Relationship Between Cognitive Dysfunction and Systemic Metabolic Disorders in Elderly: Dementia Might be a Systematic Disease.

Vascular cognitive impairment (VCI) plays an important role in dementia in elderly people, and refers to the contribution of vascular pathology to the entire spectrum of cognitive disorders, ranging from mild cognitive impairment to severe dementia, as well as the pathological spectrum, from 'pure' Alzheimer disease through degrees of vascular comorbidity to 'pure' vascular dementia. In the present study, we investigated the relationship between cognitive dysfunction and systemic metabolic disorders, by employing deep learning (DL). We studied 202 patients (73.4 ± 13.0 years), 94.6% of whom were undergoing treatment for lifestyle diseases, and 68.8% of whom had a history of cerebrovascular disorder. We evaluated cognitive dysfunction by performing a Mini Mental State Examination (MMSE). We performed general blood examination, including Complete Blood Count and Basic Metabolic Panel, and measured cerebral blood oxygenation in the prefrontal cortex (PFC) using time-resolved near infrared spectroscopy (TNIRS). We then used deep neural networks to assess the MMSE scores of the subjects based on the TNIRS parameters and the blood examination data, independently. Next, we compared predicted MMSE scores based on the TNIRS and the blood examination. There was a significant positive correlation between the TNIRS parameters and the blood examination data (r = 0.6, p < 0.01). These observations suggest that cognitive dysfunction in patients with VCI may be caused by combinations of systemic metabolic disorders such as energy and oxygen metabolisms and cerebral circulatory disturbance due to arteriosclerosis resulting from lifestyle-related diseases.

Relationship Between Cerebral Blood Oxygenation and Electrical Activity During Mental Stress Tasks: Simultaneous Measurements of NIRS and EEG.

The incidence of stress-induced psychological and somatic diseases has been increasing rapidly, and it is important to clarify the neurophysiological mechanisms of stress response in order to establish effective stress management methods. We previously reported that the prefrontal cortex (PFC) plays an important role in stress response. In the present study, we employed near-infrared spectroscopy (NIRS) and electroencephalography (EEG) to investigate the characteristics of PFC activity during mental arithmetic tasks. A two-channel NIRS device was used to measure hemoglobin (Hb) concentration changes in the bilateral PFC during a mental arithmetic task (2 min) in normal adults. Simultaneously, EEG was used to also measure bilateral PFC activity during the same task. We evaluated concentration changes of oxy-Hb induced by the task while analyzing α wave changes using power spectrum analysis. It was observed that oxy-Hb in the bilateral PFC increased significantly during the task (p < 0.05), while α wave power in the PFC decreased significantly (p < 0.01). The present results indicate that mental stress tasks caused the activation of the bilateral PFC. Simultaneous measurements of NIRS and EEG are useful for evaluating the neurophysiological mechanism of stress responses in the brain.

Development of a Cuff-Less Blood Pressure Monitoring System and Its Application.

We present an unobtrusive cuff-less sphygmomanometer based on contact-type and optical pulse sensors for continuous and minimally invasive monitoring of blood pressure (BP). We developed a cuff-less sphygmomanometer that utilizes the pulse arrival time (PAT) to estimate continuous BP. To assess its accuracy, we recruited 10 healthy subjects in whom we carried out BP studies using the cuff-less sphygmomanometer compared with a standard cuff-type device in a stationary sitting patient. Preliminary results showed that the mean difference (MD) of estimated systolic blood pressure and diastolic blood pressure were 0.96 ± 9.6 (mean ± SD) mmHg and 1.14 ± 7.5 mmHg, respectively, compared to the control. The corresponding correlation between the estimated BP values and controls were 0.78 for systolic blood pressure (p < 0.01) and 0.69 for diastolic blood pressure (p < 0.01); thus, there were significant correlations. These results suggest that the developed cuff-less sphygmomanometer has the potential for continuous BP monitoring. Finally, we conducted a preliminary study of simultaneous monitoring of cuff-less BP and near-infrared spectroscopy to evaluate the potential for assessment of autonomic nervous system functions during mental stress tasks.

Reliability of Wearable Two Channel CW-NIRS in Measurements of Brain Function.

