Inaccuracy of electronic sphygmomanometers.

1. Eight electronic sphygmomanometers were purchased locally and evaluated for clinical accuracy during blood pressure recording on volunteer patients. 2. Direct comparisons of systolic and diastolic pressure were made in seven devices using a Y-tube connection to a mercury sphygmomanometer, simultaneous measurements being made by a trained observer on 16-18 subjects. 3. Indirect comparisons were made for all eight devices by comparing the average values obtained from all measurements made on each subject by the device with the average value from mercury sphygmomanometric readings made over the same time period. 4. Results were analysed by measuring the mean and standard deviation of the differences between device readings and mercury readings. Published criteria were used to grade the devices. 5. The most accurate machine was the Omron HEM-719K, which used the cuff as a sound sensor and had an internal microphone. The least accurate was the Omron HEM-812F, which used a finger-cuff method. The other devices (all oscillometric) ranged from fair to poor in performance accuracy.


Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.

1. Thirteen patients from five families had Familial Hyperaldosteronism Type II (FH-II), a new variety of familial primary aldosteronism not suppressible with dexamethasone that often involves adrenocortical adenoma formation. 2. Five patients had solitary aldosterone-producing adenomas, three had bilateral autonomous overproduction of aldosterone, and in five the subtype is yet to be determined. 3. Comparing FH-II patients with 88 patients with primary aldosteronism of other causes revealed no differences in mean age at presentation or at onset of hypertension, sex incidence, lowest recorded serum potassium, plasma aldosterone, plasma renin activity or adenoma size. 4. Analysis of DNA in peripheral blood of patients with FH-II, their affected and unaffected relatives, and in removed tumours is in progress in order to determine the underlying genetic defect(s) in FH-II, perhaps an abnormality in the P-450aldo gene (CYP11B2). 5. It is recommended that hypertensive relatives of patients with primary aldosteronism should have measurements of the aldosterone/renin ratio.


Population-based survey of human sodium and potassium excretion.

1. During the 1989 National Heart Foundation Risk Factor Prevalence Survey a subsample in Hobart collected 24 h urine samples to measure electrolyte excretion. 2. The ranges were 30-344 mmol/24 h for Na+ excretion (mean 160 mmol/24 h for men, 124 mmol/24 h for women), and 25-119 mmol/24 h for K+ excretion (mean 77 mmol/24 h for men, 68 mmol/24 h for women). 3. As in other surveys, women excreted about 20-25% less Na+ and K+ than men, although there was no significant sex difference in the ratio of Na+/K+ excretion. 4. The recommended dietary intake (RDI) for Na+ and K+ was followed simultaneously by 19% of subjects, and 13% had a 24 h urinary Na+/K+ ratio less than or equal to 1.0. 5. Observance of the RDI limited the value of iodized salt for goitre prophylaxis. 6. Sodium excretion rates were outside the therapeutic range of thiazide diuretics in 22% of subjects. 7. Diet groups for long-term prospective cohort studies to test the prophylactic value of avoiding salt could apparently be recruited from existing subsamples of the population.


Axonal projections from respiratory centres towards the rostral ventrolateral medulla in the rat.

1. Efferent pathways from brainstem respiratory centres towards bulbospinal tyrosine hydroxylase immunoreactive neurons were identified in the rat using a combination of electrophysiology, retrograde and anterograde tract-tracing, and immunohistochemistry. 2. Varicose axons originating from respiratory centres were found in close apposition to bulbospinal tyrosine hydroxylase immunoreactive neurons in the ventrolateral medulla. 3. These findings support the idea that respiratory rhythms in sympathetic nerves may be due to a synaptic connection between brainstem respiratory neurons and bulbospinal tyrosine hydroxylase immunoreactive neurons of the C1 cell group.


Haemodynamic changes in the Moncada model of atherosclerosis.

1. The application of a non-constricting silastic cuff to the rabbit common carotid artery (CCA; n = 5) results in intimal thickening within 7 days. 2. Ultrasonography showed kinking of the CCA at the cuff edges, as well as a 13% arterial narrowing (P less than 0.02) within the cuffed segment, both at days 1 and 7. Correspondingly, the time averaged diastolic Doppler velocity (TAV) was 68.8 +/- 12.8% higher (P less than 0.025) in the cuffed region in comparison with that 1 cm proximal (P 1 cm) on day 1, and 54.2 +/- 11.5% higher at day 7 (P less than 0.05). TAV values along control silastic strips were not significantly changed. 3. There was a significant increase (P less than 0.025) in intimal area within the cuffed region (0.098 +/- 0.024 mm3) compared with both the proximal control (0.014 +/- 0.001 mm3) and with that over control silastic strips (0.021 +/- 0.004 mm3, P less than 0.01). 4. Medial area within the cuff (0.433 +/- 0.017 mm3) was decreased (P less than 0.005) compared with P 1 cm control (0.602 +/- 0.069 mm3). 5. There was gross peri-arteritic thickening involving the adventitia along the non-constricted cuffed segment. Importantly, it was also noted alongside the control silastic strip. 6. Kinking of the CCA and associated vasoconstriction cause changes in blood flow velocity along even a non-constricting cuff, and this may explain the intimal thickening previously noted in this experimental model. The peri-arteritic changes, on the other hand, appear to be a reaction to the silastic itself.


Polymerase chain reaction-based DNA fingerprinting in the spontaneously hypertensive rat: potential source of cDNA library probes.

1. Using the Polymerase Chain Reaction with a primer homologous to a repetitive unit found at irregular distances in the rat genome, we were able to synthesize DNA fragments spanning such units and visualize them as a ladder of discrete bands following electrophoresis. 2. Differences between fingerprint patterns generated using SHR, WKY and SD DNA, in the form of band deletions or duplications, were readily detected. 3. Unlike traditional fingerprinting, PCR fingerprints allow the ready extraction and characterization of polymorphic bands. Such bands could then be used as probes with which to screen a cDNA library that might, in turn, identify expressed genes involved in the development of hypertension.


The heterogeneity of 11-beta-hydroxysteroid dehydrogenase activities in the rat hippocampus implies a complex regulation of steroid hormone action.

1. The rat hippocampus 11-beta-hydroxysteroid dehydrogenase (11-HSD) displays a different substrate specificity to that of other tissues. S1 nuclease analysis was used to determine whether the hippocampal messenger RNA is different from that found in other tissues. 2. S1 nuclease analysis using probes spanning the full length cDNA demonstrated that there were no differences in sequence between the hippocampal 11-HSD and the enzyme originally cloned from the liver. 3. These results suggest that there may be multiple 11-HSD isoforms in the hippocampus with different substrate specificities.


DA-1 receptors mediate renal effects of the dopamine prodrug, gludopa, in conscious rabbits.

1. Eight male rabbits were implanted with Doppler flow probes around the lower abdominal aorta and left renal artery. A 2 week recovery period was allowed prior to the experiment. 2. Normal saline, gludopa at 25 micrograms/kg per min and at 100 micrograms/kg per min were each infused i.v. for 60 min. One week later the same protocol was administered to four of these animals in addition to DA-1 antagonist SCH 23390 (0.3 mg/kg i.v.) before gludopa infusion. 3. Gludopa elicited significant increases in urine flow, urinary sodium excretion and renal blood flow, and decreased renal vascular resistance. These changes were abolished by the DA-1 antagonist. Blood pressure, heart rate and hindlimb blood flow remained unchanged. 4. Urine dopamine excretion was increased 1200-fold and 7800-fold after gludopa administration at 25 micrograms/kg per min and 100 micrograms/kg per min, respectively, while plasma dopamine concentration and plasma renin activity (PRA) were not significantly altered. However, PRA was elevated by gludopa with DA-1 antagonism. 5. The renal vasodilation, natriuresis and diuresis produced by gludopa in conscious rabbits appears to be mediated by locally generated dopamine via DA-1 receptors.


Effect of enalapril on body sodium and handling of a sodium chloride load in hypertensive and normotensive rats.

1. The effect of enalapril on handling of an Na load and on body Na during 96 h of zero Na intake was measured in hypertensive rats (GH and SHR) and their normotensive controls (N and WKY) by a whole body counting method. 2. Enalapril treatment led to a greater fall in body Na in the first 24 h after the Na load (as expected from the known effect of ACE inhibition on aldosterone production) and thus to a slightly faster excretion of an amount equivalent to the load. 3. Enalapril-treated rats were unable to maintain body Na on a zero Na intake. This was also expected from the known effect on aldosterone production, though other mechanisms are not excluded. The effect was more marked in the SHR and WKY than in GH and N but there was no significant difference in this effect between the hypertensives and their respective control strains.


Renal vasoconstriction is modulated by nitric oxide.

1. The effect of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine (NOLA), has been examined on vascular reactivity in the rat isolated perfused kidney. 2. NOLA (10 mumol/L) had no effect on basal perfusion pressure, but significantly enhanced the vasoconstrictor responses to sympathetic nerve stimulation (1-16 Hz, 10 s) and noradrenaline (10-300 pmol). The enhancements were greater with the lower frequencies of stimulation and lower doses of noradrenaline. 3. The enhancing effect of 10 mumol/L NOLA on vasoconstrictor responses to nerve stimulation was partially prevented by 100 mumol/L L-arginine while 100 mumol/L D-arginine had no effect. 4. The results suggest that nitric oxide attenuates vasoconstrictor responses in the rat kidney, and provide evidence that nitric oxide has a physiological role in the modulation of vascular reactivity.


Differential regulation by transforming growth factor-beta 1 of platelet-derived growth factor-stimulated proliferation of vascular smooth muscle cells from SHR and WKY rats.

1. This study has examined and compared the time-course of action of transforming growth factor-beta 1 (TGF-beta 1) on platelet-derived growth factor-BB-stimulated proliferation of vascular smooth muscle cells isolated from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Transforming growth factor-beta 1 inhibited vascular smooth muscle cell proliferation stimulated by platelet-derived growth factor-BB in WKY rats by approximately 60-75%. 3. In contrast, transforming growth factor-beta 1 potentiated an 8-35% growth factor action on cell proliferation in the SHR. 4. Defects in transforming growth factor-beta 1 action may be part of the molecular mechanism responsible for the development of vascular hypertrophy in the SHR.


