Dysregulation of autoimmunity caused by silica exposure and alteration of Fas-mediated apoptosis in T lymphocytes derived from silicosis patients.

Silicosis patients suffer from pulmonary fibrosis caused by silica inhalation, as well as autoimmune diseases known as the adjuvant effects of silica. Caplan syndrome complicated with rheumatoid arthritis (RA) is well known epidemiologically, and the incidence of complicated systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and antineutrophilic cytoplasmic antibody (ANCA)-related nephritis have been reported frequently in silicosis patients. To explore the detailed mechanisms of silica-induced dysregulation of autoimmunity, we had focused on Fas/CD95 and Fas-mediated apoptosis because Fas is one of the most important molecules regarding apoptosis of lymphocytes and its alteration makes some T cells survive longer. Additionally, if the long-survived T cells include the self-recognizing T-cell clones, it is easily thought that autoimmune diseases will appear in this situation. Furthermore, regulatory T cells (Treg) showing CD4+25+ and forkhead box P3 (FoxP3)-positive have been a central player in regulating activation of self- and foreign-antigen recognizing T cells, and it has been reported that activation of Treg causes its higher expression of Fas/CD95. Thus, in this review, we introduce the alteration of Fas and related molecules as found in silicosis and also present the Treg function of the CD4+25+ fraction in peripheral blood mononuclear cells derived from silicosis patients.

Quantitative inter-segmental and inter-laminar comparison of corticospinal projections from the forelimb area of the primary motor cortex of macaque monkeys.

Corticospinal projections from the forelimb area of the primary motor cortex to the C2-Th2 spinal cord segments were quantitatively analyzed using the high resolution anterograde tracer, biotinylated dextran amine (BDA), in rhesus monkeys (n=5). The majority of descending axons were located in the contralateral dorsolateral funiculus (DLF) (85-98%), but a minor portion was observed in the ipsilateral DLF (1-12%) and ventromedial funiculus (VMF) (1-7%). In the gray matter, axon collaterals and terminal buttons were found mainly in the contralateral laminae VI-VII and IX and ipsilateral lamina VIII. The majority of projections to the contralateral gray matter originated from the contralateral DLF, but a minority originated from the ipsilateral DLF. Axons from the ipsilateral DLF were not found to project collaterals on the ipsilateral side, but directly entered the contralateral side after crossing the midline. On the other hand, projections to the ipsilateral lamina VIII were from the ipsilateral VMF, and commissural axons were from the contralateral DLF. Terminal buttons in the motoneuron pool in the contralateral lamina IX were found mainly at the C7-Th1 spinal cord segments, whereas the projections to the contralateral laminae VI-VII, ipsilateral lamina VIII, and commissural axons were also found in more rostral segments, abundantly at the C4-C8 segments, 1-3 segments rostral to the motoneuronal projections. These results suggest that cortical control of contralateral forelimb motoneurons accompanies regulation of interneuronal systems in the contralateral laminae VI-VII and the ipsilateral lamina VIII located a few segments rostral to the motoneurons.

Depressive mood is independently related to stroke and cardiovascular events in a community.

