Is endoscopic submucosal dissection an effective treatment for operable patients with clinical submucosal invasive early gastric cancer?

BACKGROUND AND STUDY AIMS: Gastrectomy with lymph node dissection is the gold standard curative treatment for clinical submucosal invasive early gastric cancer (cSM EGC), but a relatively small number of operable patients with cSM EGC have undergone endoscopic submucosal dissection (ESD) instead because they refused surgery. The aim of this study was to determine the effectiveness of ESD in these operable patients. METHODS: The therapeutic outcomes of ESD were retrospectively assessed for 38 patients with 38 operable cSM EGC lesions who initially refused surgery at the National Cancer Center Hospital, Tokyo, from January 1999 to December 2008. RESULTS: The en bloc resection rate was 84.2% (32 lesions) and the complete (R0) resection rate was 63.2% (24 lesions). A total of 33 lesions (86.8%) involved submucosal invasion on pathology. Resection was non-curative in 34 patients (89.5%), 22 of whom (64.7%) underwent subsequent gastrectomy after the need for such surgery was carefully explained to them again. The median follow-up period was 73.2 months (range 3-115 months). Local recurrence was detected in one patient, distant metastasis in two patients, and both local recurrence and distant metastasis were detected in one patient. None of these four patients with recurrence (10.5%) had undergone surgery when their recurrent disease was detected and all of them died from gastric cancer. The 5-year cause-specific survival rate for all patients was 91.8%. CONCLUSION: The 5-year cause-specific survival rate for all patients was lower than the previously reported rate of 96.7% for pathologically submucosal invasive EGC patients after gastrectomy; therefore, ESD appears to have been an ineffective treatment for operable patients with cSM EGC.

Feasibility of endoscopic mucosal resection for superficial pharyngeal cancer: a minimally invasive treatment.

BACKGROUND AND STUDY AIMS: New diagnostic techniques have recently been developed so detection of superficial pharyngeal cancer is dramatically increasing and endoscopic mucosal resection (EMR) can now be performed on an experimental basis. The aim of this study was to clarify the effectiveness of EMR for superficial pharyngeal cancer. PATIENTS AND METHODS: Between 2004 and 2007, 31 patients with 37 pharyngeal lesions underwent EMR at our hospital. EMR using a cap-fitted endoscope (EMR-C) was used on 34 lesions and strip biopsies on the remaining three. We retrospectively assessed the effectiveness of those procedures in treating superficial pharyngeal cancer. RESULTS: Median procedure time was 45 minutes (range 20 - 180 minutes) and median hospital stay was 7 days (range 4 - 12 days). Regarding complications, one patient experienced laryngeal edema, one suffered aspiration pneumonia, and two sustained dermatitis around the mouth caused by Lugol staining. Histologically, 18 lesions were confirmed as carcinoma in situ and the other 19 lesions demonstrated microinvasion of the subepithelial tissue with lymphatic invasion in one case. During the median follow-up period of 40 months (range 21 - 62 months), two patients received radiotherapy and two patients underwent an additional EMR because of recurrent tumors. Five other patients developed metachronous superficial pharyngeal cancers, but all those lesions were resected primarily by EMR while two of the study's 31 patients died from esophageal cancer. None of the remaining 20 patients experienced any recurrent or metachronous tumors during their follow-up periods. CONCLUSIONS: Our results indicated that EMR was a safe, effective, and minimally invasive treatment for superficial pharyngeal cancer.

Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis.

KIF3A is a classical member of the kinesin superfamily proteins (KIFs), ubiquitously expressed although predominantly in neural tissues, and which forms a heterotrimeric KIF3 complex with KIF3B or KIF3C and an associated protein, KAP3. To elucidate the function of the kif3A gene in vivo, we made kif3A knockout mice. kif3A-/- embryos displayed severe developmental abnormalities characterized by neural tube degeneration and mesodermal and caudal dysgenesis and died during the midgestational period at approximately 10.5 dpc (days post coitum), possibly resulting from cardiovascular insufficiency. Whole mount in situ hybridization of Pax6 revealed a normal pattern while staining by sonic hedgehog (shh) and Brachyury (T) exhibited abnormal patterns in the anterior-posterior (A-P) direction at both mesencephalic and thoracic levels. These results suggest that KIF3A might be involved in mesodermal patterning and in turn neurogenesis.

Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein.

Cytoplasmic dynein, a minus end-directed, microtubule-based motor protein, is thought to drive the movement of membranous organelles and chromosomes. It is a massive complex that consists of multiple polypeptides. Among these polypeptides, the cytoplasmic dynein heavy chain (cDHC) constitutes the major part of this complex. To elucidate the function of cytoplasmic dynein, we have produced mice lacking cDHC by gene targeting. cDHC-/- embryos were indistinguishable from cDHC+/-or cDHC+/+ littermates at the blastocyst stage. However, no cDHC-/- embryos were found at 8.5 d postcoitum. When cDHC-/- blastocysts were cultured in vitro, they showed interesting phenotypes. First, the Golgi complex became highly vesiculated and distributed throughout the cytoplasm. Second, endosomes and lysosomes were not concentrated near the nucleus but were distributed evenly throughout the cytoplasm. Interestingly, the Golgi "fragments" and lysosomes were still found to be attached to microtubules. These results show that cDHC is essential for the formation and positioning of the Golgi complex. Moreover, cDHC is required for cell proliferation and proper distribution of endosomes and lysosomes. However, molecules other than cDHC might mediate attachment of the Golgi complex and endosomes/lysosomes to microtubules.

Endoscopic diagnosis of pharyngeal carcinoma by NBI.

Head and neck cancer, especially pharyngeal cancer, frequently co-exist with esophageal cancer, but pharyngeal cancer has proven difficult to detect in such cases before its progression to an advanced stage. Several recent reports have indicated that narrow-band imaging (NBI) endoscopy with magnification is able to improve the detection of superficial pharyngeal cancer. NBI is a relatively new optical technology based on limiting the depth of light penetration into the mucosa. The recognition of these lesions is dramatically improved and the microvascular structure of the mucosal surface is significantly enhanced by NBI. As a result, NBI enables more accurate diagnosis and increases the detection rate of superficial pharyngeal cancer. This particular field has only been developed in recent years, however, and there are still a number of problems that need to be addressed in the future. It will be necessary to accumulate and evaluate resected specimens and follow up patients in order to establish the appropriate criteria for curative endoscopic treatment in these patients. The ease in using NBI in combination with this new diagnostic concept based on microvascular changes makes NBI suitable for worldwide use in the future.

Salsolinol is present in the bovine posterior pituitary gland and stimulates the release of prolactin both in vivo and in vitro in ruminants.

The aims of the present study were to determine whether salsolinol (SAL), a dopamine-related compound, is present in the bovine posterior pituitary (PP) gland, and to clarify the effect of SAL on the secretion of prolactin (PRL) in ruminants. SAL was detected in extract of bovine PP gland using high-pressure liquid chromatography with electrochemical detection (HPLC-EC). A single intravenous (i.v.) injection of SAL (5 and 10mg/kg body weight) significantly and dose-dependently stimulated the release of PRL in goats (P<0.05). Plasma PRL levels reached a peak 10min after the injection, then gradually returned to basal values in 60-80min. The PRL-releasing pattern was similar to that in response to sulpiride (a dopamine receptor antagonist). The intracerebroventricular (i.c.v.) injection of 1mg of SAL had no significant effect on the release of PRL in calves, however, 5mg significantly stimulated the release (P<0.05) with peak values reached 30-40min after the injection. Moreover, SAL significantly stimulated the release of PRL from cultured bovine anterior pituitary cells at doses of 10(-6) and 10(-5)M, compared to control cells (P<0.05). Taken together, our data clearly show that SAL is present in extract of the PP gland of ruminants, and has PRL-releasing activity both in vivo and in vitro. Therefore, this endogenous compound is a strong candidate for the factor having PRL-releasing activity that has been previously detected in extract of the bovine PP gland.