Labor after prior cesarean section.

1. All women with PCS should be considered candidates for vaginal delivery. Certain high-risk factors then should be used to recommend elective repeat cesarean section. Currently, a scar in the active segment of the uterus is considered an absolute contraindication to labor. 2. Women should be informed of the chances of success (which in most instances are excellent), course of action in labor, and the rare risk of uterine rupture. 3. Women in a very low risk category (one low-transverse PCS) should be managed like any laboring patient but including fetal monitoring. 4. The remaining laboring patients may benefit from more intensive intrapartum surveillance, including continuous electronic fetal monitoring, early rupture of the fetal membranes, and placement of an intrauterine pressure catheter. 5. The labor course in women with PCS will depend on the number of vaginal deliveries achieved previously and the stage of labor reached before the cesarean section was done. 6. Labor disorders in patients with PCS, as in all patients, should be diagnosed and managed promptly. 7. Neither oxytocin nor epidural use is contraindicated in these patients. As in any patient, care should be taken to avoid iatrogenic uterine hyperstimulation. 8. Uterine rupture may have many different presentations. However, the most common is abnormal fetal heart rate patterns that are especially variable or prolonged decelerations. 9. Most uterine ruptures can be repaired and do not require hysterectomy. Hysterectomy may be the appropriate choice in some situations. 10. A history of a prior uterine rupture is not a contraindication to future childbearing, but it may place the woman at greater risk for a repeat event.


Effects of analgesia on labor.

Uterine activity may be defined in terms of the frequency of contractions of the uterus and the pressure generated by these contractions. Most studies that report an effect of analgesia on labor are retrospective, and, if prospective, are nonrandomized. Drug effects on uterine activity and labor progress are probably dose related, but are also influenced by a myriad of other factors including, but not limited to, the mother's emotional state, degree of cervical change, uterine contractility pattern, phase of labor, and individual differences in pharmacokinetics and drug sensitivity. The latest phase of labor may be prolonged by excessive narcotic or inappropriate timing of regional analgesia. The normal active phase tends to be resistant to the inhibitory effects of the usual amount of any analgesia. A brief period of decreased uterine activity often follows institution of analgesia. This may effectually accelerate labor in some patients by decreasing maternal anxiety and serum concentrations of catecholamines. A combination of sedation epidural blockade, and subsequent oxytocin use may prove effective in correcting a dysfunctional or hyperstimulatory pattern during the active phase. The second stage of labor may be slightly prolonged by effective epidural analgesia, but this delay is not necessarily harmful as long as the fetal heart rate tracing is normal, maternal hydration is adequate, and maternal pain relief is sufficient.


Issues in the diagnosis and research of premenstrual syndrome.

The diagnosis of PMS depends on the identification of a core symptom complex, including behavioral symptoms of either irritability, accompanied by an internal state of anxiety or depression, and fatigue. (Fatigue is the most common symptom of PMS.) At least one core physical symptoms, bloating of the abdomen or extremities, breast tenderness, and headache also is required to establish the diagnosis. Although these core symptoms are required, none is pathognomonic for the disorder and the timing of the symptoms with respect to the menstrual cycle also must be established. This can only be done accurately using valid and reliable prospective recording instruments, such as COPE. Personality factors, the degree of psychosocial stress faced by the woman, and biochemical markers have little utility in establishing the diagnosis. The literature with respect to the prevalence of PMS in the population, effective treatments for the disorder, and the diagnosis of the disease must be interpreted by recognizing the inclusion in these studies of women with comorbid psychiatric disease, invalid and unreliable symptom inventories, and inadequate characterization of menstrual cycle phases. There are sociologic reasons why the true prevalence and treatment response to interventions may not be seen by the clinician. Nonetheless, the availability of effective treatment for the disorder necessitates accurate diagnosis of the syndrome based on the strict criteria presented. Additional research founded on the development of psychoneuroendocrine models is likely to provide insight into both the pathophysiology and treatment alternatives for PMS.


Female-specific mood disorders.

Hormones are partial determinants of certain sexually dimorphic behaviors and interact with psychosocial, environmental, and other physiologic factors. The part played by sex hormones in the direct control of overt human behavior is, compared with that found in lower animals, slight and less readily definable. In humans, these hormones, although necessary for maintenance of libido and sexual behavior, seem to control the intensity of such behavior rather than its direction. In most women of reproductive age, the different phases of the menstrual cycle are not associated with major physical or psychologic discomfort. Some women actually report positive changes during the premenstrual period. Only 5-10% of women in this age group have changes in mood, sleep, eating habits, level of energy, and physical symptoms that appear to be linked temporally to the late-luteal phase of the cycle. It is plausible to assume that women with LLPDD are vulnerable to the menstrual cycle as a Zeitgeber. In these women, a cascade of events triggered originally along the HPG axis brings about the shift from an existing vulnerability to the actual manifestations of LLPDD and other forms of female-specific mood disorders. The degree of vulnerability becomes apparent at puberty when girls are exposed to increasing estrogenic influences. Particularly vulnerable times are the periods that mark shifts in the reproductive stages (menarche, the premenstruum, puerperium, and menopause), periods associated with major hormonal turmoil and psychosocial stresses. A conditioning-sensitization model has been described to explain the longitudinal course of affective disorders, and it also has been proposed for PMS. According to this model, even low levels of psychosocial stress are capable of triggering episodes of dysphoria in vulnerable previously sensitized subjects. LLPDD is associated strongly with a lifetime diagnosis of major depression, and the concurrent comorbidity in these women is also high. Future epidemiologic studies on depression should consider the effects of female-specific Zeitgeber on mood disorders in the populations studied.


A retrospective of normal oral healthcare procedures vs. power brush/jet lavage with a corroborative study.

The efficacy of power brushes and/or oral irrigating devices in comparison to manual brushing has been the subject of study and controversial results for some thirty years. Recently, a well-designed study has reported that carefully taught, consistently reinforced and monitored toothbrushing combined with necessary professional intervention is as effective as power brushing with and without oral lavage. Because the usual individual in the work-a-day world cannot or will not indulge regularly in these elaborate procedures, a simple, small sample test of comparative efficacy was done and submitted to a paired analysis. Results demonstrated that not only are these power devices as good as demonstrated by the reported studies, but also are superior for the type of patient most often encountered in daily practice--the person who does not or who cannot comply completely with instructions and who cannot constantly be monitored for compliance.


Treatment of adult acute leukemia.

The epidemiology, etiology, pathophysiology, classification, and clinical appearance of adult acute leukemia are reviewed, and treatment strategies are discussed. Some 18,000 Americans die of leukemia each year, with acute leukemia account for half of these deaths. The etiology of acute leukemia is unknown, but current theories propose that the disease is caused by environmental factors acting on a genetically susceptible host. Acute leukemia occurs when a single hematopoietic precursor cell undergoes neoplastic transformation; autonomous proliferation of the leukemia clone continues until the patient dies of infection or bleeding. Acute leukemias are broadly classified as myelogenous and lymphocytic on the basis of cell lineage. Signs and symptoms are related to infiltration of the bone marrow by leukemic cells and the resultant failure of normal hematopoiesis. Therapy for acute myelogenous leukemia includes remission induction and consolidation with an array of antineoplastic agents. Allogeneic or autologous bone marrow transplantation is the therapy of choice for eligible patients in the first complete remission. Neither low-dose maintenance therapy nor prophylaxis for CNS involvement is indicated. Therapy for acute lymphocytic leukemia includes induction, consolidation, maintenance, and CNS prophylaxis. Allogeneic bone marrow transplantation should be reserved for standard-risk patients in second or subsequent complete remission and for high-risk patients in first remission. Intensive combination chemotherapy and bone marrow transplantation have improved the outlook for many adult patients with acute leukemia.


Improved diagnostics: clinical evaluation of a color-coded, polymeric periodontal probe.

The objective of this study was to compare the accuracy, reproducibility and patient comfort of a newly designed, color-coded, polymeric periodontal probe to a traditional, color-coded metal probe. Twenty-four adult subjects with varying degrees of periodontal disease (from slight to severe) reported for two visits, one week apart. A randomization schedule for probe use was adopted over the two visits so that the gingival crevices in two quadrants were probed with the same probe (metal or polymeric) providing reproducibility information for each probe, while the other two quadrants were probed first with one probe then the other for comparison data yielding information on accuracy. A bleeding index was obtained using the same schedule. Clinical scoring was performed by the same examiner. After probing each quadrant, subjects rated discomfort using a visual analog scale (VAS). Results showed no significant difference in depth readings greater than 2 mm between the polymeric and metal probes (3.41 +/- 0.37 mm vs. 3.38 +/- 0.32 mm, p = 0.55). Significantly less discomfort (assessed by VAS) was recorded by patients after polymeric probe use (3.70 +/- 2.40 cm vs. 4.44 +/- 2.49 cm, p = 0.015). The bleeding index indicated significantly less bleeding with the polymeric probe (0.80 +/- 0.56 vs. 1.24 +/- 0.65, p = 0.0001). Both the polymeric and metal probes were found to produce highly reproducible results in all measures across visits.


Dapsone-induced methemoglobinemia and hemolytic anemia.