By means of a multivariate Cox model, we investigated the predictive value of a depressive mood on vascular disease risk in middle-aged community-dwelling people. In 224 people (88 men and 136 women; mean age: 56.8 +/- 11.2 years) of U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), a chronoecological health watch was started in April 2001. Consultations were repeated every 3 months. Results at the November 30, 2004 follow-up are presented herein. 7-day/24-h blood pressure (BP) and heart rate (HR) monitoring started on a Thursday, with readings taken at 30-min intervals between 07:00 h and 22:00 h and at 60-min intervals between 22:00 h and 07:00 h. Data stored in the memory of the monitor (TM-2430-15, A and D company, Japan) were retrieved and analyzed on a personal computer with a commercial software for this device. Subjects were asked to answer a self-administered questionnaire inquiring about 15 items of a depression scale, at the start of study and again after 1-2 years. Subjects with a score higher by at least two points at the second versus first screening were classified as having a depressive mood. The other subjects served as the control group. The mean follow-up time was 1064 days, during which four subjects suffered an adverse vascular outcome (myocardial infarction: one man and one woman; stroke: two men). Among the variables used in the Cox proportional hazard models, a depressive mood, assessed by the Geriatric Depression Scale (GDS), as well as the MESOR of diastolic (D) BP (DBP-MESOR) and the circadian amplitude of systolic (S) BP (SBP-Amplitude) showed a statistically significant association with the occurrence of adverse vascular outcomes. The GDS score during the second but not during the first session was statistically significantly associated with the adverse vascular outcome. In univariate analyses, the relative risk (RR) of developing outcomes was predicted by a three-point increase in the GDS scale (RR = 3.088, 95% CI: 1.375-6.935, P = 0.0063). Increases of 5 mmHg in DBP-MESOR and of 3 mmHg in SBP-Amplitude were associated with RRs of 2.143 (95% CI: 1.232-3.727, P = 0.0070) and 0.700 (95% CI: 0.495-0.989, P = 0.0430), respectively. In multivariate analyses, when both the second GDS score and the DBP-MESOR were used as continuous variables in the same model, GDS remained statistically significantly associated with the occurrence of cardiovascular death. After adjustment for DBP-MESOR, a three-point increase in GDS score was associated with a RR of 2.172 (95% CI: 1.123-4.200). Monday endpoints of the 7-day profile showed a statistically significant association with adverse vascular outcomes. A 5 mmHg increase in DBP on Monday was associated with a RR of 1.576 (95% CI: 1.011-2.457, P = 0.0446). The main result of the present study is that in middle-aged community-dwelling people, a depressive mood predicted the occurrence of vascular diseases beyond the prediction provided by age, gender, ABP, lifestyle and environmental conditions, as assessed by means of a multivariate Cox model. A depressive mood, especially enhanced for 1-2 years, was associated with adverse vascular outcomes. Results herein suggest the clinical importance of repetitive assessments of a depressive mood and the need to take sufficient care of depressed subjects. Another result herein is that circadian and circaseptan characteristics of BP variability measured 7-day/24-h predicted the occurrence of vascular disease beyond the prediction provided by age, gender, depressive mood and lifestyle, as assessed by means of a multivariate Cox model. Earlier, we showed that the morning surge in BP on Mondays was statistically significantly higher compared with other weekdays. Although a direct association between the Monday surge in BP and cardiovascular events could not be demonstrated herein, it is possible that the BP surge on Monday mornings may also trigger cardiovascular events. We have shown that depressive people exhibit a more prominent circaseptan variation in SBP, DBP and the double product (DP) compared to non-depressed subjects. In view of the strong relation between depression and adverse cardiac events, studies should be done to ascertain that depression is properly diagnosed and treated. Chronodiagnosis and chronotherapy can reduce an elevated blood pressure and improve the altered variability in BP and HR, thus reducing the incidence of adverse cardiac events. This recommendation stands at the basis of chronomics, focusing on prehabilitation in preference to rehabilitation, as a public service offered in several Japanese towns.

The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours.

It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

Ionic mechanisms underlying burst firing of layer III sensorimotor cortical neurons of the cat: an in vitro slice study.

We examined the ionic mechanisms underlying burst firing in layer III neurons from cat sensorimotor cortex by intracellular recording in a brain slice. Regular spiking was observed in 77.4% of 137 neurons in response to constant intracellular current pulses of 0.5- to 1-s duration. The rest of the neurons showed burst firing. An initial burst followed by regular-spike firing was seen in 71.0% of 31 bursting neurons. The rest of the bursting neurons (n = 9) exhibited repetitive bursting. In the bursting neurons, spikes comprising the burst were triggered from the afterdepolarization (ADP) of the first spike of the burst. We examined the ionic mechanisms underlying the ADP by applying channel-blocking agents. The ADP was enhanced (rather than blocked) by Ca2+ channel blockade. This enhancement of the ADP by Ca2+ channel blockade was apparent even after blockade of the afterhyperpolarization by apamin or intracellular Ca2+ chelation by EGTA. The firing rate of the regular-spiking cells was increased by apamin, intracellular EGTA or Ca2+ channel blockers. In 17.9% of the neurons examined (n = 56), these agents switched the regular-spiking pattern into a bursting one. Burst firing could not be changed to regular spiking by these agents. Four neurons that responded with a single initial burst in control solution responded with repetitive bursting after application of these agents. We conclude that the main function of Ca2+ influx in layer III neurons is to activate Ca2+-dependent K+ conductance, which prevents or limits burst firing. At a time when spike amplitude was unchanged, the ADP was blocked and the burst firing changed to regular spiking by extracellularly applied tetrodotoxin (TTX) or intracellularly applied N-(2,6-dimethylphenylcarbamoylmethyl) triethyl ammonium bromide (QX314). We concluded that a TTX- and QX314-sensitive Na+ current underlies the ADP and therefore contributes to the burst firing of layer III neurons from the cat cortex.