Multi-channel NIRS, so-called optical topography (OT), allows functional mapping of the cortex; however, it takes a long time to set optodes on the head and is relatively expensive. Thus, OT is not suitable as a screening test of brain disorders evaluating many subjects. Recently, a wearable two-channel continuous wave NIRS (CW-NIRS) device has been developed. Such a simple NIRS device may be applicable as a screening test of brain disorders; however, its reliability in measurements of brain function is not yet clear. Here, we tested a two-channel CW-NIRS, which employs single LED (800 nm) for measurement of total hemoglobin (t-Hb) changes. We measured t-Hb changes in the bilateral prefrontal cortex (PFC) during mental arithmetic tasks, employing the CW-NIRS and time-resolve NIRS (TNIRS). The left-right asymmetry of the PFC activity was evaluated by calculating the laterality index (LI; (R-L)/(R + L) of t-Hb), which reflects mental stress. The interval between CW-NIRS and TNIRS measurements was 1-13 days. A significant positive correlation was observed between LI measured by CW-NIRS and TNIRS. These results suggest the reliability of the simple CW-NIRS, and it may be applicable to prevent stress-induced various diseases. Finally, it should be emphasized that the left-right asymmetry of PFC activity is relatively stable.

Differences in Tissue Oxygenation, Perfusion and Optical Properties in Brain Areas Affected by Stroke: A Time-Resolved NIRS Study.

Near infrared spectroscopy (NIRS) has been applied to measurements of cerebral blood oxygenation (CBO) in normal subjects and patients with various brain disorders including cerebrovascular diseases. However, it is not known whether NIRS allow us to measure CBO correctly in patients with abnormal cortices where optical characteristics such as optical pathlength (OP) may differ from those in normal cortex. In the present study, employing a time-resolved NIRS (TNIRS), we compared baseline hemoglobin (Hb) concentrations and OPs between normal and abnormal cortices in chronic stroke patients. We studied five patients with chronic cerebral infarction (two males, three females, age 59.0 ± 24.2 years) who were admitted to the University Hospital of Fukushima Prefectural Medical University. Employing TNIRS (TRS-20, Hamamatsu Photonics), we measured baseline Hb concentrations and OPs (760, 800, 830 nm) at various positions on the head. We observed that deoxy-Hb concentrations were significantly lower on the affected side (p < 0.01), and the tissue oxygen saturation was significantly higher than that on the affected side (p < 0.01), suggesting that oxygen consumption was reduced on the affected side. In addition, the OPs (760, 800 nm) were significantly longer on the affected side (p < 0.05); these changes might be caused by a possible increase of cerebrospinal fluid layer associated with brain tissue degeneration by ischemia. The present results suggest that NIRS should be performed on patients with abnormal cerebral cortices, giving special consideration to the possible difference in optical characteristics between normal and abnormal brain tissues.

Effect of topical application of a stable prostacyclin analogue, SM-10902 on wound healing in diabetic mice.

The mechanism of wound healing induced by topical application of an ointment containing a new stable prostacyclin analogue, SM-10902 ((+)-methyl[2-[(2R,3aS,4R,5R, 6aS)-octahydro-5-hydroxy-4-[(E)-(3S,5S)-3-hydroxy-5-methyl-1- nonenyl]-2-pentalenyl] ethoxy] acetate), was investigated in the full-thickness wounds of genetically diabetic mice (db/db mice). The db/db mice treated with SM-10902 ointment (1, 10 and 100 micrograms/g) showed greater decrease in wound lesion area not covered with epidermis and fewer complete healing days than those treated with ointment base, and the effects of this prostacyclin analogue were greater than those of lysozyme chloride ointment (50 mg/g, Reflap ointment). SM-10902 ointment increased skin blood flow in the central site of the wound with development of wound healing. Histological evaluation of wounds revealed that SM-10902 ointment increased the capillary number during the early stage of the wound-healing process. These results suggest that SM-10902 ointment promotes wound healing through the stimulation of angiogenesis and the improvement of blood flow in neovascularization of repairing wound and may be useful in the treatment of skin ulcers caused by peripheral circulatory insufficiency.

Effects of prostaglandins and cyclic AMP on cytokine production in rat leukocytes.

Prostaglandins E1, prostaglandin E2, 3-oxa-methano-prostaglandin I1 (SM-10906), a stable prostaglandin I2 analog, and dibutyryl cyclic AMP suppressed the production of tumor necrosis factor and interleukin-1 in lipopolysaccharide-stimulated rat pleural resident monocytic cells, whereas they enhanced the production of interleukin-6 and cytokine-induced neutrophil chemoattractant (CINC), a rat interleukin-8-like chemokine, in these cells. SM-10906 also inhibited the in vivo production of tumor necrosis factor and interleukin-1 in pleural exudates, when injected into the rat pleural cavity concomitantly with carrageenin. The cyclic AMP (cAMP) level in the lipopolysaccharide-stimulated resident cells was increased when the cells were incubated in the presence of prostaglandin E1, prostaglandin E2 or SM-10906. Prostaglandin I2 showed only slight effects. The addition of pentoxifylline, a phosphodiesterase inhibitor, to the incubation mixture increased the cAMP level and also enhanced the effect of prostaglandins, indicating that these regulating actions of prostaglandins may be exerted partly through a mechanism involving an increased intracellular cAMP level.

