Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-ß1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis.

Congenital absence of the internal carotid artery diagnosed during investigation of trigeminal neuralgia.

Congenital absence of the unilateral internal carotid artery (ICA) was found in a patient during MR imaging examination for right trigeminal neuralgia. Magnetic resonance angiography showed complete absence of the right ICA and a large tortuous basilar artery (BA). The source images revealed a deformed right trigeminal nerve resulting from compression by the BA. Computed tomography of the skull base showed absence of the right carotid canal, suggesting agenesis of the right ICA. Longstanding hemodynamic stress may have caused the BA to become extremely tortuous, resulting in the trigeminal neuralgia.

[Perioperative administration of bicarbonated solution to a patient with mitochondrial encephalomyopathy].

A 16-year-old man with mitochondrial encephalomyopathy underwent biopsy and nephrectomy under general anesthesia. Mitochondrial encephalomyopathy is caused by mitochondrial dysfunction, and frequently accompanies elevation of lactic and pyruvic acid levels in the blood. It has been considered that problems of anesthesia for the patient with mitochondrial encephalomyopathy are the probability of hyperlactacidemia, the relevance to malignant hyperthermia, the possibility of myocardial disease and dysfunction of heart conduction system, respiratory depression due to muscle weakness, and so on. Therefore, to prevent hyperlactacidemia, we prepared the extracellular fluid solution including bicarbonic acid but no lactic and acetic acid, and infused the solution to the patient during anesthesia. By use of this solution, his lactic acid level was kept within the normal range during anesthesia and no metabolic acidosis occurred. His hemodynamics was stable and he showed normal response to vecuronium, recovering from anesthesia smoothly and postoperative course was uneventful.

Unanswered and uncounted items of the illness behavior questionnaire count: a comparison between patients who answered all the items in the questionnaire and those who left one or more items unanswered in a pain management program.

PURPOSE: This study aimed to understand the significance of unanswered and uncounted items on the illness behavior questionnaire (IBQ) in the setting of the Mayo Clinic pain management program for patients with chronic pain. METHODS: Three hundred and seventy-eight patients who completed the questionnaire were studied. The data included (1) age, (2) IQs, (3) IBQ score profiles, (4) litigation status, (5) admission status (inpatient vs outpatient), and (6) dismissal status ("graduates" vs "dropouts"). RESULTS: Comparison between patients who answered all the items (n = 272) and those who left one or more items unanswered (n = 106) showed a significant difference in the completion rate of the Wechsler Adult Intelligence Scale ( P < 0.05), Scale 5 (affective disturbance) score (P < 0.05), and the rate of dropout from the program (P < 0.05). Also, those who dropped out of the pain management program had a significantly lower score on Scale 5 (P < 0.001) and a significantly greater number of unanswered items that were not counted toward the scale score (P < 0.05). CONCLUSION: Unanswered and uncounted items of the IBQ seem to count toward a better understanding of patients' pain behavior.

Acetazolamide-induced increase in blood flow to rabbit organs is confirmed using colored microspheres.

Inhibitors of carbonic anhydrase activity have been found to increase blood and organ PCO2 and to increase blood flow (BF) in individual organs. To determine whether carbonic anhydrase inhibition coordinately induces an increase in BF in several organs, we assayed the effect of the carbonic anhydrase inhibitor, acetazolamide (AZ), on BF in rabbit organs using the colored microsphere (CM) assay. Eight female white rabbits were anesthetized with ketamine and urethane, and administered three sequential doses of 4 mg/kg AZ. After each dose, the rabbits were injected with 9 x 10(5) CMs of different colors, and arterial blood was collected. We found that AZ had no effect on blood pressure, body temperature, hemoglobin concentration, or PaCO2. In contrast, 12 mg/kg AZ significantly increased PaO2 and significantly decreased base excess. When we measured organ BF, we observed, in response to 12 mg/kg AZ, an 82% increase in brain BF and a 55% increase in kidney BF, but no change in BF of the liver, stomach wall, or abdominal muscle. These findings suggest that the inhibition of carbonic anhydrase activity by AZ, which decreases the rate of CO2 conversion to HCO3-, causes the retention of CO2 in tissues and organs, and thus increases BF in specific organs. Administration of carbonic anhydrase inhibitors, such as AZ, may increase BF to the brain and kidney without reducing PaO2, thereby increasing the supply of oxygen in conditions involving hypoxia such as ischemia and shock.