The treatment of two common adverse effects of dapsone (methemoglobinemia and hemolytic anemia) is discussed, and a case of acute dapsone intoxication is described. A pregnant 29-year-old woman was admitted to an emergency room three hours after ingesting 50 tablets of dapsone (100 mg each) and six alcoholic drinks. One hour after admission 50 g of activated charcoal was given p.o., and 65 mg of methylene blue was given i.v. The patient was found to have a methemoglobin concentration of 25.1%. Arterial blood gases while the patient was breathing 4 L/min of oxygen by nasal cannula were PO2, 136 mm Hg (72.1% saturation); PCO2, 28.9 mm Hg; bicarbonate content, 18.9 mmol/L; and pH, 7.42. Oxygen therapy was changed to 100% oxygen by face mask, 50 g of activated charcoal in sorbitol was administered p.o., and another 65 mg of methylene blue was given i.v. Two more 50-g doses of activated charcoal in sorbitol were given (18.5 and 22 hours after dapsone ingestion). Methylene blue 130 mg was given 14 hours after dapsone ingestion, and 65 mg was given 21, 36, and 55.5 hours after ingestion. Methemoglobin concentrations never rose above 20% after the sixth dose of methylene blue. On hospital days 2 and 3, laboratory values were consistent with a diagnosis of hemolytic anemia; the patient received two units of packed red blood cells. The hematocrit decreased over the next three days to 23.9%, and the patient received four units of packed red blood cells.(ABSTRACT TRUNCATED AT 250 WORDS)


A clinical study on the control of dental plaque using an electronic toothbrush with piezo-electric element.

A double-blind clinical study was conducted to compare the plaque-removing efficiency of a newly designed electronic toothbrush to that of a placebo, conventional toothbrush. Twenty-six students were selected at Asahi University, School of Dentistry in Japan. The subjects were divided into two groups, one which used the electronic toothbrush and the other which used the placebo toothbrush. The subjects served as their own control by brushing manually for 3 minutes. The plaque elimination ratio, however, showed no significant difference between the testing and the control group. The main conclusion of this study is that an electronic toothbrush is not superior to the conventional toothbrush.


Sickle-cell anemia: a case report and literature review.

Sickle-cell disease is characterized by the pathophysiological features of chronic hemolytic anemia, vaso-occlusion resulting in ischemic tissue injury and painful episodes. The organs at greatest risk are the spleen, kidney and bone marrow, where oxygen tension is low and blood flow is diminished. However, disease may also present in the mandible. The oral manifestations and radiographic findings of a sickle cell patient with a left mandibular neuropathy, along with dental management guidelines are presented in the context of interdisciplinary care.


Effectiveness of three mouthrinses to inhibit acid formation by dental plaque under home-use conditions.

A study was conducted to assess the effectiveness of three mouthrinses (Plax, Cepacol and Fluordent) to inhibit acid formation from plaque collected from 21 volunteer dental students. Plaque was collected on each side of the mouth, two hours after breakfast, once-a-week, after a period of 48 hours without any oral hygiene other than the use of the mouthrinses. Initial pH and the change in pH of plaque incubated with sucrose were recorded up to 120 min. Excepting Cepacol for the first week only, no inhibitory effect on acid formation was observed.


The role of upper airway anatomy and physiology in obstructive sleep apnea.

Research efforts to date have determined that both anatomic and physiologic variables may contribute to the pathophysiology of OSA. Whether specific factors within either of these two categories will be shown to predominate remains to be seen. Surely, experience with sleep apnea patients teaches us that different variables are important in different OSA patients. However, even those patients who initially appear to have predominantly an anatomic or physiologic cause of their OSA often fail to respond to specific treatment. Treatment failure implies the following: (1) The initial impression of the importance of a given variable was wrong. This may happen in the patient who has a narrow transpalatal airway and fails to respond to uvulopalatopharyngoplasty. In this individual, physiologic variables such as pharyngeal collapsibility or periodic breathing may need to be addressed. Of course, the reverse may occur; patients may be treated pharmacologically for an assumed physiologic mechanism and important anatomic factors may have been overlooked. Our ability to differentiate the importance of these different variables is poor. Therefore, our diagnostic acumen needs further refinement. (2) Of course, it is likely that the proper diagnosis was made, but the therapy chosen was imperfect. In the area of anatomy, investigators are just beginning to try surgical approaches designed specifically for the pharyngeal site of obstruction. In other words, uvulopalatopharyngoplasty is not the best approach for everyone. In physiology, treatments beyond continuous positive airway pressure will be needed. It is hoped that advances in the pharmacology of sleep disorders will establish more convenient and successful therapies. It is likely that OSA is a heterogenous disease process. We must realize that a treatment that helps one patient may not be applicable to the next individual. Through a better understanding of the pathophysiology of OSA, better treatment modalities should be developed, resulting in improved quality of life for OSA patients.


Upper airway imaging in relation to obstructive sleep apnea.

A variety of imaging techniques have been used to assess upper airway size and function in patients with OSA. Each technique has certain advantages and limitations. Many of the imaging techniques study awake and upright patients, whereas OSA typically occurs while the patient is asleep in the supine position. Upper airway imaging may identify specific upper airway abnormalities that cause OSA. Furthermore, the majority of patients with OSA have a narrow and more collapsible airway in the velopharynx. Upper airway occlusion during sleep usually starts in the velopharynx and extends caudally. Obesity results in both extrinsic upper airway narrowing and soft tissue enlargement. Upper airway edema may occur secondary to OSA and subsequently exacerbate the OSA by causing further upper airway narrowing. Upper airway imaging provides some insights into the mechanism of action of certain treatments and is increasingly used to help direct treatment. Weight loss reduces upper airway collapsibility. Nasal CPAP increases upper airway size and reduces upper airway edema. UPPP enlarges the oropharynx and reduces upper airway collapsibility. Patients with a narrow upper airway, particularly relative to tongue size, have a good response to UPPP.


Evaluation of daytime sleepiness.

In summary, the evaluation of the tired patient requires an awareness of the various meanings of tiredness. Furthermore, it is important to differentiate normal sleepiness that is a product of circadian rhythm variation in vigilance from pathologic sleepiness. Sleepiness that results from faulty habits, e.g., altered sleep scheduling, drugs, or sleep restriction, can be readily discerned with the aid of a sleep-wake diary. Because subjective sleepiness is often unappreciated, especially in patients with sleep apnea, methods that rely on self-ratings of the severity of sleepiness, e.g., visual analogue scale, 10-cm line, or SSS may not coincide with performance tasks, observer assessments, or such physiologic methods as the MSLT. Less commonly employed neurophysiologic methods include pupillometry and averaged evoked potentials. On the other hand, the MSLT is commonly used for the detection of physiologic sleepiness. Moreover, it is helpful in evaluating response to treatment. A variation of the MSLT, the MWT, which instructs the individual to remain awake, does not discriminate between sleep onset times for wakefulness and the MSLT for sleepiness in normal subjects. The MWT may be useful for the assessment of treatment responses for excessive daytime sleepiness, e.g., narcolepsy, and for determining the frequency of daytime sleep episodes. The differences that have been observed between behavioral measures and physiologic measures of sleepiness suggest that these techniques assess different aspects of sleepiness. HLA typing (DR2, DQw1) has been shown to be a useful method for corroborating narcolepsy-cataplexy, but the antigens are neither specific for the disorder nor for sleepiness alone.


Driving performance and automobile accidents in patients with sleep apnea.

Patients with untreated obstructive sleep apnea have poorer driving performance than patients without sleep apnea. This poor driving has been demonstrated by studies on a wide variety of driving simulators. Patients with sleep apnea show a significant improvement in driving performance after successful treatment of their apnea with nasal CPAP. After treatment with CPAP, their driving performance is similar to control subjects. Several studies show that patients with untreated sleep apnea are poor drivers and have two to three times more auto accidents than other drivers. These studies reveal that almost one quarter of these patients report frequently falling asleep while driving. Patients with severe sleep apnea or those who perform poorly on driving simulators may be at highest risk of auto accidents. Automobile accidents involving patients with sleep apnea may lead to severe injury or death. Patients, individual physicians, and the medical profession have responsibilities to help prevent these accidents. Finally, more study is needed to improve patient care, protect drivers, and formulate a fair and rational policy concerning drivers with sleep apnea.


Hypertension, cardiac arrhythmias, myocardial infarction, and stroke in relation to obstructive sleep apnea.

The cyclical changes in heart rate and systemic blood pressure that accompany apneic events are predominantly mediated by fluctuations in the activity of the autonomic nervous system. Increased vagal efferent parasympathetic activity is responsible for the cyclical reductions in heart rate during apnea. In contrast, the cyclical elevations in systemic blood pressure are believed to result from recurrent peripheral vasoconstriction mediated by repetitive activation of the sympathetic nervous system. Maximal activation and pressures coincide with apnea termination and brief arousal from sleep. These cyclical elevations in systemic pressure during sleep increase ventricular workload and, thereby, may contribute to the development of ventricular hypertrophy. Systemic hypertension is present during wakefulness in approximately 50% of patients with OSA. Although age and obesity are the predominant risk factors for diurnal hypertension, OSA probably makes an independent contribution in younger obese men. Sinus bradycardia, Mobitz type 1 second-degree heart block, and prolonged sinus arrest have all been documented in association with the apneic events. Increased ventricular ectopy has been observed with oxyhemoglobin desaturations below 60%. Myocardial ischemia, infarction, sudden death, and stroke all demonstrate similar circadian variations in time of onset. Peak frequencies occur between 6 AM and noon, generally within several hours of awakening. Although sleep is associated with decreased frequencies of these adverse cardiovascular events in the general population, evidence exists linking REM sleep to an increased risk of myocardial ischemia. In men who habitually snore, epidemiologic data have detected an increased risk for ischemic heart disease and stroke. Habitual snoring has also been associated with an increased risk of sudden death during sleep. In patients with clinically significant OSA, there is reasonable information indicating excessive mortality in the absence of treatment. This mortality is predominantly cardiovascular and tends to occur during sleep.


Right and left ventricular functional impairment and sleep apnea.