Antiplatelet functions of a stable prostacyclin analog, SM-10906 are exerted by its inhibitory effect on inositol 1,4,5-trisphosphate production and cytosolic Ca++ increase in rat platelets stimulated by thrombin.

The mechanism of the antiplatelet functions of SM-10906, the active form of the 3-oxa-methano-prostaglandin (PG) I1 analog SM-10902, was examined in rat platelets. SM-10906 activated adenylate cyclase in crude membrane fractions, and inhibited platelet aggregation and release of adenine nucleotides stimulated by thrombin. SM-10906 also inhibited malondialdehyde production induced by thrombin, but not that induced by arachidonic acid. This may account for its inhibitory effects on phospholipase A2. SM-10906 prevented thrombin-induced inositol 1,4,5-trisphosphate production, Ca++ mobilization from intracellular Ca storage and 45Ca++ influx into platelets, which were all reversed by pretreatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine. PGI2 and PGE1 have the same antiplatelet profiles in the order of PGI2 > or = SM-10906 > PGE1. These results indicate that SM-10906 as well as PGI2 and PGE1 may exert antiplatelet activities by stimulating adenylate cyclase to prevent thrombin-induced phospholipase C and A2 activations and increase in cytosolic Ca++ level.

Acute acalculous cholecystitis with a decrease in CD4/CD8 ratio.

Acute acalculous cholecystitis (AAC) usually occurs in the elderly and in those with severe pre-existing pathological conditions. However, there have recently been reports of AAC in relatively young immunosuppressed patients, such as those with acquired immunodeficiency syndrome (AIDS). We report here a 27-year-old woman with AAC who received an emergent cholecystectomy. Although anti-human immunodeficiency virus antibody (anti-HIV) was not detected, a decrease in the CD4/CD8 ratio in sera was found. This rare case of AAC in a patient with decreased CD4/CD8 ratio who showed no other related diseases suggests that surgeons should keep in mind the possible presence of immunosuppression in this condition.

Effects of the new histamine H2 receptor antagonist, FRG-8813, on gastric mucin in rats with or without acidified ethanol-induced gastric damage.

It is not presently well understood whether the histamine H2 receptor antagonist has a function other than the inhibition of gastric acid secretion, such as the effect on the gastric mucosal defence mechanism. In this paper, we report the effect of FRG-8813 (N-[4-[4-(piperidinylmethyl)pyridyl-2-oxy]-(Z)-2-butenyl]-2- (furfurylsulfinyl) acetamide), a new histamine H2 receptor antagonist, on the rat gastric mucin content with or without 0.15N HCl-ethanol (60 %)-induced gastric damage. The prior administration of FRG-8813 significantly inhibited the occurrence of macroscopically observable hemorrhagic lesions induced by the acidified ethanol treatment. Using a newly developed biochemical method, the mucin content of the deep corpus and antral mucosa of the acidified ethanol-treated animals was significantly reduced to 50% and 32% of the control, respectively. These reductions were inhibited by the pretreatment with FRG-8813. Total mucin content in the entire stomach recovered to about 80% of the control value after pretreatment with FRG-8813. A single oral administration of FRG-8813 (30 mg/kg) caused no significant change in the total mucin content, but mucin in the adherent mucus gel layer selectively and significantly increased to 250% of the control. These results suggest that FRG-8813 not only inhibits acid secretion but may also affect the gastric mucosal defensive mechanism as well.

Cisplatin sensitivity of ovarian cancer in the histoculture drug response assay correlates to clinical response to combination chemotherapy with cisplatin, doxorubicin and cyclophosphamide.

The histoculture drug sensitivity assay (HDRA) has been demonstrated to have high predictability for resistance, sensitivity, and survival for gastrointestinal cancer (Clin Cancer Res 1: 305-311, 1995; Clin Cancer Res 1: 1537-1543, 1995). In this report, we evaluated the clinical usefulness of the HDRA in ovarian cancer. HDRA was performed on tumors from patients with ovarian cancer. Eighty-five cases (97%) were evaluable. Tumor fragments were cultured on collagen-sponge gels. The cultures were incubated with cisplatin (CDDP) for seven days. Cell viability were assessed with the MTT end point. The optimal cut off concentration of CDDP was determined to be 25 micrograms/ml by correlation with the historical clinical response rate to CDDP. HDRA results were correlated to clinical response of 15 patients who received CDDP-based therapy that included doxorubicin and cyclophosphamide (CAP therapy). The true positive rate was 88%, the true negative rate was 86%, the sensitivity was 88%, the specificity was 86%, and the accurate prediction rate was 87% when HDRA results were compared to the response of the treated patients. The data suggest that the HDRA is capable of predicting the response to antitumor chemotherapy in patients with ovarian cancer and that measuring response to CDDP can be useful for optimization of CAP chemotherapy for patients with this disease.

