smooth muscle contractile activity identified in the venom of Agkistrodon halys blomhoffii.

A novel peptide has been isolated from the venom of Agkistrodon halys blomhoffii using a bioassay that monitors the stimulant effect on rat stomach fundus. The 11-amino acid peptide, named blomhotin, was purified to homogeneity by gel-filtration column chromatography and reverse-phase HPLC. The amino acid sequence of blomhotin was determined to be pGlu-Gly-Arg-Pro-Pro-Gly-Pro-Pro-Ile-Pro-Arg, which is similar to that of bradykinin-potentiating peptides which themselves cause no contraction of smooth muscle. The contraction induced by blomhotin showed homologous desensitization, implicating the involvement of a blomhotin-specific site in the response.

Effects of PAF on histamine H1 receptor mRNA expression in rat trigeminal ganglia.

The application of platelet-activating factor (PAF) to the nasal mucosa of humans has been shown to increase histamine-induced hyper-reactivity. To test the hypothesis that PAF acts by increasing the reactivity of sensory nerve endings in the nasal mucosa to histamine, we examined PAF-stimulated rat trigeminal nerve ganglion cells. We found that relatively low concentrations of PAF (10(-12)-10(-9) M) induced increased histamine H1 receptor mRNA expression. This increase appeared as early as 1 h after PAF stimulation, peaked at 4 h, and disappeared after 24 h. The PAF receptor antagonist WEB2086 inhibited the increased expression of histamine H1 receptor mRNA induced by PAF, suggesting that the effects of PAF are mediated by specific receptors. This PAF effect was abolished by actinomycin D, suggesting that PAF induces de novo transcription of histamine H1 and/or PAF receptor mRNA. PAF may be important in the hyper-responsiveness of nasal mucosa exposed to histamine.

Dynamics of immunoglobulins at the feto-maternal interface.

Transplacental transport of maternal immunoglobulin G (IgG) to the developing fetus is extremely important in the protection of the newborn from infection. Although the exact mechanisms of the selective and active transfer of IgG across the placental barrier are not fully understood, receptors for the Fc part of IgG (FcgammaRs) in the placenta are believed to play a key role. Several known Fc receptors, FcgammaRI, FcgammaRII, FcgammaRIII and FcRn (neonatal FcR), demonstrate heterogeneous expression patterns in placenta. Immunohistochemical analysis shows the expression of FcgammaRI on Hofbauer cells in stromal tissue, FcbetaRII on Hofbauer cells and fetal blood endothelium, FcgammaRIII on Hofbauer cells and trophoblasts, and FcRn on syncytiotrophoblasts and endothelial cells. Recent studies provide evidence for important associations among these receptors and transcytosis of IgG, as well as scavenger mechanisms for clearing immune complexes in the placenta during pregnancy.

Suicide gene therapy for human uterine adenocarcinoma cells using herpes simplex virus thymidine kinase.

In gene therapy, the herpes simplex virus thymidine kinase (HSV-tk) gene is widely used as a suicide agent. Tumor cells expressing HSV-tk are sensitive to nucleoside analogs such as ganciclovir (GCV). An advantage of this system is the bystander killing effect whereby HSV-tk-positive cells exposed to GCV are lethal to surrounding HSV-tk-negative cells. We transfected the HSV-tk gene into a human cervical adenocarcinoma cell line, BU25TK-, and a human endometrial adenocarcinoma cell line, HHUA, by the Lipofectine method. The sensitivity of HSV-tk-positive cells to GCV and bystander killing effect on HSV-tk-negative cells were examined in vitro. HSV-tk-positive cells were sensitive to GCV at concentrations of 1 to 100 microg/ml in a dose- and time-dependent manner. The growth of HSV-tk-negative cells was inhibited when the population of cultured cells contained more than about 3% HSV-tk-positive cells. Moreover, for BU25TK- cells, HSV-tk-positive cells were injected into SCID mice subcutaneously and the effects of GCV therapy and bystander killing at a daily concentration of 25 mg/kg for 14 days were examined. HSV-tk-positive tumors transduced into SCID mice almost disappeared upon GCV treatment. Furthermore, tumor reduction was observed when mixtures of HSV-tk-negative cells containing more than 20% HSV-tk-positive cells were injected into SCID mice. In conclusion, the HSV-tk/GCV system might be applied to both cervical and endometrial adenocarcinoma.

cAMP stimulates the bystander effect in suicide gene therapy of human choriocarcinoma.