Obstructive sleep apnea may contribute to the development of pulmonary hypertension and RVF primarily through pulmonary vasoconstriction secondary to hypoxia. Several recent studies indicate, however, that intermittent apnea-related hypoxia is not sufficient to cause sustained pulmonary hypertension. These studies have been consistent in showing that pulmonary hypertension and RVF are almost invariably seen in the presence of diurnal hypoxia. Sustained pulmonary hypertension, therefore, appears to be associated with sustained hypoxia as is the case in COPD. Patients with OSA who have hypoxia while awake are, as a rule, obese and have mild-to-moderate diffuse obstructive airways disease. Thus, most cases of pulmonary hypertension in association with OSA result from a combination of OSA, obesity, and diffuse obstructive airways disease, a so-called overlap syndrome. However, from the therapeutic viewpoint, it is apparent that treatment of OSA by NCPAP or tracheostomy, in such cases, is usually sufficient to reverse pulmonary hypertension and RVF. More recent work has provided strong evidence that OSA can play a role in the pathogenesis of LV heart failure in patients with CHF of otherwise unknown etiology. It is likely that this occurs through a combination of increased LV afterload related to exaggerated negative Pit swings during obstructive apneas, to intermittent hypoxia, and to chronically elevated sympathoadrenal activity. Reversal of OSA by NCPAP in these patients may relieve LV heart failure. These findings add a new dimension to our understanding of the pathophysiologic effects of OSA on the cardiovascular system by demonstrating that the LV is a structure that may suffer functional impairment secondary to the stresses imposed by OSA. Finally, it has now become apparent that CSR in patients with CHF can cause symptoms of a sleep apnea syndrome when associated with intermittent hypoxia and arousals from sleep. Reversal of CSR during sleep by NCPAP can lead to alleviation of these symptoms and possibly to reduced cardiac dyspnea and LV systolic function as well. Taken together, this suggests that much more extensive use of polysomnography may be warranted in the investigation of cardiovascular disease. The reasons are compelling: sleep apnea disorders are common and eminently treatable conditions whose reversal can result in improved right and left heart function and symptomatic improvement in patients with impaired myocardial function.


Management of obstructive sleep apnea.

Although the indications for treatment of obstructive sleep apnea are controversial, there is general agreement that treatment is warranted in patients with a combined apnea and hypopnea frequency of 20 events per hour of sleep. General therapeutic measures include abstinence from alcohol and weight loss in obese patients. A minority of patients with specific abnormalities of the nose, pharynx, or jaw may require surgical management. In the absence of specific upper airway abnormalities, the most effective treatment is nasal continuous positive airway pressure or, if necessary, bilevel positive airway pressure during sleep. The role of uvulopalatopharyngoplasty remains controversial, due in part to the reported variability in long-term efficacy of this procedure. Drug therapy may be effective in selected patients.


Central sleep apnea.

The critical issue in considering the diagnosis and management of CSA is to determine the physiologic process underlying the disorder. CSA includes a pathophysiologically and clinically heterogeneous group of disorders that can be divided into two main groups on the basis of the awake PaCO2: a hypercapnic group, in whom the disorder is related to central alveolar hypoventilation or neuromuscular disease, and a nonhypercapnic group, in whom there is no identifiable underlying disorder. The common feature of these two groups is recurrent episodes of central apnea during sleep related to withdrawal of the wakefulness drive to breathing. In the hypercapnic group the clinical history is dominated by recurrent episodes of respiratory failure and its complications, with the sleep disturbance being a secondary feature. CSA in these patients is simply an exaggeration, by sleep, of their hypoventilation disorder. Treatment in most cases involves mechanical assisted ventilation during sleep, which can be very effective in reversing CSA and respiratory failure. In contrast, idiopathic CSA is characterized by a tendency to hyperventilation. This tendency is reinforced during sleep by recurrent arousals, which tend to propagate the CSA. Unlike hypercapnic CSA, idiopathic CSA is a relatively benign condition in which cardiorespiratory failure is not a feature. Treatment of this disorder is problematic, but the use of nocturnal nasal CPAP appears to be quite effective.


Hypoventilation: neuromuscular and chest wall disorders.

Patients with neuromuscular and chest wall disorders are vulnerable at night when alterations in ventilatory mechanics and control associated with their disease are imposed on the changes in mechanics and control associated with sleep. The physiologic and clinical consequences of these events may be reversed by nocturnal mechanical ventilatory support.


Nocturnal hypoxemia in patients with chronic obstructive pulmonary disease.

Marked hypoxemia occurs during REM sleep in patients with chronic obstructive pulmonary disorder. This article deals with the mechanisms, pathophysiologic consequences, and treatment of REM hypoxemia.


Nocturnal asthma.

The nocturnal worsening of asthma is a common problem that can have significant related morbidity and mortality. There are many circadian biologic rhythms that contribute to the increased nocturnal bronchial reactivity and decrement in lung function. Therapy directed at the nocturnal aspect of this asthma process can produce marked improvement in symptoms and lung function.


Use of the laboratory in infertility and recurrent spontaneous miscarriage.

The laboratory is an important contributor to patient evaluation for infertility or recurrent spontaneous miscarriage. Hormonal determinations, cultures for microorganisms, andrology tests, immunologic tests, karyotype analysis, and histopathology are valuable components of laboratory evaluation. The use of clinical laboratory tests must be integrated with other clinical and radiologic studies.


In vitro fertilization. Technology and methods.

The laboratory component of assisted reproductive technologies involves the manipulation and culture of male and female gametes in vitro, with the goal of producing viable embryos for transfer to a woman to enable the establishment of pregnancy. The biology of the gametes and resulting embryos dictates how they should be handled in vitro to maximize their potential at establishing a viable pregnancy. This article examines the biology of gametes and offers some suggestions as how best to proceed with the process of in vitro fertilization, embryo culture, and embryo transfer.


The technology, law, and ethics of in vitro fertilization, gamete donation, and surrogate motherhood.

This article examines some of the legal, ethical, and policy issues raised by the development and use of technologies for noncoital reproduction: gamete transfer and manipulation, in vitro fertilization, and zygote transfer and manipulation. After briefly describing these technologies, this article examines three closely related concerns raised by their introduction: (1) the effect of new technologies on the social understanding of parenthood and the legal regulation of the family; (2) the impact on women and children of a market in the material and services for producing children; and (3) the rights and interests involved in conflicts over the control and disposition of extrauterine embryos.


Linkage analysis and predicting genetic disease.

Linkage analysis is an important and clinically applicable method of predicting risk for genetic disorders and traits. When a gene cannot be detected directly, evaluation of a closely linked marker may be used in risk assessment. This review of linkage analysis provides basic information and examples of the application of these methods in genetic counseling situations.


Prenatal genetics in laboratory medicine. A cytogeneticist's perspective.

A concise review of current trends in prenatal genetic diagnosis for the nongeneticist is presented in this article. Its impact on the practice of clinical laboratory medicine today is discussed, and an attempt is made to capture the sense of the growing body of knowledge and excitement in prenatal genetic diagnostic technology, and the fountain of possibilities it has created for prenatal care.


What can be learned from cordocentesis?

Cordocentesis is a well-accepted procedure that is widely practiced by experienced perinatologists. Its facile and safe access to the fetal circulation has broadened the spectrum of congenital disorders diagnosed prenatally. Some fetal disease states can now be identified and treated earlier, directly, more quickly, and more effectively than before, resulting in improved patient care. Although cordocentesis has been embraced by the perinatal community, it is, by definition, a technique of obtaining a fetal blood sample. A prerequisite for the procedure to exert its full impact on perinatal care is a highly capable clinical laboratory. The facility must be aware of the commonly requested fetal serologic, hematologic, and serum chemistry studies, as well as their normal values. Efforts must be made to perform fetal blood studies rapidly and reliably on small specimens. Laboratory personnel should be familiar with the indications and pitfalls of these tests and those that are best referred to a specialty laboratory. A general understanding of the perinatologist's needs and concerns will lead to a cooperative working relationship between clinician and laboratory. In this manner, we will truly discover what can be learned from cordocentesis.


Laboratory diagnosis of fetal infections.

In utero infections of the fetus can lead to significant morbidity and mortality in the newborn child. The signs and symptoms of clinical disease, however, do not always suggest a given pathogen. The laboratory must be able to provide an early and accurate diagnosis of the causative agent so that prompt and appropriate antimicrobial therapy and medical care can be initiated. The scope of this article includes the methods employed by the laboratory to assist in the diagnosis of bacterial, fungal, parasitic, and viral infections of the fetus. Where appropriate, detection methods were addressed for the diagnosis of the major pathogens responsible for infection during the birth process.


Maternal immunity to red cell antigens and fetal transfusion.

This article has presented an overview of developments in the treatment of HDN. The number of cases requiring treatment that have occurred in the last decade has dropped because of the development and implementation of Rh immunoprophylaxis, although this treatment still appears to be underutilized in the United States. Failure to recognize the need for immunoprophylaxis in certain situations (including unrecognized abortion) has led to a small residual population of alloimmunized mothers who will require comprehensive treatment during subsequent pregnancies. Alloimmunization to other red cell antigens remains a small but significant problem in other women. Although great advances have been made in the monitoring of these pregnancies, amniotic fluid analysis remains a mainstay for the third-trimester evaluation of alloimmunized pregnancies. Noninvasive methods such as ultrasound evaluation and the monocyte assays may supplement, but cannot entirely replace, the need for direct assessment. The most striking advancement in the evaluation and treatment of these infants has been the ability to access the fetal circulation directly through intravenous umbilical cord sampling. This method allows for an immediate assessment of fetal anemia as well as a route for direct fetal transfusion. The method has also permitted a more complete assessment of fetal physiology. However, the method may be overutilized at the present time and has some degree of risk to the fetus, even in experienced hands. Additional methods of treatment for the alloimmunized pregnancy include plasma exchange, intravenous immunoglobulin infusion, and promethazine hydrochloride. The popularity of plasma exchange has probably decreased with the advent of more direct fetal sampling and treatment techniques, but it may be useful in the treatment of first-trimester pregnancy losses. Intravenous immunoglobulin and promethazine hydrochloride appear to be promising alternatives that require more investigation. It is apparent that efforts need to be channeled towards prevention of HDN in a health system that is highly aware of increasing costs and the benefits of preventive medicine.


Neonatal alloimmune thrombocytopenia.

Neonatal alloimmune thrombocytopenia is caused by the transplacental passage of maternal antibodies directed against platelet-specific antigens. Because complications from bleeding may result, prompt institution of therapy may be necessary. Accurate diagnosis by serologic techniques permits appropriate therapy to be administered both prenatally and postnatally.


Hemapheresis in pregnancy.

