A case of vitiligo that followed the path of a varicose vein in the lower leg.

Vitiligo is an acquired chronic depigmenting disorder of the skin and is characterized by the destruction of melanocytes. One of the clinical features of vitiligo is that damage to normal skin frequently results in the formation of depigmented macules, which is known as Köebner's phenomenon (KP). Here, we presented a case of vitiligo, in which depigmented macules followed the course of a dilated varicose vein. Dilatation of blood vessels was considered to contribute to the development of the vitiliginous lesions as a trigger for KP. Any kind of skin injury can trigger KP, but this is only the second case in which a dilated blood vessel caused KP in vitiligo. J. Med. Invest. 71 : 177-178, February, 2024.

A shigellosis outbreak associated with a sports festival at a kindergarten in Kitakyushu City, Japan.

INTRODUCTION: Shigellosis cases have decreased gradually in Japan in recent years, but indigenous shigellosis outbreaks sometimes occur in childcare facilities. From national surveillance data, we identified a shigellosis outbreak involving a kindergarten. METHODS: After detecting Shigella sonnei in Kitakyushu City, we conducted active case finding and epidemiological investigation in Kindergarten Z, including stool specimen collection and interviews. The stool specimens were cultured, and isolated strains were subjected to pulsed-field gel electrophoresis (PFGE) and multiple-locus variable-number tandem-repeat analysis (MLVA). RESULTS: Between September 1 and December 31, 2014, we identified 19 cases: 14 confirmed, 2 suspected, and 3 asymptomatic. Of the 19 cases, 16 were epidemiologically associated with Kindergarten Z (10 pupils, 5 family members, and 1 teacher). On October 19, a pupil with gastrointestinal illness participated in the kindergarten's sports festival, in which the pupils were split into "red" and "white" teams; the pupil in question belonged to the red team. Attack rates of the red and white teams were 8% (7/82) and 0% (0/108), respectively (relative risk, 10.5; 95% confidence interval, 1.3-82.1). PFGE patterns were identical or similar for the isolates in all 17 cases; 7 isolates were identical, and the others had one locus difference on MLVA. CONCLUSIONS: We concluded that contact during the sports festival could have been responsible for spread of the shigellosis outbreak at the kindergarten, although the infection source was not determined. It is vital to inform guardians immediately after detection of shigellosis cases that symptomatic pupils should not participate in activities such as sports festivals.

Z-505, an Oral Ghrelin Receptor Agonist, Attenuates Anorexia After Total Gastrectomy in Rats.

BACKGROUND: Anorexia is a serious problem in patients with gastric cancer who have undergone gastrectomy. Ghrelin, an orexigenic hormone primarily secreted from the stomach, has been proposed to prevent anorexia. Significant reduction in plasma ghrelin levels after gastrectomy may contribute to lack of appetite and weight loss. In this study, we investigated the effects of Z-505, a ghrelin receptor agonist, on anorexia after total gastrectomy (TG) in a rat model. METHODS AND MATERIALS: Male Sprague-Dawley rats were used to establish a TG model, and then sham-operated (control) and TG rats were randomly assigned to four subgroups receiving administration of Z-505 (100 mg/kg, p.o., once daily) or vehicle for 14 d from day 14 to day 27 after TG. The food intake, body weight, and fat weight were evaluated during the test period. Moreover, the neuronal activity in the hypothalamus was evaluated on day 21 to investigate the mechanism of action of Z-505. RESULTS: In TG rats, Z-505 significantly improved the decrease in cumulative food intake induced by the surgery over 14 d (TG + vehicle; 213.8 ± 15.3 g, n = 12 versus TG + Z-505; 258.2 ± 13.1 g, n = 14, P < 0.05). Z-505 also significantly increased fat weight and had a milder effect on body weight over 14 d. In addition, Z-505 significantly increased the number of c-Fos-positive cells in the hypothalamic arcuate nucleus (TG + vehicle; 17.8 ± 2.0, n = 12 versus TG + Z-505; 72.2 ± 11.8, n = 12, P < 0.001). CONCLUSIONS: Z-505 may be a useful therapeutic treatment for anorexia after TG.

Z-360 Suppresses Tumor Growth in MIA PaCa-2-bearing Mice via Inhibition of Gastrin-induced Anti-Apoptotic Effects.