In gene therapy, tumor cells expressing herpes simplex virus thymidine kinase (HSV-tk) are sensitive to ganciclovir (GCV) and HSV-tk positive cells exposed to GCV are lethal to adjacent HSV-tk negative cells. This phenomenon has been called the bystander effect, and the gap junction is thought to mediate it. In this study, sensitivity to GCV and bystander effect in a human choriocarcinoma cell line, BeWo, transfected with HSV-tk were investigated. Furthermore, the effect of 8-bromo-cAMP on bystander effect and connexin40 gene transcription were examined. HSV-tk positive cells were sensitive to GCV at the concentration of 10 micrograms/ml in a time-dependent manner. The growth of HSV-tk negative cells was inhibited when the population of cultured cells contained more than 10% HSV-tk positive cells and 8-bromo-cAMP enhanced bystander effect. 8-bromo- cAMP increased connexin40 mRNA expression and gap junctional intercellular communication.

Modulation of normal human eosinophil chemotaxis in vitro by herbimycin A, erbstatin and pervanadate.

BACKGROUND: The mediators involved in eosinophil accumulation in diseases such as allergy continue to be an area of interest, even though little is known regarding the signaling involved in the human cell type recruitment. In the present study, we demonstrate a novel modulatory role of tyrosine kinase and tyrosine phosphatase activities on normal human eosinophil chemotaxis induced by different groups of chemoattractant. METHODS: Purified eosinophils were obtained from normal healthy volunteers with the CD16-negative procedure. Chemotactic activities against platelet-activating factor (PAF), vasoactive intestinal peptide (VIP) and eotaxin were assessed using a 48-well microchemotaxis chamber assay. Purified eosinophils were pretreated with herbimycin A, erbastatin or pervanadate to examine the role of tyrosine kinase in chemoattractant signaling. RESULTS: Pretreatment of eosinophils with the tyrosine kinase inhibitors herbimycin A and erbstatin significantly blocked chemotaxis induced by eotaxin whilst both inhibitors augmented chemotaxis induced by VIP; however, they had no effect on PAF-induced chemotaxis. On the other hand, pretreatment of eosinophils with the phosphotyrosine phosphatase inhibitor pervanadate resulted in augmentation of eotaxin-induced chemotaxis and inhibition of VIP-induced chemotaxis, but it had no effect on PAF-induced chemotaxis. CONCLUSIONS: These results suggest that protein kinase plays a modulatory role in eosinophil chemotaxis induced by various chemoattractants.

Human eotaxin induces eosinophil-derived neurotoxin release from normal human eosinophils.

BACKGROUND: Eosinophil granule proteins deposition at the site of allergic inflammation contributes to the late-phase reaction of hypersensitivity diseases. In the present communication, we describe the effect of human eotaxin on normal human eosinophil exocytosis measured as degranulation of eosinophil-derived neurotoxin (EDN). METHODS: Purified eosinophils were obtained from normal healthy volunteers with the CD16-negative procedure. Purified eosinophils were stimulated with various concentrations of eotaxin and the amount of EDN released was analysed by radioimmunoassay. Flow cytometry was used to examine the surface expression of adhesion molecules on eosinophils. RESULTS: Eotaxin significantly induced EDN release in a dose-dependent manner. The potency of eotaxin in this effect was equal to that of RANTES, and comparable to that of platelet-activating factor. Eotaxin-induced EDN release was blocked by cytochalasin B in a dose-dependent manner. The surface expression of CD11a, CD11b, CD18 and VLA-4 adhesion molecules on normal human eosinophils were not modulated by eotaxin stimulation. CONCLUSIONS: These results indicate that eotaxin may play an important role not only as a selective chemotaxin for the cell type but also as a secretagogue. Furthermore, they demonstrate a degranulation mechanism(s) involving cytoskeletal changes which is probably independent of the quantitative expression of adhesion molecules.