Plasma exchange in pregnancy has benefited those diseases that occur and are treated in the nonpregnant patient. In addition, special emphasis was given to diseases unique to pregnancy, such as hemolytic disease of the newborn, which is significantly modified by plasma exchange therapy. Fluid volumes, replacement solution, and techniques were discussed.


Assessment of fetal lung maturity by laboratory methods.

I have reviewed many of the methods available for the assessment of fetal lung maturity. The difficulty of using diagnostic tests for diseases of low prevalence has been discussed. By reviewing the nature of the amniotic fluid surfactant material, and some of the principles underlying analytical methods, the bases of some of the recurring methodologic problems have been pointed out. It is concluded that a number of reasonably straightforward tests will provide information of essentially the same utility as more costly, difficult, and time-consuming assays commonly employed.


An initial comparison of intensive care in Japan and the United States.

The objective of this study was to compare the utilization of, and outcome from, critical care services in selected medical centers providing secondary and tertiary care in the United States and Japan. Prospective data collection on 1,292 patients from each of the participating Japanese study hospitals in 1987 to 1989 and compared with the 5,030 patients in the United States 1982 Acute Physiology and Chronic Health Evaluation (APACHE II) database used to develop the APACHE II equation. Detailed organizational characteristics of the participating ICUs and hospitals were also obtained. Data collection took place in the ICUs of 13 U.S. hospitals and six Japanese hospitals. Data were collected on consecutive, unselected patients from medical, surgical, and mixed medical/surgical critical care units, with a spectrum of medical and surgical diagnoses. U.S. and Japanese ICUs have a similar array of diagnostic and therapeutic modalities. Only 2% (range 0.6 to 3.5) of beds in Japanese hospitals were designated to intensive care. The organization of the Japanese and U.S. ICUs varied by hospital. There were significantly fewer women admitted to Japanese ICUs and a substantially lower proportion of low-risk-of-death patients. Despite a rapidly aging population, there were relatively fewer elderly patients with chronic health ailments in the Japanese ICU population (8%) compared with the U.S. cohort (18%). In this sample of hospitals, similar high-technology critical care is available in the United States and Japan. Variations in utilization between the two countries represent differences in case mix and bed availability. The APACHE II equation stratified patients in the Japanese patient cohort across the full spectrum of increasing severity of illness.


Use of extracorporeal life support in patients with congenital heart disease.

To review a large experience with extracorporeal life support in patients with congenital heart disease. To determine the major causes of mortality and morbidity in order to improve the results of using this technology in this patient population. Retrospective chart review. Twenty-five patients between the ages of 1 day and 8 yrs. These patients had congenital heart disease and were clinically felt to be at high risk for death caused by cardiac failure or by respiratory failure complicated by congenital heart disease. All patients in this report were placed on extracorporeal life support to allow recovery of myocardial or pulmonary function. Of these 25 patients, 52% were weaned from bypass support and 40% survived to discharge. Patients who were not weaned from extracorporeal life support characteristically suffered from irreversible neurologic injury, multiple organ failure, or bleeding complications. Only one patient died of irreversible cardiac failure. Extracorporeal life support can be useful in supporting patients with congenital heart disease with life-threatening cardiac or pulmonary failure. Improvements in limiting neurologic and bleeding complications may lead to improvements in the use of extracorporeal life support for this indication. However, prospective, randomized studies are needed to appreciate the role of extracorporeal life support in these patients.


Acute hypoxemic respiratory failure in infants and children: clinical and pathologic characteristics.

To examine the clinical and pathologic features of acute hypoxemic respiratory failure in children. Retrospective review of medical records and pathologic material during a 44-month period. Multidisciplinary pediatric ICU. With the assistance of a computerized database, the medical records of 2,254 pediatric ICU admissions were evaluated to identify children with respiratory failure. Children with acute hypoxemic respiratory failure who met the following definition were selected for inclusion: a) PaO2 less than 75 torr (less than 10.0 kPa) with an FIO2 of greater than 0.5; b) diffuse bilateral infiltrates on chest radiograph; and c) exclusion of cardiogenic pulmonary edema clinically or by pulmonary artery catheterization. Patients were excluded if they did not receive tracheal intubation and assisted ventilation. The medical records were reviewed for demographic, clinical, and physiologic information. Pathologic findings from autopsy or lung biopsy were also reviewed. Patients were placed in one of six groups based on their underlying disorder. In addition, the presence of neutropenia, septic shock, or a history of bone marrow transplantation was noted as a coexisting condition. A total of 100 acute hypoxemic respiratory failure patients were identified (4.4% of all 2,254 pediatric ICU admissions; 50 male, 50 female). Mean age was 6.0 +/- 5.4 (SD) yrs (range 1 month to 18 yrs). The overall mortality rate was 72%. The mortality rate was not affected by the underlying disorder, but it was higher in the presence of septic shock (80% vs. 58%; odds ratio 2.8), neutropenia (88% vs. 64%; odds ratio 4.0), and bone marrow transplantation (95% vs. 66%; odds ratio 10.4). When multivariate regression analysis was performed using all coexisting conditions, human immunodeficiency virus status, and patient gender, only a history of bone marrow transplantation and gender appeared to affect outcome. Oxygenation ratio (PaO2/FIO2), alveolar-arterial oxygen tension difference, duration of exposure to high levels of oxygen, and airway pressure measurements indicated more severe derangement of pulmonary function in those patients who died. Cardiac function was similar in survivors and nonsurvivors. Respiratory failure occurred in 32 children with severe neutropenia (mean absolute neutrophil count 55 +/- 101 cells/mm3), including 16 children with an absolute neutrophil count of 0. Pulmonary tissue from 37 children was studied. Diffuse alveolar damage was observed in 24%; morphologic evidence of infectious pneumonitis was encountered in an additional 41%. Children with acute hypoxemic respiratory failure represent a heterogeneous subset of patients. In our group of patients, infectious pneumonitis was more commonly encountered than diffuse alveolar damage. The mortality rate of children with acute hypoxemic respiratory failure has not improved since 1980.


Effects of tolazoline and prostacyclin on pulmonary hypertension in infants after cardiac surgery.

To evaluate the hemodynamic effects of tolazoline and prostacyclin in infants with pulmonary vasospasm after cardiac surgery. Prospective cohort study. Pediatric ICU. The cohort consisted of 42 infants and children with congenital heart disease and pulmonary hypertension who underwent corrective surgery and were monitored postoperatively using pulmonary artery catheters. Fourteen infants (2 to 12 months old) in this group required postoperative treatment with tolazoline or prostacyclin. Tolazoline was administered as a bolus of 0.5 mg/kg for treatment of persistent pulmonary hypertension or acute pulmonary hypertensive crisis. If its effectiveness was proved after 30 mins by hemodynamic measurements, a continuous iv infusion of 0.5 mg/kg/hr was established. Higher doses of tolazoline were avoided. If tolazoline treatment did not fulfill the criteria for pulmonary vasodilation, prostacyclin was given by continuous iv infusion at a starting rate of 5 ng/kg/min, followed by 10 ng/kg/min. In three patients, the infusion rate was increased to 15 ng/kg/min. Bolus administration of tolazoline resulted in a distinct pulmonary vasodilation in seven infants: mean pulmonary artery pressure and pulmonary vascular resistance decreased by an average of 35% and 45%, respectively. In these patients, tolazoline was infused over the following 12 to 72 hrs. One infant who received tolazoline for 72 hrs developed a clinically important gastrointestinal hemorrhage. In seven nonresponders to tolazoline, prostacyclin (PGI2) at an infusion rate of 5 ng/kg/min led to pulmonary vasodilation in five patients, at an iv infusion rate of 10 ng/kg/min in all seven infants studied. The latter dose of PGI2 reduced the mean pulmonary artery pressure by an average of 37%, and pulmonary vascular resistance by 43%. Transient withdrawal of prostacyclin in five infants demonstrated its short half-life and clinical effectiveness. Apart from a facial flush, no side-effects were encountered using PGI2 as an infusion over durations ranging from 12 to 504 hrs. These data suggest that, if tolazoline in a relatively low dose proves to be inefficient, prostacyclin can still be used as a safe and effective drug for treatment of pulmonary vasospasm. Prostacyclin offers more than a pharmacologic alternative to increased tolazoline dosages.


Relationship between infusion rates, plasma concentrations, and cardiovascular and metabolic effects during the infusion of norepinephrine in healthy volunteers.

To determine the relationship between iv infusion rate, plasma concentrations, and hemodynamic and metabolic actions of norepinephrine. Norepinephrine was administered by using five iv infusion rates (0.01 to 0.2 micrograms/kg/min) for 30 mins each to eight volunteers, for the purpose of constructing cumulative plasma concentration-response curves. Laboratory of the Department of Anesthesiology at a university hospital. Systolic and diastolic BP, heart rate, and the plasma concentrations of norepinephrine, glucose, nonesterified fatty acids, and insulin were measured at the end of each infusion rate. During the highest infusion rate, plasma norepinephrine concentrations increased from 199 +/- 75 to 7475 +/- 1071 pg/mL (1.18 +/- 0.44 to 44.18 +/- 6.33 nmol/L). Typical hemodynamic responses, such as increases in BP and decreases in heart rate, were seen, while the plasma concentrations of glucose and nonesterified fatty acids increased from 92 +/- 10 to 132 +/- 17 mg/dL (5.1 +/- 0.6 to 7.3 +/- 0.9 mmol/L) and 11 +/- 4 to 34 +/- 6 mg/dL (0.11 +/- 0.04 to 0.34 +/- 0.06 g/L), respectively, during the 0.2 micrograms/kg/min infusion rate (p less than .05). Despite the increase in glucose concentration, insulin remained at baseline values. Metabolic and hemodynamic effects occurred at similar plasma concentrations throughout the study. Administration of norepinephrine showed no selective hemodynamic actions. The metabolic responses observed in this investigation were similar to those responses seen during increased endogenous sympathetic nervous system activity, such as stress, exercise, or trauma.


Factors related to quality of life 12 months after discharge from an intensive care unit.