Effect of a selective PAF antagonist SM-10661 ((+/-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl) on experimental disseminated intravascular coagulation (DIC).

Intravenous infusion of endotoxin (0.25 mg/kg/hr for 4 hr) was shown to induce disseminated intravascular coagulation (DIC) in rats, which resulted in hypofibrinogenemia, prolongation of prothrombin (PT) and partial thromboplastin time (PTT), thrombocytopenia, and elevated levels of fibrinogen/fibrin degradation products (FDP). Oral administration (100 mg/kg) of the selective PAF antagonist, SM-10661 ((+/-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl), counteracted the changes caused by the endotoxin. Intravenous infusion of SM-10661 (6mg/kg bolus 2 min before endotoxin infusion + 6 mg/kg/hr for 4 hr infusion) also counteracted DIC. When suboptimal doses of gabexate mesilate, a synthetic protease inhibitor (3 mg/kg i.p.), and SM-10661 (2 mg/kg bolus + 2 mg/kg/hr for 4 hr infusion) were administered concomitantly, hematological parameters improved. The results suggest that PAF may play a role in the pathogenesis of DIC, and that together with the results already reported for other PAF antagonists, SM-10661 may be useful in the treatment of DIC.

Prediction of tumor radiosensitivity in rectal carcinoma based on p53 and Ku70 expression.

The identification of predictive indicators of radiosensitivity is extremely useful in selecting patients suited for preoperative radiotherapy and avoiding unnecessary preoperative treatment. In this study, we evaluated the possible role of the immunohistochemical expression pattern of p53 and Ku70 protein in determining tumor radiosensitivity in rectal cancer before preoperative irradiation. We examined pretreatment biopsy materials from 111 patients by immunohistochemistry. The expression pattern of p53 and Ku70 was evaluated for association with tumor radiosensitivity, which was defined according to the criteria of the Japanese Research Society for Cancer of the Colon and Rectum. There was a significant correlation between the expression pattern of p53 and tumor radiosensitivity (P = 0.045); Ku70 and tumor radiosensitivity (P < 0.001); and the combination of p53 and Ku70, and tumor radiosensitivity (P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in both p53 and Ku70-positive cases for radioresistance were all superior to those of the group positive for p53 alone. In conclusion the examination of the combination of p53 and Ku70 may predict the radiosensitivity of rectal cancer before preoperative irradiation.

Case report of serous ovarian tumor of borderline malignancy (Stage Ic) in a pregnant woman.

We encountered a case of Stage Ic ovarian serous borderline malignancy in the first trimester of pregnancy. At laparotomy, spontaneous rupture of the capsule and a small amount of serous ascites was observed. Because of the laparotomy during pregnancy, correct staging of the tumor might not be performed. This case presented a major problem in deciding the treatment strategy, which are reported here together with some discussion of the literature on the preservation of fertility in borderline ovarian malignancy.

The histologic analysis of distraction osteogenesis of the mandible in rabbits.

The process of bone formation in mandibular lengthening by distraction was studied in 30 rabbits. The mandible was subjected to a corticotomy, held in a neutral position for 2 weeks, and then lengthened at 0.18 mm per 12 hours for 24 days using a unilateral external fixation device (Orthofix M-100). On completion of the distraction, x-ray analysis showed that the distracted gap was filled with callus organized into three zones, namely, two sclerotic zones with a central radiolucent zone. These zones became indistinguishable from the adjacent preexisting mandible at 10 weeks after distraction. Histologically, new bone, which was formed by both intramembranous and endochondral ossification, underwent remodeling and resulted in cortical bone by 8 to 10 weeks after completion of distraction.

Correction of pectus excavatum and pectus carinatum assisted by the endoscope.