BACKGROUND/AIM: The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model. MATERIALS AND METHODS: The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity. RESULTS: In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect. CONCLUSION: These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.

Z-100, an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B, prevents spontaneous lymphatic metastasis of B16-BL6 melanoma.

Lymphatic metastasis is common in advanced-stage carcinoma and is associated with a poor prognosis. However, few effective treatments to inhibit it are available. Z-100 is an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B that contains polysaccharides such as arabinomannan and mannan. Here, we investigated the inhibitory effect of Z-100 on spontaneous lymphatic metastasis. C57BL/6N mice injected subcutaneously with B16-BL6 melanoma cells in the right hind footpad were administered Z-100 subcutaneously in the right inguinal region on a daily basis. On day twenty-one after the injection, the right inguinal lymph nodes were excised, and the extent of metastasis, the number of immune cells, and the amount of granzyme B protein in the lymph nodes were examined. We also investigated the combined effect of Z-100 and irradiation in this model. Results showed that Z-100 reduced number of animals with metastasis, with respective metastasis rates of 85.7%, 42.9%, 7.1% and 0.0% in saline, 0.1 mg/kg Z-100, 1 mg/kg Z-100 and 10 mg/kg Z-100 group. Further, mice that had been given Z-100 were found to have more immune cells and granzyme B protein in the lymph nodes than control mice. The combination of low dose Z-100 and irradiation also inhibited spontaneous lymph node metastases. These findings suggest that Z-100 may be beneficial in preventing lymphatic metastasis by enhancing the immune response.

Long-term follow-up of surgical treatment of spinal anaplastic astrocytoma in a cat.

A 10-year-old spayed female chinchilla feline presented with gradually progressive tetraparesis and cervical pain that had begun 1 month before the onset of a 4-day tetraplegic episode. Magnetic resonance imaging revealed a large elliptical intramedullary mass at the fourth cervical vertebrae. The mass was removed surgically and diagnosed as an anaplastic astrocytoma. No neurological abnormalities were observed 3 weeks postsurgery. Magnetic resonance at 3.5 year follow-up revealed neither mass regrowth nor recurrence of signs.

Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats.

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 µg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 µmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia.

Concentration dependence of 5-aminosalicylic acid pharmacological actions in intestinal mucosa after oral administration of a pH-dependent formulation.

Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH ≥ 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients.

Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Z-360, a novel therapeutic agent for pancreatic cancer, prevents up-regulation of ephrin B1 gene expression and phosphorylation of NR2B via suppression of interleukin-1 ß production in a cancer-induced pain model in mice.

BACKGROUND: Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1ß (IL-1ß) production. RESULTS: In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1ß production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1ß production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1ß in the cancer-inoculated region. CONCLUSIONS: We have identified a novel pain cascade, in which IL-1ß production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1ß production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

Pharmacological evaluation of analgesic effects of the cholecystokinin2 receptor antagonist Z-360 in mouse models of formalin- and cancer-induced pain.

Z-360, a novel cholecystokinin(2) (CCK(2)) receptor antagonist, has been developed as a therapeutic drug for pancreatic cancer and showed pain relief action in phase Ib/IIa clinical trial. This study was attempted to elucidate the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-dependent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK(2) receptor antagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK(1) receptor antagonist devazepide inhibited the nociceptive responses to formalin. In a mouse model of cancer pain, significant anti-allodynic effect of Z-360 was observed after single and repeated oral administration of 100 and 300 mg/kg doses. Anti-allodynic effect was also observed after repeated administration of devazepide. Combined single treatment with morphine and Z-360 caused an increase inhibition of pain-related responses in the pain models produced by formalin and cancer. Although Z-360 has lower affinity for CCK(1) receptor than for CCK(2) receptor, Z-360 exhibited an inhibitory effect on sulfated CCK-8-induced gallbladder emptying, a CCK(1) receptor-mediated effect, at a dose of 100 mg/kg. These results suggest that Z-360 inhibits inflammatory and cancer pain probably through the blockade of CCK(1) receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effects as well as the prolongation of survival.

Pancreatic adenocarcinoma versus chronic pancreatitis: differentiation with triple-phase helical CT.