To perform an analysis of the quality of life of survivors after ICU discharge. Prospective study. Medical-surgical ICU of a Spanish reference hospital. Patients (n = 606) admitted in a 6-month period. A questionnaire regarding quality of life issues was completed at the time of admission by patients or surrogates (n = 606). The questionnaire was given again 12 months after ICU discharge to 444 surviving patients. Both questionnaires evaluated the patient's ability to function and communicate for the previous 3 months. A Quality of Life score of 0 corresponded to no limitations. An increasing score indicated a reduction in function. A score of greater than 10 points implied a severe physical handicap. Information was also collected on the severity of illness and the diagnosis that prompted ICU admission. The mean Quality of Life score of all survivors worsened from a mean of 4.62 at the time of ICU admission to a mean of 6.11 at 12 months after ICU discharge (p less than .01) and was most evident for patients greater than 75 yrs of age (from a mean of 6.33 to a mean of 9.54). However, patients with the highest initial Quality of Life scores had a significant improvement at 12 months (14.61 +/- 0.50 to 12.48 +/- 0.78 points [p less than .05]). A higher severity of illness score corresponded to a higher Quality of Life score, but a multivariate analysis indicated that the factors with the greatest influence on the post-discharge Quality of Life score were the initial Quality of Life score and age. Twelve months after discharge from the ICU, a patient's functional status, as measured by the Quality of Life score, is influenced most by age and their Quality of Life score at the time of ICU admission. While there is an overall decrease in the Quality of Life score for survivors, admission and treatment in an ICU do not always result in deterioration of the Quality of Life score. This study indicates that Quality of Life scores could become a routine part of patient evaluation.


DNR or CPR--the choice is ours.

To assess changes in the terminal care of critically ill patients before and after the institution of do-not-resuscitate (DNR) order policies, and policies on the care of the hopelessly ill. Retrospective chart review that comprises the following groups: 82 consecutive deaths from 1981 to 1982, representing our older practice pattern of frequent utilization of terminal resuscitative efforts (group A); 37 consecutive deaths between June and December 1987, the 6-month period immediately preceding the adoption of the DNR policy (group B); and 61 consecutive deaths in calendar year 1988 after the DNR policy went into effect (group C). Surgical ICU of a large tertiary care center. Consecutive patients who died during the study periods before and after the implementation of a DNR policy. The implementation of hospital-wide policies on DNR orders and care of the hopelessly ill patient. There were no significant differences between the three groups for age, Acute Physiology and Chronic Health Evaluation II scores, Mortality Risk Ratio scores, or lengths of ICU stay. There was a significant (p less than .0001) decrease in the frequency of terminal resuscitative efforts, as evidenced by a decrease from 52% in group A to 3% in group C. The preterminal identification and acceptance of imminent death increased over the study period with an increase (p less than .0001) in the application of DNR orders from 46% in group A to 98% in group C. The ability to withdraw support increased (p less than .0001) from 23% in group A to 73% in group C. We believe that our data exemplify how our ICU has been able to identify hopelessly ill patients, and how it has implemented specific levels of care that take into account not only medical prognostication, but also the wishes of the patients and their families, while maintaining an atmosphere of comfort and dignity. We demonstrated an important change in the philosophy of care for hopelessly ill patients, which was associated with the institution of DNR policies.


Energy expenditure and gas exchange measurements in postoperative patients: thermodilution versus indirect calorimetry.

To compare a method of measuring energy expenditure and gas exchange using the Fick principle with the standard indirect calorimetry technique. Prospective study of a consecutive sample of postoperative patients. Oxygen consumption (VO2), CO2 production (VCO2), respiratory quotient, and energy expenditure were derived from measurements of variables, including oxygen content and cardiac output. Energy expenditure and gas exchange were measured simultaneously by continuous indirect calorimetry over a 60-min period. Surgical ICU in a university hospital. Twenty-six consecutive patients (45 to 80 yrs) who underwent sustained surgical trauma. Excluded from the study entry were patients with time-related fluctuations of hemodynamic variables, poor cooperation, patients who required supplemental oxygen, or mechanical ventilation. None. While the measurements of VO2 and VCO2 by calorimetry and thermodilution were significantly correlated with one another (for VO2, r2 = .93, p less than .001; for VCO2, r2 = .26, p less than .01), VO2 and VCO2 values by indirect calorimetry were consistently greater than VO2 and VCO2 values by the Fick method (p less than .01). The respiratory quotient calorimetric measurements ranged between 0.69 and 0.99, whereas the corresponding thermodilution measurements spread to impossible values, from 0.24 to 1.30 (0.821 +/- 0.07 vs. 0.740 +/- 0.24, p less than .05). There was an insignificant relationship (r2 = .06, p = .21) between the values of respiratory quotient by the two methods. A strong, positive correlation between energy expenditure measured by indirect calorimetry and energy expenditure measured by the Fick method was observed (r2 = .92, p less than .001). The limit of agreement between the two methods was -0.24 +/- 73 kcal/day/m2 (-1.00 +/- 305 kJ/day/m2). In postoperative patients, while VO2 and energy expenditure measurements by thermodilution are easy to perform and accurate for clinical purposes, VCO2, and respiratory quotient measurements are too imprecise and inaccurate to serve any useful function. Therefore, in those clinical situations in which an evaluation of respiratory quotient and substrate utilization may be useful for purposes of metabolic care of the surgical patient, precise measurements of gas exchange with indirect calorimetry are mandatory.


Hematologic changes in massive burn injury.

To study and report the striking hematologic changes that occur in patients with massive burn injury. Case reports and description of hematologic studies. A municipal general hospital burn unit. Three severely burned patients who survived, respectively, 45 mins, 22 hrs, and 57 hrs after hospitalization. Routine clinical hematologic laboratory studies. The patients had intravascular hemolysis, and their RBCs exhibited spherocytosis, fragmentation, and vesiculation. Numerous fragments of red cell membranes were originally present in the blood and cleared within 4 hrs. These fragments may have contributed to the renal failure seen in these patients. The patients also had marked pseudothrombocytosis, presumably owing to "incorrect recognition" by the automatic counter of red cell microvesicles as platelets. Pseudothrombocytosis should be anticipated with massive burn injury. Despite high or normal platelet counts reported by the laboratory, evidence of intravascular coagulation should be promptly investigated.


Changes in lung function and pulmonary capillary permeability after cardiopulmonary bypass.

To assess the possibility that changes in lung function following cardiopulmonary bypass are associated with increased pulmonary capillary permeability. A prospective, descriptive study. Adult cardiothoracic ICU in a post-graduate teaching hospital. Ten sequential patients undergoing cardiac surgery requiring cardiopulmonary bypass. Arterial blood gas tensions, helium dilution end-expiratory lung volume, and carbon monoxide transfer were measured by a rebreathing technique preoperatively and 2 hrs postoperatively. Lung extravascular protein accumulation index was measured by a double-isotope technique 2 hrs postoperatively and in a group of normal controls. Mean +/- SEM alveolar-arterial PO2 gradient increased from 77 +/- 14 torr (10.3 +/- 1.8 kPa) to 138 +/- 24 torr (18.5 +/- 3.2 kPa) (p less than .01). Functional residual capacity decreased by 20.2 +/- 5.6% (p less than .01). Carbon monoxide transfer decreased by 26.7 +/- 5.3% (p less than .01) for the lung as a whole and by 17.9 +/- 3.2% (p less than .01) per liter of accessible gas volume. Protein accumulation index ranged from 0.03 to 3.2 x 10(-3) (median 0.6) postoperatively (median for normal subjects 0.4; p less than .05), although only one patient had a value indicative of clinically important endothelial injury. Cardiac surgery involving cardiopulmonary bypass results in a deterioration in lung function characterized by a loss of lung volume, a reduction in carbon monoxide transfer, and an increase in the alveolar-arterial PO2 gradient. These changes do not appear to be mediated by an increase in pulmonary endothelial permeability.


Prediction criteria for successful weaning from respiratory support: statistical and connectionist analyses.

To develop predictive criteria for successful weaning of patients from mechanical assistance to ventilation, based on simple clinical tests using discriminant analyses and neural network systems. Retrospective development of predictive criteria and subsequent prospective testing of the same predictive criteria. Medical ICU of a 300-bed teaching Veterans Administration Hospital. Twenty-five ventilator-dependent elderly patients with acute respiratory failure. Routine measurements of negative inspiratory force, tidal volume, minute ventilation, respiratory rate, vital capacity, and maximum voluntary ventilation, followed by a weaning trial. Success or failure in 21 efforts was analyzed by a linear and quadratic discriminant model and neural network formulas to develop prediction criteria. The criteria developed were tested for predictive power prospectively in nine trials in six patients. The statistical and neural network analyses predicted the success or failure of weaning within 90% to 100% accuracy. Use of quadratic discriminant and neural network analyses could be useful in developing accurate predictive criteria for successful weaning based on simple bedside measurements.


Arterial pH and carbon dioxide tension as indicators of tissue perfusion during cardiac arrest in a canine model.

Previous studies have shown that Paco2 and end-tidal CO2 reflect coronary artery perfusion pressures during cardiac arrest. We investigated the relationship of coronary artery perfusion pressure to central arterial pH and Paco2 values during resuscitation from cardiac arrest in a canine model. Twenty-four mongrel dogs were block randomized to three different resuscitation groups after induction of ventricular fibrillation and cardiac arrest: a) standard cardiopulmonary resuscitation (CPR) and advanced life support (n = 8); b) cardiopulmonary bypass (n = 8); or c) open-chest CPR (n = 8). Central arterial blood gases and perfusion pressures were monitored during cardiac arrest and during resuscitation. Prearrest blood gases and hemodynamic values were similar between groups. Sixteen dogs from all three groups were successfully resuscitated. Survivors had significantly higher coronary artery perfusion pressure (p = .03), Paco2 (p = .015), and lower pH (p = .01) values than nonsurvivors. There was no correlation of pH and Paco2 during mechanical external CPR. However, after institution of the different resuscitation techniques, pH and Paco2 each showed a statistically significant correlation (r2 = .50 and .33, respectively) with coronary artery perfusion pressure. Central arterial pH and Paco2 monitoring during cardiac arrest may reflect the adequacy of tissue perfusion during resuscitation and may predict resuscitation outcome from ventricular fibrillation.


Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic injury to the central nervous system in the newborn pig.

Fructose-1,6-bisphosphate has been shown to improve the outcome of hypoxic ischemic brain injury in adult rabbits. We wished to see if these results could be extended to a newborn animal. Twenty-four 0- to 3-day-old piglets were randomized to receive 300 mg/kg of fructose-1,6-bisphosphate 5 mins before injury, followed by a continuous infusion of 15 mg/kg/min of fructose-1,6-bisphosphate for the next 90 mins, or the equivalent volume of normal saline. Hypoxic ischemic central nervous system damage was induced by ligating both carotid arteries and reducing their BP to two thirds of the normal value for 30 mins. In the last 15 mins of this 30 mins, the FIO2 was reduced to 0.6. At 30 mins, the piglets were resuscitated with an FIO2 of 1.0, the carotid ligatures were released, and the removed blood was reinfused. The neurologic examination scores at 1, 2, and 3 days after injury and pathologic examination scores at 3 days after injury were not different in the fructose-1,6-bisphosphate-treated and the control animals. Fructose-1,6-bisphosphate does not ameliorate hypoxic ischemic brain injury in the newborn pig.


Hyaluronan: relationship to hemodynamics and survival in porcine injury and sepsis.

Hyaluronan is a polysaccharide normally present in low concentrations in the blood, and is rapidly cleared from the blood by the liver. Increased plasma hyaluronan concentrations have been found in patients with sepsis. We studied changes in serum hyaluronan concentrations and their relationship to hemodynamics and survival in a 48-hr porcine model of injury and sepsis. Circulating hyaluronan concentrations increased to high values after induction of experimental sepsis (from mean baseline values of 242 +/- 26 [SEM] to mean maximum concentrations of 964 +/- 255 micrograms/L [p less than .01]) compared with controls (199 +/- 38 to 303 +/- 32 micrograms/L). A weak negative correlation between mean arterial pressure (MAP) and serum hyaluronan values was found (r2 = .47; p less than .01). Nonsurvivors had higher mean serum hyaluronan concentrations than survivors (603 +/- 147 vs. 285 +/- 43 micrograms/L [p less than .05]). Experimental sepsis is associated with an increase in serum hyaluronan values. The relationship between decreased MAP and increased serum hyaluronan concentrations could point to reduced liver perfusion as a cause. An association between high hyaluronan values and nonsurvival in sepsis is possible.


Peripheral and liver tissue oxygen tensions in hemorrhagic shock.

Hepatic dysfunction after severe hemorrhagic shock is common and may be a consequence of visceral tissue hypoxia. Peripheral tissue PO2 has been suggested to correlate with the development of visceral hypoxia. To test the hypothesis that changes in peripheral tissue PO2 reflect changes in hepatic PO2, we measured subcutaneous PO2, transcutaneous PO2, transconjunctival PO2, and liver tissue PO2, and their relationship with changes in mean arterial blood pressure (MAP) and systemic oxygen transport (DO2), during progressive bleeding in pigs (n = 23). In addition to the tissue PO2, portal vein PO2 and circulating lactate concentrations were also measured in six of the animals. The animals were anesthetized and bled to an MAP of 50 mm Hg within 1 hr. After an induced 10% reduction of MAP, only the DO2 decreased significantly (p less than .05). After a 20% reduction of MAP, the DO2 decreased further and was associated with a significant (p less than .05) reduction of all peripheral tissue PO2 values. A significant (p less than .05) reduction of liver tissue PO2 was observed later during bleeding, after induction of a 30% reduction in MAP. In the subgroup with portal venous PO2 and lactate measurements, reductions of all peripheral tissue PO2 and portal venous PO2 values occurred after a 20% reduction (p less than .05) of MAP. An increase (p less than .05) in the portal venous lactate concentration was observed after a 50% reduction of MAP, and a decrease (p less than .05) in liver tissue PO2 was noted after a 60% reduction of MAP. Reductions of both peripheral and portal venous PO2 values occur early during hemorrhage. The liver tissue PO2, though initially low, appears to be better defended, suggesting either redistribution of splanchnic blood flow or adaptation in hepatic oxygen demand.


Continuous breathing circuit flow and tracheal tube cuff leak: sources of error during pediatric indirect calorimetry.

To determine whether continuous gas flow in the breathing circuit or an airleak around the tracheal tube cuff will introduce errors into the measurement of oxygen consumption (VO2) with indirect calorimetry. Nonrandomized, controlled trial. Experimental laboratory. Ten healthy, anesthetized mongrel dogs, weighing 8 to 12 kg. Data were recorded at seven levels of flow, from 0 to 12 L/min in excess of minute ventilation, through a continuous breathing circuit. Data were recorded at five levels of tracheal tube cuff leak from 0% to 40% of inspiratory minute volume. VO2 was measured using an indirect calorimeter with constant internal gas flow and calculated from results of blood gas analysis, cooximetry, and thermodilution cardiac output determinations at all levels of continuous breathing circuit flow and cuff leak. BP, heart rate, respiratory rate, arterial and mixed venous blood gases, and body temperature were measured to assess stability of cardiopulmonary function. Continuous breathing circuit flow did not affect the accuracy of indirect calorimetry until the total flow reached a critical value (11.5 L/min) that was slightly below the internal flow constant of the metabolic monitor (12.4 L/min). At higher circuit flows, measured VO2 decreased in a linear fashion, while calculated VO2 remained unchanged. Above the critical flow, the error of indirect calorimetry correlated significantly only with the total circuit flow (r2 = .64), not with the exhaled concentration of CO2 (r2 = .005) or the inspiratory-expiratory oxygen difference (r2 = .004). The continuous flow rate at the critical circuit flow was 66 +/- 15% of the subjects' peak inspiratory flow. Increasing tracheal tube cuff leak produced a progressive decrease in measured VO2 but not in calculated VO2. The difference between measured and calculated VO2 was linearly related to the magnitude of the leak (r2 = .56), and was statistically significantly larger at all levels of cuff leak, when compared with measurements during complete cuff seal. An indirect calorimeter in which measurement of VO2 is based on internal constant flow rather than spirometry can be used to accurately measure VO2 from a continuous-flow breathing circuit, if the total circuit flow is less than the internal flow. This limitation may restrict the use of continuous flow to a level below the subject's peak inspiratory flow. The accuracy of indirect calorimetry cannot be guaranteed for any amount of tracheal tube cuff leak.


Aldehyde dehydrogenases and their role in carcinogenesis.

Aldehydes are highly reactive molecules that may have a variety of effects on biological systems. They can be generated from a virtually limitless number of endogenous and exogenous sources. Although some aldehyde-mediated effects such as vision are beneficial, many effects are deleterious, including cytotoxicity, mutagenicity, and carcinogenicity. A variety of enzymes have evolved to metabolize aldehydes to less reactive forms. Among the most effective pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). ALDHs are a family of NADP-dependent enzymes with common structural and functional features that catalyze the oxidation of a broad spectrum of aliphatic and aromatic aldehydes. Based on primary sequence analysis, three major classes of mammalian ALDHs--1, 2, and 3--have been identified. Classes 1 and 3 contain both constitutively expressed and inducible cytosolic forms. Class 2 consists of constitutive mitochondrial enzymes. Each class appears to oxidize a variety of substrates that may be derived either from endogenous sources such as amino acid, biogenic amine, or lipid metabolism or from exogenous sources, including aldehydes derived from xenobiotic metabolism. Changes in ALDH activity have been observed during experimental liver and urinary bladder carcinogenesis and in a number of human tumors, including some liver, colon, and mammary cancers. Changes in ALDH define at least one population of preneoplastic cells having a high probability of progressing to overt neoplasms. The most common change is the appearance of class 3 ALDH dehydrogenase activity in tumors arising in tissues that normally do not express this form. The changes in enzyme activity occur early in tumorigenesis and are the result of permanent changes in ALDH gene expression. This review discusses several aspects of ALDH expression during carcinogenesis. A brief introduction examines the variety of sources of aldehydes. This is followed by a discussion of the mammalian ALDHs. Because the ALDHs are a relatively understudied family of enzymes, this section presents what is currently known about the general structural and functional properties of the enzymes and the interrelationships of the various forms. The remainder of the review discusses various aspects of the ALDHs in relation to tumorigenesis. The expression of ALDH during experimental carcinogenesis and what is known about the molecular mechanisms underlying those changes are discussed. This is followed by an extended discussion of the potential roles for ALDH in tumorigenesis. The role of ALDH in the metabolism of cyclophosphamidelike chemotherapeutic agents is described. This work suggests that modulation of ALDH activity may an important determinant of the effectiveness of certain chemotherapeutic agents.(ABSTRACT TRUNCATED AT 400 WORDS)


Glutathione transferases and cancer.

The glutathione transferases, a family of multifunctional proteins, catalyze the glutathione conjugation reaction with electrophilic compounds biotransformed from xenobiotics, including carcinogens. In preneoplastic cells as well as neoplastic cells, specific molecular forms of glutathione transferase are known to be expressed and have been known to participate in the mechanisms of their resistance to drugs. In this article, following a brief description of recently identified molecular forms, we review new findings regarding the respective molecular forms involved in carcinogenesis and anticancer drug resistance, with particular emphasis on Pi class forms in preneoplastic tissues. The rat Pi class form, GST-P (GST 7-7), is strongly expressed not only in hepatic foci and hepatomas, but also in initiated cells that occur at the very early stages of chemical hepatocarcinogenesis, and is regarded as one of the most reliable markers for preneoplastic lesions in the rat liver. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-responsive element-like sequences have been identified in upstream regions of the GST-P gene, and oncogene products c-jun and c-fos are suggested to activate the gene. The Pi-class forms possess unique enzymatic properties, including broad substrate specificity, glutathione peroxidase activity toward lipid hydroperoxides, low sensitivity to organic anion inhibitors, and high sensitivity to active oxygen species. The possible functions of Pi class glutathione transferases in neoplastic tissues and drug-resistant cells are discussed.