Six patients with pectus excavatum and two patients with pectus carinatum had their conditions corrected by a partial costal cartilage resection with a sternal osteotomy through a 2.5-cm to 4-cm skin incision located just above the xyphoid process assisted by an endoscope. In addition to the incision, stab wounds of less than 3 mm in diameter were also made, in some cases, for insertion of the surgical instruments to facilitate the operation. The ribs and rib cartilages were exposed beyond the affected area through a prexyphoid incision under endoscopic control. The mobility of the skin incision site was thus enhanced, and it was possible to perform most of the subperichondrial partial costal cartilage resection under direct visualization. The pleura was freed from the sternum under endoscopic visualization. The advantages of this technique include minimal operative scars and the ability to free the pleura from the sternum under endoscopically magnified visualization, which prevents rupturing of the pleura in the retrosternal area.

Distraction osteogenesis for craniosynostosis.

OBJECT: The authors describe the use of distraction devices and surgical techniques of distraction osteogenesis for the treatment of patients with craniosynostosis. METHODS: Since 1994, the authors have performed distraction procedures in 23 patients with craniosynostosis in whom osteogenesis was achieved. Thirteen of the 23 patients underwent a complete Le Fort III midface osteotomy and distraction. In 10 patients the distraction osteogenesis involved the cranial bone; six underwent combined forehead and midface distraction (Le Fort IV distraction) in which multiple internal devices were used after performing a Le Fort IV osteotomy. An external distraction procedure was used to treat the first two cases. Since 1996, the authors have used internal devices developed in their unit. Distraction was initiated 1 week after the osteotomy at the rate of 0.5 mm per day for the cranium and 1.0 mm per day for the midface. The consolidation phase after distraction was initiated was 2 to 3 months. No major complications such as intracranial infection or neurological deficits were observed during the course of distraction osteogenesis. The osteogenesis generated at the distraction site was considerably satisfactory; and recurrence of the deformity in the follow-up period was minimal. CONCLUSIONS: Distraction osteogenesis for craniofacial deformity has numerous advantages: 1) bone grafting is unnecessary; 2) the procedure is less invasive, has short operating time, and less blood loss occurs than in conventional craniofacial procedures; 3) no intracranial dead space is created; 4) there is a good amount of blood flow to the bone segment; and 5) soft-tissue expansion occurs. The authors believe that distraction osteogenesis is a versatile and stable option for the treatment of patients with craniosynostosis.

Amblyomma testudinarium tick bite: one case of engorged adult and a case of extraordinary number of larval tick infestation.

This paper reports two recent cases of tick bite due to Amblyomma testudinarium. The first case was an 86-year-old farmer infested with a fully engorged adult tick attached on his inguinal region. The second case was a 57-year-old male infested with an extraordinarily large number of larval ticks (> 100 larvae). The ticks were identified as A. testudinarium based on morphological characteristics. To our knowledge, the latter case is the eleventh case of larval tick bites among all tick species and the fourth case with larval A. testudinarium in Japan.

Pharmacokinetics of topical phenylephrine hydrochloride in the normal human eye.

Solutions of phenylephrine hydrochloride at concentrations of 1, 2 and 5% were instilled in one eye of 5 normal volunteers. Both eyes were photographed concurrently with an infrared film, and the pupil diameter was determined by an image analyzer using the developed film. The mydriatic effects were expressed by the difference in the pupil diameter of the experimental and the fellow control eyes determined concurrently. The mydriatic effects with these 3 solutions reached a peak about one hour and 15 minutes after instillation; the peak effects and the logarithm of the drug concentrations showed a linear relationship. An extrapolation of the relationship gave a least effective concentration of 0.07%. From the time course of the mydriatic effects, the pharmacokinetic coefficients were calculated using a computer. The average values were 0.24 +/- 0.08 hour for the time lag of the mydriatic response to appear, 1.31 +/- 0.19 hour-1 for the apparent elimination rate constant and 1.47 +/- 0.28 hour-1 for the apparent absorption rate constant.

"Face to face": a new method for the treatment of polydactyly of the thumb that maximises the use of available soft tissue.

Some patients with distal phalangeal polydactyly of the thumb have severe hypoplastic pulps that are difficult to make sufficiently large with either the fillet flap method or a symmetrical combination, the Bilhaut-Cloquet method. We have devised a new method to reconstruct the largest possible pulp by resecting only a minimum amount of soft dorsal skin tissue with one nail and not resecting any of the palmar skin of the thumbs. By contrast, other procedures require some resectioning of soft tissue of both the dorsal and the palmar skin. We have treated 13 cases with distal phalangeal polydactyly of the thumb since 1988 in this way. All the thumbs were successfully reconstructed with a sufficiently large pulp. The only problem was slight instability of the skin of the pulp after the operation, but this condition gradually improved during a five-year follow up. We think that this method facilitates the reconstruction of a sufficiently large pulp when both bifid pulps are hypoplastic.