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This study was designed to determine if soluble Tie2 (sTie2) expression inhibits and regresses corneal neovascularization, and if VEGF contributes to its effect. The corneas of BALB/c mice were scraped and the mice were injected with either an adenovirus expressing soluble Tie2 (Ad.sTie2) or an empty adenoviral vector. When injected at the inhibition timepoint (one day prior to corneal injury), the mean percentage of neovascularized corneal area two weeks later in Ad.sTie2-treated mice vs. controls was 56.37+/-9.15% vs. 85.79+/-3.55% (p=0.04). At the regression timepoint (4 weeks after corneal scrape), the mean area of corneal neovascularization in Ad.sTie2-treated mice was 42.89+/-4.74% vs. 75.01+/-3.22% in the control group (p=0.007). VEGF expression was significantly higher in Ad.sTie2-treated mice at the inhibition timepoint and there was no significant difference at the regression timepoint. These findings suggest that sTie2 inhibits and regresses corneal neovascularization in a VEGF-independent manner.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone.

Summary There have been several studies of the possible association between oral lichen planus and chronic liver disease; however, aside from various Italian reports no consistent association has been observed. In the present study, frequencies of historical, physical and biochemical evidence of liver disease in 180 UK patients with oral lichen planus were compared with those of 25 disease control patients and 25 healthy controls. No significant association between oral lichen planus and chronic liver disease; however, aside from various Italian reports no consistent

A case study is presented in which a patient received magnetic resonance (MR) imaging of the brain 3 months prior to a severe traumatic brain injury (TBI). The post-TBI MR findings are compared and contrasted with the pre-TBI MR images. The posltraumatic changes demonstrate a significant dilation of the ventricular system which reflects diffuse axonal injury and loss of brain substance. Correspondingly, the neuropsychological studies in this individual reflect global deficits which match the nonspecific, traumatically induced degenerative changes found in the postinjury MR scan. This case study is unique in that specific preinjury MR findings are available for direct comparison and quantitative analysis of TBI-associaled changes in brain structure with neuropsychological outcome.

Surgical stress, but not anesthesia induction, produced a significant increase in plasma beta-endorphin immunoreactivity in eight patients undergoing abdominal surgery. This increase was closely correlated with a parallel increase in plasma cortisol. Post-operative morphine administered for pain relief was associated with a significant reduction in plasma levels of both beta-endorphin and cortisol. These results demonstrate the responsiveness of the endorphin system to acute stress in humans and provide additional evidence linking plasma beta-endorphin to the hypothalamic-pituitary-adrenal axis.

As part of a protocol of the National Cancer Institute, 21 selected patients were submitted to total body hyperthermia for treatment of metastatic carcinoma. Elevation body temperature up to 41.8°C for 2 h was achieved using a computer driven external heating system. Patients were sedated during treatment. To ensure the safety of the procedure, a battery of physiological parameters was monitored. Continuous EEG recordings were carried out in all patients. Analysis of the EEG included visual assessment, compressed spectral array and power spectrum. EEG data were compared mainly to body temperature, state of consciousness and drug administration. Consciousness during the treatment varied from very light sedation to light anesthesia, with some rare delirious episodes. No motor seizures were observed. All EEG recordings demonstrated major changes in both rhythmicity and amplitude (slower and lower) indicating a diffuse decrease of cortical activity during the hyperthermia period. All changes reversed themselves during the cooling period. Spectral power showed a statistically significant inverse relationship with temperature. At temperatures above 41°C, decrease in total EEG spectrum was not related to decrease in clinical reactivity. The degree of EEG slowing varied with the extent and duration of the hyperthermia, and was totally reversible within a few hours of cooling, without evidence of any EEG or neurological sequelae. However, at temperatures above 41.5°C, EEG changes compatible with metabolic or toxic encephalopathy were observed. Possible mechanisms are discussed.

The Imugard IG 500 cotton wool filter and the Cellselect cellulose acetate filter were adapted for filtration of leucocytes from packed cell transfusions at the bedside. Sixty five transfusions were given via the Imugard IG 500 filter and 54 transfusions were given via the Cellselect filter. Packed red cell concentrates from the National Blood Transfusion Service provided for routine blood transfusions were used in all cases. No patient in either group of multitransfused patients experienced a febrile blood transfusion reaction during the study. The Imugard IG 500 removed 91% +/- 9 (SEM) leucocytes; the Cellselect removed 96% +/- 7 (SEM) leucocytes. In the Imugard IG 500 group one patient received greater than 0.5 X 10(9) leucocytes. In the Imugard IG 500 group one patient received greater than 0.5 X 10(9) leucocytes, but no patient in the Cellselect group received greater than 0.5 X 10(9) leucocytes in any single transfusion. This is a safe method of providing leucocyte poor blood at the bedside.

Two hundred twenty-two spinal anesthesias were administered with 10 mg. of tetracaine and 1 ml. of 10 percent dextrose to investigate the effects of vasopressors, patients age, and pH of cerebrospinal fluid on the onset and duration of spinal anesthesia. Neither the differences in overall age, cerebrospinal fluid pH, nor the addition of vasopressors had any significant effect on onset. Duration, however, was significantly prolonged by the addition of vasopressors, 53 percent prolongation by 0.2 mg. of epinephrine and 72 percent prolongation by 2 mg. of phenylephrine.