Three-dimensional assessment of the normal Japanese glenoid and comparison with the normal French glenoid.

INTRODUCTION: In 2014, reverse total shoulder arthroplasty was approved in Japan. We were concerned that the base plate might be incompatible with Japanese who were generally smaller than Westerners. Therefore, we investigated the dimensions and morphology of the normal Japanese glenoid and compared with the normal French glenoid. MATERIALS AND METHODS: One hundred Japanese shoulders without glenoid lesions (50 men and 50 women) were investigated and compared with 100 French shoulders (50 men and 50 women). Computed tomography was performed with 3-dimensional image reconstruction and images were analyzed using Glenosys software. Glenoid parameters (width, height, retroversion and inclination) were compared between Japanese and French subjects. RESULTS: In Japanese subjects, the mean glenoid width was 25.5mm, height was 33.3mm, retroversion was 2.3° and inclination was 11.6° superiorly. In French subjects, the mean glenoid width was 26.7mm, height was 35.4mm, retroversion was 6.0° and inclination was 10.4° superiorly. Glenoid width and height were significantly smaller in Japanese subjects than French subjects (P=0.001 and P<0.001), while retroversion was significantly greater in French subjects (P<0.001). There was no significant difference of inclination. CONCLUSIONS: These findings will help surgeons to identify suitable patients for RSA and perform the procedure with appropriate preoperative planning. LEVEL OF EVIDENCE: IV: retrospective or historical series.

The influence of UVA and visible radiation on acute damage by short-wave UVR (lambda less than 320 nm).

The influence of UVA and visible radiation on the acute damage by short-wave ultraviolet radiation (UVR) (lambda less than 320 nm) was investigated in human volunteers, using delayed erythema and sunburn cell production as markers of injury. It was found that subsequent exposure to UVA + visible radiation produced a significant reduction of the threshold erythema dose by short-wave UVR, in a dose-dependent manner. Subsequent exposures to varying doses of UVA + visible radiation, as well as to visible light alone failed to influence sunburn cell production. It is concluded that there is a positive interaction between short-wave UVR and UVA in the induction of delayed erythema, but this may not apply to epidermal cell injury. Photorecovery was not observed.

The extracellular domain of BPAG2 has a loop structure in the carboxy terminal flexible tail in vivo.

The 180 kDa bullous pemphigoid antigen is a hemidesmosome-associated transmembranous protein with a molecule length estimated to be 190-230 nm, which is much longer than the transverse length of the lamina lucida and lamina densa. The purpose of this study was to clarify the precise in vivo structure of the 180 kDa bullous pemphigoid antigen in normal human skin. We used three monoclonal antibodies directed to (i) the intracellular globular head of the 180 kDa bullous pemphigoid antigen, (ii) the mid-portion of the flexible tail of the antigen, corresponding approximately to amino acids 1000-1320, and (iii) the carboxyl terminal end, corresponding approximately to amino acids 1320-1500 of the antigen. Using low temperature postembedding immunoelectron microscopy, we quantitated the distribution of immunogold labeling of these monoclonal antibodies in normal human skin. The results showed that the monoclonal antibodies (i) bound to the intracellular portion of the hemidesmosome at a mean distance of 20 nm from the plasma membrane, (ii) bound to the lamina densa beneath the hemidesmosome at a mean distance of 65 nm from the plasma membrane, and (iii) bound to the lamina densa-lamina lucida interface at a mean distance of 39 nm from the plasma membrane. Considering the reported size of the 180 kDa bullous pemphigoid antigen, our results indicate that the extracellular domain of the antigen has at least one loop structure in the lamina densa in vivo. This unique structure of the antigen is thought to contribute to dermo- epidermal adhesion by intertwining with other basement membrane components.

Rapid identification of Leishmania species from formalin-fixed biopsy samples by polymorphism-specific polymerase chain reaction.