An 11-year-old girl with reflex sympathetic dystrophy successfully treated by thoracoscopic sympathectomy.

We report on an 11-year-old girl with reflex sympathetic dystrophy (RSD) complaining of severe pain in her right upper extremity. Oral administration of narcotics or non-steroid anti-inflammatory drugs gave no relief in pain. Thoracoscopic electrocauterization of the thoracic sympathetic ganglion at the level of T3 was performed 3 months after the start of symptoms, and brought complete resolution of pain.

Chronic lead exposure may inhibit endothelium-dependent hyperpolarizing factor in rats.

We designed experiments to determine the effect of chronic lead exposure on endothelium-dependent responses to acetylcholine (Ach) in rat isolated blood vessels. Male Wistar rats were maintained for 1 or 3 months with or without oral lead administration. Membrane potential and isometric tension were measured in mesenteric arteries. Ach caused concentration- and endothelium-dependent relaxation in rings with endothelium contracted with phenylephrine (PE). There was no significant difference in relaxation between lead-exposed and control animals. In the presence of NG-nitro-L-arginine methyl ester (L-NAME), both endothelium-dependent hyperpolarization and relaxation to Ach were significantly reduced in animals from the 3-month lead-exposed group. In aorta from lead-exposed groups, endothelium-dependent relaxation to Ach was not significantly different from that of age-matched controls, whereas both were completely inhibited in the presence of L-NAME. The basal levels of cyclic GMP in the aorta were not affected by lead exposure regardless of duration. These data indicate that both endothelium-dependent hyperpolarization and L-NAME-resistant relaxation decrease with chronic lead exposure in rat mesenteric arteries and suggest that lead is an inhibitor or endothelium-derived hyperpolarizing factor (EDHF).

MR imaging of idiopathic trigeminal neuralgia: correlation with non-surgical therapy.

Magnetic resonance (MR) findings in patients with idiopathic trigeminal neuralgia were evaluated and correlated with the effectiveness of non-surgical treatments. Thirty-four patients with idiopathic trigeminal neuralgia (ITN) were examined using T1- and T2-weighted spin-echo (SE) pulse sequence techniques to evaluate their trigeminal root-entry zones and the vessels contacted prior to non-surgical treatment (retrogasserian glycerol injection, peripheral nerve block, or only oral analgesics). Vascular contact at the proximal portion of the preganglionic segment (PGS) of the trigeminal nerve and deformity of the PGS on the affected side were observed in 97% and 47% of the patients, respectively. Non-surgical treatments were curative in 12 (67%) but failed in two (11%) of the 18 patients without deformed PGS. However, among 16 patients with deformed PGS, they were curative in only six (37.5%) and failed in four (25%). Results of this study suggest that MR imaging could be useful in the clinical assessment of trigeminal neuralgia prior to instituting non-surgical treatment.

Immunocytochemical study of parvalbumin, calbindin D-28k, and calretinin in the superficial dorsal horn of the rat spinal cord following unilateral hindpaw inflammation.

The effect of noxious stimulation on the immunore-activity of the calcium-binding proteins parvalbumin (PV), calbindin-D-28k (CB) and calretinin (CR) was investigated in the superficial dorsal horn of lumbar levels L5-L3 of the rat spinal cord. Freund's adjuvant was injected unilaterally into the hindpaw to induce inflammation. Immunohistochemical techniques were utilized to investigate changes in the calcium-binding proteins 2h and 1, 2, 4, and 7 days after injection. At 24h after injection, a decrease in the intensity of fluorescence of PV-immunoreactive (IR) fibers was observed in the superficial layer (substantia gelatinosa) of the ipsilateral dorsal horn (L5-L3) in most animals. Comparatively fewer animals exhibited changes in the CB- and CR-IR fibers, except at the L3 level 2 days after, and at the L4 level 7 days after the hindpaw injection. After the peak response, at 24h in most animals, there was a decline in the number of responders at 2 days and no differences were noted at 4 days. However, at 7 days, there was again an increase in the number of animals revealing diminished fluorescence intensity in the ipsilateral substantia gelatinosa. Changes in immunoreactivity of calcium binding proteins in the interneurons of the superficial lumbar dorsal horn may reflect hyperactivity within these neurons following noxious stimulation.

Three-dimensional analysis of the intrinsic cardiac ganglia in a young dog.