Pollen tube attraction by the synergid cell.

In flowering plants, guidance of the pollen tube to the embryo sac (the haploid female gametophyte) is critical for successful fertilization. The target embryo sac may attract the pollen tube as the final step of guidance in the pistil. We show by laser cell ablation that two synergid cells adjacent to the egg cell attract the pollen tube. A single synergid cell was sufficient to generate an attraction signal, and two cells enhanced it. After fertilization, the embryo sac no longer attracts the pollen tube, despite the persistence of one synergid cell. This cessation of attraction might be involved in blocking polyspermy.

Neurosyphilis showing transient global amnesia-like attacks and magnetic resonance imaging abnormalities mainly in the limbic system.

We report a case of neurosyphilis with transient global amnesia (TGA)-like attacks on the first presentation. MRI abnormalities in bilateral limbic systems, including a few lesions in the basal ganglia and thalamus, were identified. Depression and dementia became apparent, accompanied by a high treponemal antibody titer and mild cortical atrophy. Antisyphilitic therapy brought about mild improvement, and the MRI abnormalities decreased.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (5)--Six-month repeated oral dose toxicity study and supplement study in rats].

Cefmatilen hydrochloride hydrate (S-1090) was orally administered to rats at dose levels of 100, 300 and 1000 mg potency/kg once daily for 6 months. All the S-1090 treated groups showed soft feces, reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet), abdominal distention, increased food and water consumption, lower urine pH, and a decrease of white blood cells counts (except for males of the 100 mg potency/kg group). One male in the 300 mg potency/kg group showed mucous feces and marked decrease in body weight, and diet in the middle stage of the administration period. In necropsy of the survivors of all treated groups, marked cecal enlargement was noted. No remarkable changes were observed in the other examination items. From the early stage of the withdrawal period, animals in the 1000 mg potency/kg group showed again soft or mucous feces and a marked decrease in body weight. Of these animals, one male died and another male was sacrificed in a moribund state at about 2 weeks of the withdrawal period. Enterocolitis was observed in these cases. Almost all animals recovered within 3 weeks of withdrawal. A supplemental study of the 6-month toxicity study was conducted to examine the mechanisms of enterocolitis and the changes observable in the 100 or 300 mg potency/kg groups after drug withdrawal. As a reference, cefdinir (CFDN), an oral cephem antibiotic the same as S-1090, was added in the 1000 mg potency/kg group. No deaths occurred in any groups. Decreased intestinal flora were noted in all the groups treated with S-1090 or CFDN at the end of the dosing period. At 2 weeks of the withdrawal period, C. difficile and its D-1 toxin in the cecal contents were highly detected in the S-1090 300 and 1000 mg potency/kg groups and CFDN group. Inflammatory changes in the cecum and colon were observed in these groups. At 4 weeks of the withdrawal period, intestinal flora in the S-1090 groups almost returned to the condition before dosing, but those in the CFDN group were retained highly. Cecal D-1 toxin in the CFDN group was positive and higher than in the S-1090 groups. It was thus considered that the critical condition with enterocolitis resulted from C. difficile, which proliferated more rapidly than the other bacteria and D-1 toxin produced by this bacteria in the withdrawal period. Above changes were commonly observed in the CFDN group. The NOAEL of S-1090 was assessed to be 100 mg potency/kg/day which induced no enteritis.

Calcium-dependent activation of nuclear factor regulated by interleukin 3/adenovirus E4 promoter-binding protein gene expression by calcineurin/nuclear factor of activated T cells and calcium/calmodulin-dependent protein kinase signaling.

An increase in the intracellular Ca(2+) concentration controls a diverse range of cell functions, including gene expression, apoptosis, adhesion, motility, and proliferation. We have investigated Ca(2+) regulation of gene expression in rat aortic smooth muscle cells. We found that the expression of nuclear factor regulated by interleukin 3 (NFIL3)/adenovirus E4 promoter-binding protein (E4BP4)/basic region/leucine zipper (bZIP) type of a transcription factor that has a very important function in cell survival, was activated by thapsigargin (TG). This activation was inhibited by chelation of extra- or intracellular Ca(2+), suggesting that the induction by TG was dependent on the elevation of [Ca(2+)](i). Specific inhibition of calcineurin or calcium/calmodulin-dependent protein kinase (CaM kinase) by chemical means impaired the TG-induced NFIL3/E4BP4 expression. Expression of dominant negative forms of calcineurin or nuclear factor of activated T cells (NFAT) inhibited the induction of NFIL3/E4BP4 mRNA by TG. These results suggest that intracellular Ca(2+) plays a critical role in regulating gene expression of NFIL3/E4BP4 by calcineurin/NFAT and CaM kinase signaling in vascular smooth muscle cells.