In the intact canine heart a gradient of systolic intramyocardial pressure from a minimum at the epicardial region to a maximum at the endocardial region is well established. No information is, however, available regarding the effects of various anaesthetic agents on this gradient. In the present study the effects of halothane on intramyocardial pressure recorded from subendocardial and subepicardial layers of the canine left ventricular free wall were assessed. Experiments were performed on seven anaesthetised mongrel dogs ventilated with 100% oxygen. Intramyocardial pressure was recorded simultaneously from the inner and outer regions of the myocardium using two Mikro-tip pressure transducers. Halothane concentration in the inspired gas varied from 0% to 2%. In the pentobarbital anaesthetised dog halothane does not significantly change the heart rate. With increasing concentrations of halothane in inspired gas systolic intramyocardial pressure at both endocardium and epicardium decreased significantly from control values. As the halothane concentration increased, the normal differential between systolic left ventricular pressure and endocardial intramyocardial pressure was abolished. The intramyocardial pressure gradient from endocardium to epicardium, however, persisted during systole. During diastole the pressure gradient was reversed, becoming maximum in the epicardial region and minimum in the endocardial region in both control and halothane treated animals. Over the range of 0-2% halothane concentration there was no significant effect on the diastolic intramyocardial pressure gradient. These results suggest that halothane affects the myocardial tissue pressure non-uniformly across the left ventricular free wall and therefore influences the transmural distribution of coronary blood flow. Compared with control animals, halothane treated animals generated an equivalent systolic left ventricular pressure with a lower endocardial intramyocardial pressure, suggesting a beneficial effect on myocardial mechanics during systole.

Protamine administration may induce arterial hypoxaemia in dogs and humans. However, the responsible mechanism has not been established. Protamine, as it is a pulmonary vasoactive substance, may interfere with normal hypoxic pulmonary vasoconstriction (HPV) and cause arterial hypoxaemia. This possibility was tested in dogs utilizing a one lung hypoxic model. One lung hypoxic ventilation decreased pulmonary blood flow in the hypoxic lung from 1022 +/- 96 ml X min-1 (mean +/- SEM) to 846 +/- 39 ml X min-1 (p less than 0.05) while increasing blood flow from 833 +/- 85 ml X min-1 to 1109 +/- 101 ml X min-1 (p less than 0.05) in the normoxic lung, resulting in 24 per cent effective diversion of blood flow. Protamine infusion, after heparinization, markedly elevated pulmonary vascular resistance in both lungs but preferentially in the normoxic lung (102 +/- 27 per cent increase in normoxic lung, 60 +/- 6.4 per cent increase in hypoxic lung) and significantly reversed the pulmonary blood flow shift induced by one lung hypoxic ventilation (effective diversion of blood flow was reduced to four per cent). Concurrently, arterial PO2 further decreased. Our results demonstrate that protamine interferes with effectiveness of pre-existing HPV and suggest that this mechanism, at least in part, may be responsible for arterial hypoxaemia observed after protamine infusion. The marked generalized pulmonary vasoconstriction with protamine appears to be the direct force that interferes with pre-existing auto-regulatory HPV. In addition to the well known haemodynamic effects of protamine, protamine infusion may also cause arterial hypoxaemia in those patients in whom HPV plays a significant role in maintaining arterial oxygenation.

Anesthesiologists are now active in the diagnosis of unusual neurologic and neuromuscular disorders. Their skill derives both from a firm understanding of basic sciences and a facility with invasive procedures. Five representative cases are presented to illustrate the scope of diagnostic neuroanesthesiology and the endeavors of the neuroanesthesiologist outside the operating theater.

Beta-endorphin appears to play a definite role in the biologic response to stress and in the endogenous mechanism of pain perception. Opiates exogenously administered during surgery decrease or even suppress the activation of "stress hormones" such as ACTH and cortisol. In the present study, the authors tried to assess the effects of fentanyl administration on plasma beta-endorphin immunoreactivity PBE(ir) during surgical stress. In one group of nine patients, a standard enflurane-based general anesthetic technique without opiates was used for a staging laparotomy. A second group of ten patients undergoing the same type of surgery received fentanyl (10-20 micrograms/kg) as the primary anesthetic drug. In both groups, multiple blood samples were collected prior to, during, and after surgery, following the same time protocol. PBE(ir), plasma cortisol and, in five patients, plasma ACTH were determined by radioimmunoassay. There was no significant change in PBE(ir) in either group after anesthetic induction. Unlike the enflurane group, the fentanyl group did not demonstrate any significant increase from baseline in PBE(ir) during surgery. There was a significant group difference between enflurane and fentanyl in PBE(ir) levels for both "early" and "late" surgery values, but not for the "awake" values (recovery period) where both groups had elevated PBE(ir) levels. Plasma cortisol and plasma ACTH changes followed a trend similar to those of PBE(ir). The suppression of both cortisol and PBE(ir) responses during surgery after administration of fentanyl provides further evidence for the involvement of the endorphin system in the stress response and for its physiologic association with the hypothalamo pituitary axis.