The intrinsic ganglia of the heart of a young dog were studied by computer graphic reconstruction to determine the accurate location. The heart was embedded in celloidin, and transverse sections were cut. Using every third 60 microns section, a series of 49 sections was mapped. Three-dimensional (3D) images were constructed by a personal computer. Numerous intrinsic ganglia, most of which were located in the epicardiun, were observed. The intrinsic ganglia were found in the base of the aorta and pulmonary vessels and from the base of the superior vena cava to the right atrium, i.e., the sinoatrial nodal region. Using the 3D reconstruction technique, the locations of the intrinsic ganglia could be accurately identified. Furthermore, it was demonstrated that these ganglia formed several groups which formed a continuity. This study suggested that it was necessary to consider the existence of the numerous intrinsic ganglia, when we studied the cardiac innervation.

Prevention by ulinastatin of decreased carbonic anhydrase activity induced by PMN elastase in vitro.

Disturbed carbon dioxide (CO2) elimination in adult respiratory distress syndrome (ARDS) has been considered to result from the dead space created by microthrombosis and vasoconstriction. However, another disturbance factor in CO2 elimination has been reported; the chemical dead space resulting from the inhibition of carbonic anhydrase (CA). This experiment was conducted to quantify the inhibition of CA activity by polymorphonucleocyte (PMN) elastase, which increases in ARDS. Different flasks containing solutions of CA, buffer, elastase, ulinastatin (an elastase antagonist), CA with PMN elastase, and CA with both PMN elastase and ulinastatin were prepared. Each flask was injected with sodium bicarbonate labeled with radioactive carbon (14C) and was shaken for 20 minutes; CA activity in each flask was measured by calculating the decrease in the coefficient (K) of 14C. It was observed that CA activity was inhibited dose-dependently by PMN elastase and that the inhibited activity was recovered by ulinastatin, which can inhibit PMN elastase. These findings indicate that CA activity in vitro could be inhibited by PMN elastase, which increases in ARDS, and suggests that disturbance of CO2 elimination could be reduced by using ulinastatin. It was concluded that ulinastatin could prevent the CA activity induced by PMN elastase in vitro.

Treatment of severe pertussis by administration of specific gamma globulin with high titers anti-toxin antibody.

Our patient presented with severe respiratory distress and marked pleocytosis. She was mechanically ventilated and received gamma globulin with high titers of anti-pertussis toxin and anti-filamentous hemagglutinin. Her clinical signs improved and a notable decrease in white blood cell count was observed. Ten months after treatment, the patient showed normal physical and mental development and anti-pertussis toxin and anti-filamentous hemagglutinin titers were significantly increased. Recently, the effectiveness of gamma globulin therapy has been emphasized again. Our experience supports the use of iv gamma globulin infusion. Also, gamma globulin did not influence the patient's own immunologic response to pertussis. Gamma globulin therapy with high anti-pertussis toxin titers could be considered for treatment of severe pertussis.

Retention of carbon dioxide in tissue following carbonic anhydrase inhibition in dogs.

To evaluate the retention of carbon dioxide in tissue during the reduction of carbonic anhydrase activity following the administration of 5, 10, 20, or 30 mg/kg of acetazolamide in dogs, we measured carbon dioxide pressure (PCO2) in arterial blood, mixed venous blood, alveoli, and tissue. Respiration was maintained at a constant level. In the control (noninjected) group, PCO2 in tissue did not change for 3 hours under controlled respiration. Following the injection of 5 to 30 mg/kg of acetazolamide, PCO2 increased in arterial blood, mixed venous blood, and tissue in a dose-related manner, and decreased in the alveoli. The (a-et)PCO2 widened to 21.9 +/- 1.0 mmHg from 0.6 +/- 1.0 mmHg, and the (t-v)PCO2 to 16.1 +/- 2.0 mmHg from 5.1 +/- 0.6 mmHg, in response to acetazolamide. It is suggested that carbon dioxide is retained in tissue when carbonic anhydrase activity is inhibited by acetazolamide.

Epidural block for treatment of intestinal obstruction--clinical and experimental studies.

Seventy patients with intestinal obstruction were managed with usual conservative treatments and epidural anesthesia to block splanchnic and somatic nervous systems, for nine years from 1981 to 1990. Improvement of clinical symptoms and general conditions was accomplished in 48 patients (68.6%). In these 48 patients, 41 patients (58.6%) had complete remission of intestinal obstruction, showing flatus in 8.3 hours on an average, but seven (10.0%) had incomplete remission. For these seven, after improvements of their clinical symptoms, elective radical operations were performed within three weeks. In 22 (31.4%) patients whose symptoms were not improved at all with the epidural block, emergency exploratory celiotomies were performed, 15.4 hours on an average after the initial epidural block. Indications for surgical intervention of intestinal obstruction were decided by the absent movement of gas in the bowel in a series of plain X-rays. The effectiveness of the epidural block on the motility of the obstructed intestinal loop was experimentally confirmed in monkeys. We suggested that the epidural block, accompanied with usual conservative treatments, be recommended as the initial treatment for intestinal obstruction.