The precise identification and classification of Leishmania species is important for public health surveillance since different species cause different clinical features of the disease. A highly specific polymerase chain reaction (PCR) panel was developed to enable the identification of the five major Leishmania species that cause New World cutaneous leishmaniases. The primers used for this panel were designed to distinguish the polymorphism in sequences of commonly amplified DNA bands of the parasites produced by arbitrarily primed PCR. These polymorphism-specific PCR diagnoses were performed with formalin-fixed biopsy specimens of the leishmanial lesions from four patients in Ecuador and one hamster skin lesion, and these lesions were determined to be caused by Leishmania (Viannia) panamensis, L. (Leishmania) mexicana, and L. (L.) amazonensis. The PCR panel may offer an important and practical approach to the standardized identification of Leishmania species in field examinations.

Presence of neuronal nitric oxide synthase in autonomic and sensory ganglion neurons innervating the lacrimal glands of the cat: an immunofluorescent and retrograde tracer double-labeling study.

It is generally considered that parasympathetic postganglionic nerve fibers innervating the lacrimal gland (LG) arise from the pterygopalatine ganglion (PPG), while sympathetic and sensory innervations arise from the superior cervical ganglion (SCG) and trigeminal ganglion (TG), respectively. Recently, we reported for the first time that the parasympathetic innervation of the cat LG was also provided by the otic ganglion (OG) and ciliary ganglion (CG), and that the sensory innervation was also provided by the superior vagal ganglion (SVG) and superior glossopharyngeal ganglion (SGG). To determine if nitric oxide (NO) is a neurotransmitter of the autonomic and sensory neurons innervating the LG, we injected the cholera toxin B subunit (CTB) as a retrograde tracer into the cat LG, and used double-labeling fluorescent immunohistochemistry for CTB and nitric oxide synthase (NOS). We found that NOS-/CTB-immunofluorescent double-labeled perikarya were localized in the PPG, OG, TG, SVG and SGG, but not in the CG and SCG. The highest numbers of NOS-/CTB-immunofluorescent double-labeled neurons were found in the PPG and TG. In addition, we examined the presence of nitrergic nerve fibers in the LG using NADPH-d histochemistry and found that a large amount of NADPH-d-stained nerve fibers were distributed around the glandular acini and in the walls of glandular ducts and blood vessels. This study provides the first direct evidence showing that NO may act as a neurotransmitter or modulator involved in the parasympathetic and sensory regulation of lacrimal secretion and blood circulation, but may not be implicated in the sympathetic control of LG activities, and that nitrergic nerve fibers in the LG arise mainly from parasympathetic postganglionic neurons in the PPG and sensory neurons in the TG. The present results suggest that NO plays an important role in the regulation of LG activities.

Seroepidemiologic studies on rubella in Fukuoka in southern Japan during 1965-1981: rubella epidemic pattern, endemicity and immunity gap.

The epidemiology of rubella in most areas of Asia has not been defined. In Fukuoka city in southern Japan, rubella epidemics occurred in 1956-58, in 1966 and in 1976-77. During the first halves of the 1960s and 1970s, neither epidemic nor endemic clinical rubella occurred. Rubella mass vaccination for girls of 14 years of age started in 1978. Rubella seroepidemiologic studies were performed in 1965, 1974, 1978-79 and 1981 in Fukuoka city. Current studies indicated that children of 6-10 years of age during the epidemics of 1956-58, 1966 and 1976-77 were infected with rubella in 72%, 37% and 57% of cases, respectively. Just before the epidemics of 1966 and 1976-77 100% of the children under nine years of age had no antibodies to rubella indicating absence of recent outbreaks. Whereas 95% of the population (young women of 15-18 years of age in 1981) which participated in the rubella mass vaccination programme since 1978 have rubella Hl antibodies, 46% of the nonparticipating population (19-23 years of age in 1981) remains susceptible to rubella. These facts indicate that rubella epidemics occurred in 1956-58, 1966 and 1976-77, that the magnitude of each epidemic was different, and that there were intervals without endemicity in the inter-epidemic periods. However, after the nation wide rubella epidemic in 1975-77, endemic rubella continued, and rubella epidemics again occurred in 1980-82. The unique rubella epidemic pattern in Japan may be changing in the 1980s to that which existed in most areas of the world where rubella was endemic with periodic increased incidence of epidemicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative analysis of ferrochelatase mRNA in blood cells of erythropoietic protoporphyria patients.