Auriculotemporal syndrome frequently follows trauma to the auriculotemporal nerve, a branch of the mandibular nerve. Classic symptoms are gustatory sweating and hyperemia, with pain occurring in less than 10% of cases. We have treated six patients for a variant of auriculotemporal syndrome following combined modality therapy for head and neck cancers. Unique was the presence of pain and the absence of gustatory sweating in all cases. The combination of radical surgery, chemotherapy, and irradiation obscured the "textbook" presentation, leading to initial misdiagnosis. Long-term relief (one year) from this atypical presentation of auriculotemporal syndrome was afforded by a simple mandibular nerve block, a technic that is of no sustained therapeutic benefit in the classic cases.

Diagnosis of amniotic fluid embolism is difficult in a patient under general anesthesia and may initially resemble several other conditions. Successful treatment requires maintenance of adequate cardiac output and oxygenation and prompt heparin treatment of the disseminated intravascular coagulation. The presented case exemplifies another group of patients who are ar risk for amniotic fluid embolism.

Noncardiogenic pulmonary edema occurred in an anesthetized patient during an otherwise uneventful laparotomy. Following transfusion of an individual unit of whole blood, routine intraoperative monitoring detected sudden major pulmonary shunting (increased alveolar-arterial oxygen gradient) and an increased physiological alveolar dead space (increased arterial-alveolar carbon dioxide gradient). The noncardiac pulmonary edema probably resulted from the presence of a leukoagglutinin against the patient's granulocytes in the donor's plasma. This antibody had no apparent specificity for known HLA, neutrophil, or blood group antigens. The acute respiratory failure was transient, resolving in 72 hours with respiratory support. The presence of otherwise unexplained noncardiogenic pulmonary edema during or soon after a blood transfusion should suggest the possible diagnosis of a leukoagglutinin reaction. (JAMA244:2186-2189, 1980)

Sensory level of anesthesia following the injection of 20 ml of 1.5% lidocaine with epinephrine (1:200,000) in 238 adult males averaged T7.7, T5.6, and T5.1 at 10, 20, and 30 minutes, respectively. Patient age had no significant effect on local anesthetic requirements per spinal segment per unit height until age 40 years, which age the calculated amount of local anesthetic decreased significantly to 0.62 ml from 0.69 ml/segment/meter of height. Above age 40 there was no further decrease in epidural anesthetic requirement with advancing age. Patient height was inversely related to sensory level (p < 0.001). Time required for anesthesia ro recede to T12 averaged 164 minutes and was slightly but significantly (p < 0.05) prolonged with advancing age.

The effects of enflurane anesthesia on brainstem auditory evoked responses (BAERs) was determined in 10 patients with normal hearing undergoing various surgical procedures. Arterial blood pressure, body temperature, and arterial Pco2 were controlled during the 2- to 5-hour recording sessions. End-tidal enflurane concentrations were continuously recorded on a chemetron Medspect II mass spectrometer in three subjects. BAERs were obtained by, and recorded on a Nicolet CA 1000, from C2 with reference to A1 or !2, with a 2000 click-averaging for each measurement. Enflurane administered at clinical concentrations (0.5% to 3%) produced a consistent changes in BAER latencies. The waves significantly affected (p less than 0.01) were waves III, IV, and V and interpeak latency I-V. The magnitude of theses changes was related to the concentration of enflurane and was magnified by temporarily decreasing the Paco2. These findings confirm similar data obtained in animals which have shown the same effects at doses that can produce generalized seizure activity. BAER analysis shows that changes predominate at the pons and midbrain levels and affect the brain stem conduction time, which likely reflects the action of enflurane on the activity of the reticular activating system.

We evaluated the effect of halothane on the balance of subendocardial oxygen supply and demand in six dogs by estimating the endocardial viability ratio (EVR) based on the pressure generated within the subendocardium (ENDO-IMP). Concurrently, the conventional EVR based on left ventricular pressure (LVP) was estimated and compared with the EVR based on ENDO-IMP. The subendocardial oxygen supply-demand ratio based on ENDO-IMP (IMP-EVR) was significantly less than EVR based on LVP (LVP-EVR) (0.87 +/- 0.03 vs 1.07 +/- 0.06, P less than 0.05) during the control period. With 0.5% halothane administration, IMP-EVR improved significantly (1.04 +/- 0.07, P less than 0.05) while LVP-EVR remained unchanged (1.08 +/- 0.09). No further changes in EVR (either IMP-EVR or LVP-EVR) were observed with increasing halothane concentrations up to 2%. The relationship between the two indices was weak (r2 = 0.44, P less than 0.001) but statistically significant. Because an estimate of EVR based on direct measurement of subendocardial tissue pressure (IMP-EVR) would reflect more accurately the oxygen supply-demand balance of this region than the LVP-EVR, our results suggest that the oxygen balance of the subendocardium improves with halothane administration. The use of LVP-EVR as a hemodynamic index of subendocardial oxygen balance during halothane anesthesia, therefore, is questionable.