BACKGROUND: Chronic pancreatitis and pancreatic adenocarcinoma often show similar clinical and imaging appearances. This study aims to differentiate chronic pancreatitis from pancreatic adenocarcinoma by defining enhancement patterns in both pathologic conditions during triple-phase helical CT. METHODS: The study included 42 patients with chronic pancreatitis and 85 patients with pancreatic adenocarcinoma. CT images obtained according to protocol A (scan delays, 30, 60, and 150 s; 300 mg I/mL contrast material) or protocol B (scan delays, 40, 70, and 150 s; 370 mg I/mL contrast material) were retrospectively evaluated. RESULTS: Mean contrast enhancement value of normal pancreas peaked in the first phase (early-washout pattern) while that of chronic pancreatitis peaked in the second phase (delayed-washout pattern), and that of pancreatic adenocarcinoma gradually rose (increasing pattern) in both protocols. Diagnostic indices for pancreatic adenocarcinoma were 82.4% and 94.1% for sensitivity, 83% and 83% for specificity, 82.7% and 90.4% for accuracy in protocols A and B, respectively, when differentiation between chronic pancreatitis and pancreatic adenocarcinoma was performed based on time-attenuation curve patterns. CONCLUSION: Our results indicate that time attenuation curves obtained from triple-phase helical CT in protocol B provide useful information in differentiating chronic pancreatitis from pancreatic adenocarcinoma.

Stretching short biopolymers by fields and forces.

We study the mechanical properties of semiflexible polymers when the contour length of the polymer is comparable to its persistence length. We compute the exact average end-to-end distance and shape of the polymer for different boundary conditions, and show that boundary effects can lead to significant deviations from the well-known long-polymer results. We also consider the case of stretching a uniformly charged biopolymer by an electric field, for which we compute the average extension and the average shape, which is shown to be trumpetlike. Our results also apply to long biopolymers when thermal fluctuations have been smoothed out by a large applied field or force.

A hybrid deterministic-stochastic algorithm for modeling cell signaling dynamics in spatially inhomogeneous environments and under the influence of external fields.

Cell signaling dynamics mediate myriad processes in biology. It has become increasingly clear that inter- and intracellular signaling reactions often occur in a spatially inhomogeneous environment and that it is important to account for stochastic fluctuations of certain species involved in signaling reactions. The importance of these effects enhances the difficulty of gleaning mechanistic information from observations of a few experimental reporters and highlights the significance of synergistic experimental and computational studies. When both stochastic fluctuations and spatial inhomogeneity must be included in a model simultaneously, however, the resulting computational demands quickly become overwhelming. In many situations the failure of standard coarse-graining methods (i.e., ignoring spatial variation or stochastic fluctuations) when applied to all components of a complex system does not exclude the possibility of successfully applying such coarse-graining to some components of the system. Following this approach alleviates computational cost but requires "hybrid" algorithms where some variables are treated at a coarse-grained level while others are not. We present an efficient algorithm for simulation of stochastic, spatially inhomogeneous reaction-diffusion kinetics coupled to coarse-grained fields described by (stochastic or deterministic) partial differential equations (PDEs). The PDEs could represent mean-field descriptions of reactive species present in large copy numbers or evolution of hydrodynamic variables that influence signaling (e.g., membrane shape or cytoskeletal motion). We discuss the approximations made to derive our algorithm and test its efficacy by applying it to problems that include many features typical of realistic cell signaling processes.

Elasticity of semiflexible polymers in two dimensions.

We study theoretically the entropic elasticity of a semiflexible polymer, such as DNA, confined to two dimensions. Using the worm-like-chain model we obtain an exact analytical expression for the partition function of the polymer pulled at one end with a constant force. The force-extension relation for the polymer is computed in the long chain limit in terms of Mathieu characteristic functions. We also present applications to the interaction between a semiflexible polymer and a nematic field, and derive the nematic order parameter and average extension of the polymer in a strong field.

Effect of pH on the conformation of gellan chains in aqueous systems.