PAF- and histamine-receptor antagonists lessen allergen-induced hearing impairment in guinea pigs.

We have demonstrated degranulation of mast cells in the endolymphatic sac as well as an increase in audiological threshold shift in the experimental animal models following antigen provocation. Mast cells, however, release such chemical mediators as histamine, platelet activating factor (PAF), and leukotriene due to an antigen-antibody reaction on the cell surface. The aim of this study was to clarify the major chemical mediators responsible for hearing impairment in the animal models following antigen provocation. Guinea pigs were actively sensitized with DNP-Ascaris and provoked with an injection of DNP-BSA. A significant audiological threshold shift was observed at 1, 10, 24, and 72 h following challenge with allergen. The peak shift was at 10 h; all changes were reversed after 7 days. This threshold shift was abolished by prior injection of either a histamine- or PAF-receptor antagonist to allergen, but not of a leukotriene-receptor antagonist. Results suggest that histamine and PAF are involved in the hearing impairment induced by allergen exposure in the guinea pig.

Activated mast cells release extracellular type platelet-activating factor acetylhydrolase that contributes to autocrine inactivation of platelet-activating factor.

IgE-dependent and -independent activation of mouse bone marrow-derived mast cells (BMMC) elicited rapid and transient production of platelet-activating factor (PAF), which reached a maximal level by 2-5 min and was then degraded rapidly, returning to base-line levels by 10-20 min. Inactivation of PAF was preceded by the release of PAF acetylhydrolase (PAF-AH) activity, which reached a plateau by 3-5 min and paralleled the release of beta-hexosaminidase, a marker of mast cell exocytosis. Immunochemical and molecular biological studies revealed that the PAF-AH released from activated mast cells was identical to the plasma-type isoform. In support of the autocrine action of exocytosed PAF-AH, adding exogenous recombinant plasma-type PAF-AH markedly reduced PAF accumulation in activated BMMC. Furthermore, culture of BMMC with a combination of c-kit ligand, interleukin-1beta and interleukin-10 for > 24 h led to an increase in plasma-type PAF-AH expression, accompanied by a reduction in stimulus-initiated PAF production. Collectively, these results suggest that plasma-type PAF-AH released from activated mast cells sequesters proinflammatory PAF produced by these cells, thereby revealing an intriguing anti-inflammatory aspect of mast cells.

Preferential infiltration by activated eosinophils in allergic sinusitis.

Although Type I allergy is a trigger for provoking chronic inflammation, whether allergic sinusitis (AS) can be distinguished from sinusitis due to chronic infection is still debated. This study was performed to characterize inflammatory cells in AS and to determine whether patients with AS differ from patients with chronic suppurative sinusitis (CSS). 5 patients with AS and 10 patients with CSS were investigated. Cellular infiltration was studied using immunohistochemistry with monoclonal antibodies using CD3, CD4, CD8, CD25, major basic protein (BMK13), eosinophil cationic protein (EG2), neutrophil elastase, and tryptase. There were no differences in CD3+, CD4+, CD25+, and tryptase+ cells between the groups. Whereas the total number of eosinophils (BMK13+) also did not significantly differ, the number of activated eosinophils (EG2+) was significantly higher (P < 0.05) in patients with AS. Furthermore, a statistically significant increase in the percentage of activated eosinophils to total eosinophils (P < 0.05) was observed in patients with AS. In contrast, the number of neutrophil elastase+ cells was significantly higher (P < 0.05) in patients with CSS. These results suggest that patients with AS can be distinguished immunohistochemically from patients with CSS, with AS being distinguished by activated eosinophil infiltration.