[Reevaluation of spinal anesthesia in elderly people--an evaluation of circulatory changes].

Appropriate methods of anesthesia for the elderly people are being discussed as the ratio of elderly people in our society increases. During spinal anesthesia, hypotension was frequently observed in patients with hypertension, arteriosclerosis, coronary deficiency, and so on. It is also difficult to pass the needle between degenerated vertebrae. However, general inhaled anesthesia accompanies the respiratory complications and consciousness derangement after surgical operations more frequently than after spinal anesthesia. In this study, circulatory conditions during spinal anesthesia in elderly people (30-91 years old) were analyzed in 109 cases of spinal anesthesia. Hypotension occurred about 10 minutes and 40-60 minutes after injection of anesthetics and was frequent in patients of high aged group, but tachycardia was not observed among them. In addition, their blood pressure in the recovery room could not recover to the level before anesthesia. It is thought that hypotension during spinal anesthesia was induced by the vascular dilatation caused by sympathetic nerve block and the deficiency of reflective venous constriction in upper extremities and abdominal organs. Tachycardia may also produce hypotension. However, the reflexive vasoconstriction and tachycardia are thought to be poor on account of arteriosclerosis and down regulation of beta-receptor in elderly people. Therefore, during spinal anesthesia in the elderly people, the catecholamine released by the surgical stimulation could not increase blood pressure effectively. To prevent hypotension during spinal anesthesia in elderly people, it is advisable to employ the treatment for upregulation of beta-receptor before anesthesia and the administration of alpha . beta-receptor, epinephrine and dopamine for control of blood pressure during spinal anesthesia.

Intra-operative blood pressure control by prostaglandin E1 in patients with hypertension and ischemic heart disease--a multi-center study.

The purpose of this multi-center study was to evaluate the efficacy and safety of prostaglandin E1 (PGE1) administration in achieving deliberate hypotension and in treating intraoperative hypertension for patients with a history of hypertension and ischemic heart disease. PGE1 (0.08 microg.kg(-1).min(-1)) decreased systolic blood pressure from 125 +/- 29 to 106 +/- 22 mmHg (mean +/- SD) in the deliberate hypotension group (n = 158) and from 155 +/- 34 to 125 +/- 32 mmHg in the antihypertension group (n = 55). The heart rate significantly increased from 80 +/- 15 to 85 +/- 18 beats.min(-1) in the deliberate hypotension group, but was not significantly altered in the antihypertension group. The time required to obtain the desired level of blood pressure was approximately 20 min in the deliberate hypotension group. When the infusion was stopped, blood pressure returned approximately to the preinfusion level within about 20 min. No rebound hypertension was observed. PGE1 significantly increased the urine flow in patients who had a low urine flow before PGE1 infusion. Thirteen out of 213 patients (5.6%) had side effects such as excessive hypotension (1%), phlebitis (3%), and unexpected tachycardia (1%), which were alleviated gradually after discontinuation of PGE1 infusion. No dysarrhythmia and further ST segment changes in the electrocardiograms were observed. These findings suggest that PGE1 can be safely used to control arterial blood pressure during surgery in patients having preoperative hypertension and ischemic heart disease.

Sympathetic innervation of the young canine heart using antero- and retrograde axonal tracer methods.

The present study was performed to determine the origin of cardiac sympathetic postganglionic fibers and to demonstrate their distribution in the heart. Young dogs were used in this study. Wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into various regions of the heart, and cholera toxin B subunit (CTB) and WGA-HRP were injected into the middle cervical ganglion or the stellate ganglion. In our retrograde axonal transport study, a large number of WGA-HRP-labeled cells were observed in the middle cervical and stellate ganglia bilaterally. Only a small number of the labeled cells were observed in the superior cervical ganglia bilaterally. In the anterograde axonal transport study, CTB and WGA-HRP labels showed terminal-like structures in the intrinsic ganglia located in the sinoatrial node, left atrium, and the origin of the ascending aorta. The labeled fibers were also observed around the coronary arteries.