The optical rotation and fluorescence anisotropy for gellan aqueous systems were measured at pH 4, 7, and 10 to elucidate the effect of pH on the conformation of gellan chains. The optical rotation study suggests that pH affects the conformation of helical gellan chains and their aggregation behavior but the coil-helix transition temperature. By comparing the chain mobility estimated from the fluorescence anisotropy between different pH conditions, it has been revealed that the degree of expansion of random-coiled gellan chains varies with pH. These results indicate that the effect of pH is explained by the change in the anionic nature of gellan chains rather than in the shielding effect of hydrogen ions surrounding gellan chains as a cation species.

[Anaphylaxia induced by etoposide--a case report].

A 32-year-old woman, gravida 4, para 2, visited Teikyo University Hospital with complaints of abnormal uterine bleeding and lower abdominal pain. Urine hCG level was 1,024 x 10(3) IU/l. MRI examination showed a vascular, rich solid mass 10 cm in diameter at the posterior region of the uterus. Under the clinical diagnosis of choriocarcinoma, she underwent total hysterectomy with right salpingooophorectomy. The ovarian choriocarcinoma was confirmed by pathologic examination. Additional chemotherapy was planned using the combined regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide and oncovin. After 2 min of etoposide administration (100 mg/m2), the patient complained of acute dyspnea, which was caused by bronchospasms and cutaneous flushing. Etoposide infusion was immediately stopped, and anti-anaphylaxic treatment was done by administering hydroxyzine hydrochloride. Five min after the episode had occurred, the patient recovered. This episode was thought to have been induced by etoposide, but etoposide was a key agent for choriocarcinoma. Thus, we devised a modified chemotherapy using etoposide as follows. The regimen was hydrocortisone 100 mg i.v. q6 h and promethazine hydrochloride 50 mg i.m. q6 h for 24 h before infusion of etoposide. The etoposide concentration was diluted to 50%, and the drug administration rate reduced by half. With the modified regimen, the patient showed no anaphylaxic symptoms. The few reports on anaphylaxic reactions to chemotherapeutic agents induced by side effects must be taken into account when we use these drugs.

Low T cell receptor expression and thermal fluctuations contribute to formation of dynamic multifocal synapses in thymocytes.

Mature T cell activation and selection of immature T cells (thymocytes) are both initiated by binding of T cell receptor (TCR) molecules on the surface of T cells to MHC peptide (MHCp) molecules on the surface of antigen-presenting cells. Recent experiments have shown that the spatial pattern of receptors and ligands in the intercellular junction (synapse) is different during thymocyte selection compared with mature T cell activation. Using a statistical mechanical model, we show that lower TCR expression in thymocytes contributes to effecting these differences. An analogy with the phase behavior of simple fluids helps clarify how, for low TCR expression, thermal fluctuations lead to the dynamic synapse patterns observed for thymocytes. We suggest that a different synapse pattern resulting from lower TCR expression, which could mediate differential signaling, may be the reason why TCR expression level is low in thymocytes.

Parotid tumors: MR imaging with pathological correlation.

Most parotid tumors grow slowly, whether benign or malignant; thus, it is difficult to predict the malignant or benign nature of a tumor clinically. Magnetic resonance imaging may have a place in the diagnostic work-up of parotid tumors. The purpose of this article is to illustrate the MR imaging findings of parotid tumors and to correlate them to pathologic findings. The MR imaging may be helpful in differentiation of benign and malignant tumors of the parotid gland, and can provide important clues in the diagnosis of their histologies.

Correlation of a dynamic model for immunological synapse formation with effector functions: two pathways to synapse formation.

During antigen recognition by T cells different receptors and ligands form a pattern in the intercellular junction called the immunological synapse, which might be involved in T-cell activation. Recently, a synapse assembly model has been proposed, which enables the calculation of the propensity for synapse assembly driven by membrane-constrained protein binding interactions. We bring together model predictions of mature synapse assembly with data on the dependence of T-cell responses on T-cell receptor (TCR)-MHC-peptide (pMHC) binding kinetics. Predictions of mature synapse assembly, based on TCR-pMHC binding kinetics, correlate well with observed cytokine responses by T cells bearing the relevant TCR but not with cytotoxic T lymphocyte-mediated killing. We discuss the suggested different role for the synapse in pre- and post-nuclear activation events in T cells. The view of immunological synapse assembly given here emphasizes the importance of both the on and off rates for the TCR-pMHC interaction and in this context recent data on a positive role for analogs of self-peptides in synapse assembly is considered.