Combined effects of tirapazamine and mild hyperthermia on anti-angiogenic agent (TNP-470) treated tumors-reference to the effect on intratumor quiescent cells.

PURPOSE: To evaluate the efficacy of the use of tirapazamine (TPZ), especially combined with mild hyperthermia (40 degrees C, 60 min), in the treatment of solid tumors following an anti-angiogenic treatment with TNP-470. In addition, we assessed the effect of TPZ and/or mild hyperthermia (MHT) combined with conventional radiotherapy or chemotherapy on TNP-470 treated tumors. MATERIALS AND METHODS: C3H/He mice bearing SCC VII tumors subcutaneously received TNP-470 at two doses of 100 mg/kg after tumor cell inoculation. At the same time, the tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps to label all proliferating (P) cells. The mice then received TPZ administration combined with or without MHT, gamma-ray irradiation combined with or without TPZ and/or MHT, or cisplatin injection with or without TPZ and/or MHT. Another group of mice received a series of test doses of gamma-rays while alive or after being killed to obtain hypoxic fractions (HFs) in the tumors at various time points after the above-mentioned cytotoxic treatment point. After each treatment, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (or quiescent [Q] cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. For the measurement of the HFs, the MN frequency of BrdU-unlabeled cells was then used to calculate the surviving fraction of the unlabeled cells from the regression line for the relationship between the MN frequency and the surviving fraction of total tumor cells. RESULTS: TPZ administration combined with TNP-470 treatment and MHT increased the MN frequency more markedly than treatment with TPZ alone, and this tendency was more remarkable in Q cells than total cells. In both total and Q cells, combined treatment with TPZ and MHT produced significant increases in MN frequencies whether gamma-rays were delivered to TNP-470 treated tumors or cisplatin was injected into the TNP-470 administered mice. Although not significantly, the HFs of total and Q cell populations within solid tumors increased after TNP-470 treatment. CONCLUSION: Combined treatment with TPZ and MHT, whether other cytotoxic treatments such as gamma-ray irradiation or chemotherapy using cisplatin were combined or not, was useful for sensitizing tumor cells in vivo including Q cells even after TNP-470 treatment.

Activity-dependent slow hyperpolarization in cat sensorimotor cortex in vitro.

The synaptic regulatory mechanism of resting membrane potential of layer III and V pyramidal neurons was analyzed intracellularly in the slice preparation of cat sensorimotor cortex. During the tetanic stimulation of white matter, subthreshold membrane depolarization was induced, and after that, a slowly developing hyperpolarization was induced in the normal solution. When the membrane potential showed a slow change, spike duration and input resistance did not change and evoked single synaptic response did not reveal the enhancement of slow IPSPs. However, afterhyperpolarization following action potential was enhanced. The slow hyperpolarization and the enhancement of afterhyperpolarization were not observed in the cells treated with an NMDA receptor antagonist or a calcium channel blocker Ni(2+) (50-100 microM), or the cells hyperpolarized more than -80 mV before the tetanic stimulation.

Concurrent chemoradiotherapy combined with intraoperative radiotherapy for locally advanced pancreatic cancer: a feasibility study.

Initial clinical results of concurrent chemoradiotherapy combined with high-dose intraoperative radiotherapy (IOR) for locally advanced pancreatic cancer were analyzed. Between June 1996 and May 1999, 6 patients with locally advanced pancreatic cancer without distant metastasis were treated with preoperative concurrent chemoradiotherapy followed by IOR. Preoperative radiation therapy was given by the dynamic arc conformal technique with a daily fraction of 1.8 Gy to a total dose of 45 Gy in 5 weeks. Cisplatin (5 mg/day for 4 weeks) and 5-fluorouracil (250 mg/day for 5 weeks) were administered continuously during preoperative radiation therapy. IOR as a single dose of 28 or 30 Gy was given to the gross tumor volume using electron beams of 15- to 22-MeV. Concurrent chemoradiotherapy was well tolerated, although all of the patients complained of nausea and fatigue. Two patients developed grade III leukopenia. No other serious acute toxicity was noted. The median survival time of the 6 patients was 17.5 months, which was significantly longer than that of our historical control treated with external radiation therapy with IOR (8 months), although the difference in survival was borderline significant (p=0.068). Concurrent chemoradiotherapy followed by high-dose IOR was well tolerated in patients with locally advanced pancreatic cancer, and the initial clinical results appeared promising.