Ferrochelatase (FC; heme synthetase, EC 4.99.1.1.) catalyses the synthesis of heme from protoporphyrin IX, the final step in the heme synthetic pathway. The hereditary deficiency of this enzyme gives rise to erythropoietic protoporphyria (EPP). We developed a rapid, non-radioactive means of measuring human FC mRNA levels in the EPP patients. It is based on the reverse transcriptase-polymerase chain reaction (RT-PCR) performed on the RNA obtained from peripheral blood. The amplified DNA was detected by agarose gel electrophoresis with ethidium bromide staining and the fluorescent intensity was measured by scanning densitometry applied directly to Polaroid 665 negative film. The relative expression level of FC mRNA, compared with that of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA, was estimated at several points in the exponential phase of PCR cycles or at a point in the exponential phase of PCR performed on serially diluted the cDNA samples. The estimate of the FC mRNA by this method correlated well with the level of the FC mRNA measured by Northern blotting in the EB virus-transformed lymphocytes of the same patients. The level of the FC mRNA appeared to vary among the patients in whom a decreased level of enzymatic activity was indicated.

Alteration of mRNA levels of delta-aminolevulinic acid synthase, ferrochelatase and heme oxygenase-1 in griseofulvin induced protoporphyria mice.

Human erythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism and its experimental murine model can be produced by treatment with griseofulvin (GF). We investigated the alteration of mRNA expression in ferrochelatase (FeC), delta-aminolevulinic acid synthase (ALAS) and heme oxygenase-1 (HO-1) in liver, skin and peripheral blood cells of GF-treated mice. In liver, ALAS mRNA was enhanced dramatically by GF administration, in accord with thesis that the expression of ALAS is regulated by feedback mechanism. The expression of HO-1 mRNA increased most rapidly and drastically in liver, however its mechanism of regulation may be different from that of ALAS mRNA. The level of FeC mRNA in liver was less affected with GF treatment. Our results indicate that the inhibition of FeC by GF administration might occur primarily at post-transcriptional level. Similar effects were observed in the ALAS and HO-1 mRNA expression in peripheral blood cells, 2-fold increase in the ALAS mRNA and increase from undetectable level to detectable level in the HO-1 mRNA. In skin of GF-treated mice, average increases of 1.3-fold in the ALAS mRNA and 1.6-fold in the HO-1 mRNA were statistically insignificant. The FeC mRNA level was not altered in peripheral blood or in skin of GF-treated mice. The present study indicates that the molecular analysis is practicable in skin and peripheral blood. In further study, this model could contribute to investigate the pathogenesis of clinical manifestation including possibly cutaneous changes in EPP.

Pre-exposure with low-dose UVA suppresses lesion development and enhances Th1 response in BALB/c mice infected with Leishmania (Leishmania) amazonensis.

This study was conducted to determine whether exposing mice to ultraviolet (UV) radiation would alter the pathogenesis of infection with Leishmania (Leishmania) amazonensis (L. amazonensis) which causes progressive cutaneous disease in susceptible mouse strains. BALB/c mice were irradiated with 10 and 30 J/cm(2) UVA on shaved skin of the back from Dermaray (M-DMR-100) for 4 consecutive days before infection with Leishmania promastigotes. The course of disease was recorded by measuring the size of lesions at various times after infection. Mice groups irradiated with UVA 10 and 30 J/cm(2) showed significantly suppressed lesion development compared with the non-irradiated mice. Light and electron microscopy revealed a few parasites at the site of inoculation in UVA-irradiated subjects. Sandwich enzyme-linked-immunosorbent-assay (ELISA) examination of sera showed dose dependently upregulated interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, and downregulated interleukin (IL)-4 and interleukin (IL)-10 levels in UVA-irradiated as compared with the non-irradiated mice. Positive signals for IFN-gamma mRNA in irradiated mice were obtained by RT-PCR, while non-irradiated mice showed negative results. None of the examined samples showed signal for IL-4 mRNA. The present study disclosed that exposure of mice to different low-doses of UVA irradiation prior to infection may interfere with immunity to L. amazonensis in the murine model. This indicates that the cell-mediated response switch from Th2 to Th1 pattern suppressed the cutaneous lesions of L. amazonensis.

Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats.

We have recently shown that long-term, but not acute, treatment with lithium robustly protects cultured CNS neurons against excitotoxicity mediated by NMDA receptors. Since NMDA receptor over-excitation has been strongly implicated in the ischemic brain injury, we examined the effects of chronic lithium treatment on neurological deficit and brain infarct induced by occlusion of the left middle cerebral artery in rats. Subcutaneous injection of LiCl for 16 days significantly improved neurological deficits, including abnormal posture and hemiplegia, measured 24 h after artery occlusion. Importantly, the size of ischemic infarct was reduced by 56% after lithium pretreatment. These results raise the possibility that lithium may be useful for reducing focal ischemia-induced brain damage and neurological abnormalities.

Plasticity of emesis to a 5-HT3 agonist: effect of order of visceral nerve cuts.

Serotonin type 3 receptors are critical for vomiting induced by radiation and cancer chemotherapy. To investigate the mechanisms involved, we analyzed the effects of abdominal visceral denervation using cats. Thresholds for vomiting induced by the serotonin-3 receptor agonist phenylbiguanide varied depending on the order of chronic nerve transections. Lower thoracic vagotomy, splanchnicectomy, and their sequential combination increased thresholds. However, when splanchnicectomy, which causes a large increase in threshold, was followed 14-51 days later by vagotomy, thresholds dropped by an average of 40%. These results demonstrate plasticity in, and potential for modulation of, the emetic reflex.

Activities of expiratory neurones of the Bötzinger complex during vocalization in decerebrate cats.

Repetitive electrical stimulation of the midbrain peri-aqueductal grey (PAG) terminates quiet breathing and initiates inspiration that precedes vocalization. To understand the neuronal mechanisms underlying this phenomenon, activities of expiratory neurones (n = 39) of the Bötzinger complex (BOT) were examined in decerebrate cats. Most augmenting expiratory (E-aug) neurones (20/22) of the BOT, including 15 bulbospinal neurones, decreased their activities (9/20) or ceased to discharge (11/20) after the onset of stimulation of the PAG. This suggests that suppression of E-aug neurones of the BOT, which project to phrenic motoneurones, results in disinhibition of these neurones, and, in turn, terminates expiration and initiates inspiration preceding vocalization.

Mechanisms of abdominal muscle activation during vomiting.

The possible contribution of spinal reflexes to abdominal muscle activation during vomiting was assessed in decerebrate cats. The activity of these muscles is partly controlled by bulbospinal expiratory neurons in the caudal ventral respiratory group (VRG). In a previous study it was found that the abdominal muscles are still active during vomiting after midsagittal lesion of the axons of these neurons between C1 and the obex (A.D. Miller, L.K. Tan, and I. Suzuki. J. Neurophysiol. 57: 1854-1866, 1987). The present experiments indicate that this postlesion activity was due to spinal stretch reflexes because 1) such midsagittal lesions eliminate abdominal muscle nerve activity during fictive vomiting in paralyzed cats in which there are no abdominal stretch reflexes, 2) the abdominal muscles are activated during vomiting by spinal reflexes after upper thoracic cord transections, and 3) the normal 100-ms delay between diaphragmatic and abdominal activation during vomiting is reduced to approximately 20-25 ms after both types of lesions, which is consistent with postlesion abdominal reflex activation. Our results also suggest that, during normal vomiting, abdominal stretch and tension reflexes have only a minor role if any and abdominal muscle activation is probably mediated primarily or exclusively by expiratory neurons in the caudal ventral respiratory group. However, our finding that phrenic activity is reduced both during vomiting after thoracic transections and during fictive vomiting after paralysis is consistent with a contribution of reflex activity from abdominal and/or intercostal muscles to phrenic discharge during normal vomiting.