Long-term results of lipiodol-transcatheter arterial embolization with cisplatin or doxorubicin for unresectable hepatocellular carcinoma.

The long-term effects of Lipiodol-transcatheter arterial embolization (Lp-TAE) combined with cisplatin (CDDP) or doxorubicin (ADM) on unresectable hepatocellular carcinoma (HCC) were analyzed. Eighty-four consecutive patients with unresectable HCC were treated with TAE. Of the 84, 38 patients were treated with CDDP-Lp-TAE (CDDP group), whereas the remaining 46 patients were treated with ADM-Lp-TAE (ADM group). No significant difference in characteristics of patients and tumors was noted between the groups. CDDP (50 mg) or ADM (20-50 mg) was administered with Lp followed by embolization of the feeding arteries using gelatin sponge particles. The mean number of TAE treatments was 3.3 in the CDDP group and 1.9 in the ADM group (p < 0.01). The 5-year overall survival rates of the CDDP group and the ADM group were 19% and 6%, respectively. The overall survival rate of the CDDP group was significantly higher than that of the ADM group (p < 0.05). No serious side effects were observed in either group. CDDP-Lp-TAE improved the prognosis of unresectable HCC compared with ADM-Lp-TAE, which may be attributable to the fact that CDDP-Lp-TAE treatment could be repeated more times than ADM-Lp-TAE.

Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesis inhibitor.

Intratumoral localization of vascular endothelial growth factor (VEGF) following administration of hyperthermia (HT) and/or anti-angiogenic drugs (TNP-470) was evaluated using SCC VII tumours in C3H/He mice. Hyperthermia at 44.0 degrees C for 30 min was given with a water bath on day 0. TNP-470 (100 mg/kg) was administered alone or after HT on day 0 and day 3. Histological changes on day 4 were evaluated by haematoxylin-eosin (HE) staining and immunohistochemical staining for VEGF. The percentage of the necrotic area relative to the entire tumour area (the % necrotic area) was measured on HE stains. The average % necrotic area of the untreated SCC VII tumours was 7%, while those of tumours treated with TNP-470 alone and HT alone were 27 or 65%, respectively. When HT and TNP-470 were combined, the % necrotic area was 82%, which was significantly higher than that caused by HT alone (p < 0.05). Immunohistochemical staining for VEGF in untreated SCC VII tumours was weak, although strong staining for VEGF was noted in untreated EMT-6 tumours of BALB/c mice, which have spontaneous central necrosis. After administration of HT and/or TNP-470, layer-shaped staining by VEGF was observed in the residual SCC VII tumour cells adjacent to the necrotic area. In conclusion, the expression of VEGF increased in response to administration of HT and/or TNP-470. Hypoxia caused by heat-induced vascular damage may be attributable to increased expression of VEGF in SCC VII tumours.

For the clinical application of thermochemotherapy given at mild temperatures.

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.

Effect of hyperbaric oxygen on ophthalmic artery blood velocity in patients with diabetic neuropathy.

To assess the relationship between blood flow and the complications of diabetes mellitus, we investigated the changes in the velocity of blood flow in the ophthalmic artery before and after hyperbaric oxygen therapy (HBO), one of the treatments for diabetic neuropathy. Color Doppler imaging was used before and after HBO. Seven diabetic neuropathy patients, 3 diabetics without neuropathy, and 7 normal, control subjects were enrolled. The patients were subjected to breathing 100% oxygen at 2.0 atmosphere absolute (ATA) for 1 hour. Hyperbaric oxygen therapy resulted in an average decrease in blood velocity by 15.0 +/- 9.0% (mean +/- SD) in normal subjects and 10.7 +/- 8.6% in diabetics without neuropathy. Blood velocity returned to the baseline level 4 hours after discontinuation of HBO. In contrast, blood velocity increased by 20.6 +/- 9.5% in diabetic patients with neuropathy irregardless of the severity of the diabetic retinopathy. The resistance index of the ophthalmic artery was not changed during HBO in the group with diabetic neuropathy, indicating that other mechanisms may be implicated, leading to the compensatory changes of blood flow. These results suggest that the increase in the blood velocity in the ophthalmic artery after HBO in diabetic neuropathy patients could be attributed to an imbalance in autonomic nervous function.

Increased heating efficiency of hyperthermia using an ultrasound contrast agent: a phantom study.

It is known that there are large temperature elevations in proximity to air bubbles during US (ultrasound) heating. The existence of tiny air bubbles in the target tissue may enhance the temperature elevation in US hyperthermia. To examine this hypothesis, phantom tissue experiments using an US contrast agent consisting of tiny air bubbles surrounded by a 5% (w/v) human albumin shell (Alb) were performed. As a phantom tissue, a 2 cm cube of beef was used. The phantom tissue was heated with or without the US contrast agent by an US hyperthermia device for 3 min. The heating device was operated at 1.5 MHz with the US intensity of 0.9 W/cm2. Physiological saline solution, iodized oil, and ethanol were used for control experiments. The effect of multiple needle punctures to the beef phantom was also examined. The temperature elevation rate (TER) was defined as the ratio of temperature elevation by heating with Alb or control materials to the temperature elevation by US heating alone. The TER of Alb was 1.7, whereas the TERs of the control materials and of the multiple needle punctures were approximately 1. The administration of Alb significantly increased the temperature in US hyperthermia. In addition, the heating efficiency of Alb was compared to the effect of an increase in the US intensity. Phantom tissue was heated at various US intensities. When the US intensity was increased from 0.9 to 1.8 W/cm2, the temperature elevated by approximately 1.7-fold. Thus, the effect of the administration of Alb was almost equivalent to the effect of increase in US power intensities from 0.9 to 1.8 W/cm2 in the present experimental settings. The results suggest that the US contrast agent can be a potential enhancer in US hyperthermia.

Evaluation of new improved solution containing trehalose in free skin flap storage.

BACKGROUND DATA: In this study, we evaluated a new intracellular type (IT-K) solution containing trehalose in a rabbit free skin flap storage model. Trehalose is a nonreducing disaccharide that can stabilise cell membranes under various stressful conditions. MATERIAL AND METHOD: Seventy-two free skin flaps of the ear of rabbits were preserved in Euro-Collins (EC) solution or in IT-K solution for 24, 48, and 72 h at 4 degrees C. After completion of preservation, these flaps were replanted to the other ear by microsurgical techniques. Viability study and photo documentation were performed daily for 7 days. Tissue specimens were taken 24 h after vascular anastomosis, fixed in 10% formaldehyde and stained with haematoxylin and eosin (HE). Survival rates were analysed by Fisher's exact test for comparison of the two experimental groups. Values of P < 0.05 were considered to be statistically significant. RESULTS: After 7 days, a survival rate of 100% of flaps were observed in both solutions after 24 h of preservation. After preservation for 48 h in IT-K solution the survival rate was 100%. However, in EC solution survival decreased to 75% (9 of 12 preserved flaps survived). This difference increased to 33.3% (4 of 12 flaps) in EC solution and 91.6% (11 of 12 flaps) (P < 0.01) in IT-K solution when the flaps were stored for 72 h. Light microscopic examination also showed less damage in flaps preserved in IT-K solution than in these preserved in EC solution. CONCLUSION: IT-K solution was superior to EC solution in the preservation of free skin flaps on rabbit ears when stored for 48 and 72 h.

Clinical applicability of functional magnetic resonance imaging and activation study with single photon emission computerized tomography for functional mapping.

The purpose of this study is to estimate the clinical applicability of functional magnetic resonance imaging (f-MRI) combined with the activation study using single photon emission computerized tomography (SPECT) with special reference to identification of primary sensorimotor area. Five healthy volunteers and 5 patients with brain tumors located around the sensorimotor cortex were studied by both f-MRI with gradient echo and SPECT with 99mTc-ethyl cysteinate dimer using split-dose and subtraction method. In f-MRI study, the significant activation of the sensorimotor area was observed in all subjects. Various concurrent activation regions such as supplementary motor (2 volunteers vs. 4 patients), premotor (1 vs. 2) and ipsilateral sensorimotor area (1 vs. 2) were also observed. In the cases with the activation of neighboring regions of sensorimotor area, it was difficult to identify the area in f-MRI. In SPECT study, the sensorimotor area was depicted as the most increased area in regional cerebral blood flow in eight cases, the characteristics of which were helpful to diagnose the area, while significant activation of the area with edema could not be detected in two patients. Consequently, the sensorimotor area was cross-validated with both the modalities. This study demonstrated that it would be valuable to use both techniques for the clinical assessment of the sensorimotor area.