A consideration of alternative models for the initiation of translation in eukaryotes.

Although recent biochemical and genetic investigations have produced some insights into the mechanism of initiation of translation in eukaryotic cells, two aspects of the initiation process remain controversial. One unsettled issue concerns a variety of functions that have been proposed for mRNA binding proteins, including some initiation factors. The need to distinguish between specific and nonspecific binding of proteins to mRNA is discussed herein. The possibility that certain initiation factors might act as RNA helicases is evaluated along with other ideas about the functions of mRNA- and ATP-binding factors. A second controversial issue concerns the universality of the scanning mechanism for initiation of translation. According to the conventional scanning model, the initial contact between eukaryotic ribosomes and mRNA occurs exclusively at the 5' terminus of the message, which is usually capped. The existence of uncapped mRNAs among a few plant and animal viruses has prompted a vigorous search for other modes of initiation. An "internal initiation" mechanism, first proposed for picornaviruses, has received considerable attention. Although a large body of evidence has been adduced in support of such a mechanism, many of the experiments appear flawed or inconclusive. Some suggestions are given for improving experiments designed to test the internal initiation hypothesis.


Validation and reproducibility of bidirectional laser Doppler velocimetry for the measurement of retinal blood flow.

Bidirectional laser Doppler velocimetry (BLDV) for the measurement of retinal blood flow was validated in six anaesthetised minipigs, by comparing BLDV derived results with those obtained using radioactively labelled microspheres (RLM). The mean velocity of blood (Vmean) was calculated from the maximum red blood cell velocity measured by BLDV. Volumetric flow rate was determined from Vmean and vessel diameter, measure from monochromatic fundus photographs. Total retinal blood flow (TRBF) was calculated by summating flow values obtained for each retinal vein draining into the optic disc. A significant correlation was found between the TRBF results obtained by the two techniques (r = 0.99, p less than 0.001). The BLDV results were between 3-35 microliters/min lower than the corresponding RLM results (p = 0.05). Values of 57 +/- 24 microliters/min and 76 +/- 34 microliters/min were obtained for TRBF using the BLDV and RLM techniques respectively. Reproducibility studies with BLDV were also performed in six anaesthetised pigs over three hours and in six normal human volunteers over two hours and two weeks. No significant difference between measurements was found with time. Ninety five percent confidence limits of +/- 9.8% for the six pigs and +/- 8.9% for the six human volunteers were found for measurements on the same day and at two weeks. We conclude that with a sample size of six, changes in flow of approximately 20% can be detected using BLDV and monochromatic fundus photography.


Influence of vehicle and anterior chamber protein concentration on cyclosporine penetration through the isolated rabbit cornea.

The transcorneal penetration of cyclosporine A has been determined from each of three vehicles across isolated cornea into simulated aqueous humor containing either 50 mg % protein (0.5 mg/ml; as found in a normal eye) or 5000 mg % protein (50 mg/ml; as found in an inflamed eye). Cyclosporine entered the corneal epithelium and stroma/endothelium as well as passed through the cornea from an alpha cyclodextrin vehicle. Entry into the epithelium and stroma/endothelium occurred from an ointment vehicle with limited detectable anterior chamber penetration using 50 mg % protein solution in the anterior chamber. From corn oil vehicle, cyclosporine penetrated across the cornea with a permeability equal to that of alpha cyclodextrin vehicle. The concentration of cyclosporine in both corn oil and ointment vehicles is 8 times greater than that in alpha cyclodextrin vehicle resulting in a flux from corn oil vehicle about 7 or 8 times greater than that seen after alpha cyclodextrin vehicle. The amounts retained in the cornea, however, were relatively low after corn oil compared to cyclodextrin. The penetration of cyclosporine from either the cyclodextrin vehicle or ointment was at least doubled in the presence of 5000 mg % protein in the simulated aqueous humor relative to that seen in 50 mg % protein. This data indicates that the (presumed) absorption and binding of drug by the excess protein in the simulated aqueous humor may have removed free cyclosporine from the solution and sustained a high concentration gradient of free solute across the cornea.(ABSTRACT TRUNCATED AT 250 WORDS)


Oxidation of the N-terminal methionine of lens alpha-A crystallin.

Antiserum against the N-terminal peptide of bovine alpha-A crystallin has been used to monitor purification of two different seropositive peptides (i.e. T1a and T1b) from a tryptic digest of bovine lens proteins. Both these peptides have similar amino acid compositions, but peptide T1b has a molecular weight 16 atomic mass units larger than T1a, suggesting posttranslational modification. Analysis of ionization fragments of the T1b peptide by mass spectrometry demonstrates that this difference in molecular weight is due to the in vivo oxidation of the N-terminal met residue of the alpha-A crystallin molecule.


Induction of experimental autoimmune uveitis with rhodopsin synthetic peptides in Lewis rats.

Rhodopsin, a membrane protein of rod photoreceptor cells, induces an experimental autoimmune uveitis (EAU) in Lewis rats. Synthetic peptides derived from rhodopsin sequences that cover hydrophilic, exposed regions of the protein were tested for their capacity of eliciting in vitro T cell proliferation and their ability for inducing EAU in Lewis rats. Rats were injected with rhodopsin's peptides mixed in complete Freund's adjuvant containing M. tuberculosis H37Ra (5 mg/ml) three days after pretreatment with cyclophosphamide (20 mg/kg). ELISA results indicate that all peptides induce antibody responses; however antibody titers differ among sera tested. Immunization with four peptides--the amino-terminus (2-32), loop I-II (61-75), loop V-VI (230-251), and the carboxyl-terminus (324-348 and 331-342) induced both antibody and T cell responses. In all cases, the proliferative responses of cells derived from peptide-injected rats were stronger against the immunizing peptide than against native protein. Three distinct uveitogenic epitopes were identified on rhodopsin's cytoplasmic surface--within the rhodopsin carboxyl-terminus (324-348), loop I-II (61-75), and loop V-VI (230-250). Histopathologically, at the immunized doses, total destruction of the photoreceptor cell layer was observed as compared to the control group. Loop V-VI caused severe inflammation of the retina while the other pathogenic peptides produced less severe destruction with few inflammatory cells present. Our study indicates that the major immunodominant T cell epitope (331-342) is also involved in EAU induction but is not the primary uveitogenic site.


Two-dimensional gel electrophoretic analysis of human lens proteins.

Human lens proteins from clear lenses were separated and identified using two-dimensional polyacrylamide electrophoresis. Isoelectric focusing, both equilibrium and non-equilibrium, was performed in the first dimension and SDS electrophoresis in the second dimension. Proteins were identified by Western blotting and sequencing techniques and by comparison with patterns obtained with purified crystallin fractions. Analyses were performed on total urea soluble proteins of lenses varying in age from fetal to 73 yr. Several hundred protein spots representing crystallins, cytoskeletal proteins and enzymes were resolved in the fetal lens. In the older lenses there was a dramatic increase in the number of protein species in the molecular weight range of the crystallins and a reduced number of discrete protein species visible at molecular weights greater than 50,000. Conversely, a number of proteins below approximately 15 kDa were visible even in the fetal lens. The number and amount of polypeptides in this molecular weight range were increased in the older lenses. Many of these low molecular weight species could be assigned to either the alpha-, beta- or gamma-crystallin fractions. An age dependent increase in the number of acidic species of both crystallins and other proteins, such as, glyceraldehyde 3-phosphate dehydrogenase was observed as well as the loss or mobility change of gamma-crystallin. Two-dimensional gel electrophoresis provides a sensitive and practical technique for characterizing all of the proteins of the human lens.


Transforming growth factor-beta modulates effects of epidermal growth factor on corneal epithelial cells.

In order to understand the mechanisms that bring about maintenance and restoration of the integrity of corneal epithelium, we investigated independent and combined effects of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) on rabbit corneal epithelial cells in cell and organ culture. Specifically, we determined whether incubation with these factors influenced 1) cellular proliferation, 2) ability of cells to attach to a fibronectin matrix, and 3) the rate of epithelial migration over corneal stroma. Incubation with TGF-beta caused a dose-related decrease in the incorporation of 3H-thymidine by the epithelial cells. EGF increased 3H-thymidine incorporation, but this effect was antagonized by the addition of TGF-beta into the incubation medium. Incubation with EGF increased the numbers of cells that attached to a fibronectin matrix. TGF-beta itself did not affect the number of attached cells but, again, it antagonized the stimulatory effect of EGF. Similarly, when corneal blocks were cultured with EGF, epithelial migration increased in a dose-related manner. TGF-beta itself did not affect epithelial migration at any of the concentrations tested (0.1-10 ng/ml), but it antagonized EGF-stimulated epithelial migration. These findings suggest that the proliferation and the migration of corneal epithelial cells are regulated by different mechanisms, and that TGF-beta serves as a modulator of the effects of EGF.


Immunity and immune privilege elicited by autoantigens expressed on syngeneic neonatal neural retina grafts.

Achieving the long-term goal of successful engraftment of retinal tissues into eyes blinded by endogenous retinal failure will depend, at least in part, on controlling the immune response to antigens expressed on retinal grafts. Since histoincompatible tissues will have to be used for such transplants, methods to control immune rejection directed at transplantation alloantigens must be devised. In addition, it has recently been observed in mice that developing neural retinal tissues express retina-specific antigens that have the potential to contribute to graft failure. To examine the potential risk of this contribution, syngeneic neonatal neural retinas were implanted into the anterior chamber, vitreous cavity, and subconjunctival space of adult BALB/c mice. During two weeks post-implantation, the fate of these grafts was observed clinically and histologically, and the retina-specific immune responses of the recipients were evaluated. Whereas grafts placed intraocularly thrived, carried out their inherent developmental potential, and were healthy and intact at the end of the observation interval. Grafts placed extraocularly expressed their differentiation program poorly. These grafts underwent rapid decline and attrition, although the process was not accompanied by significant inflammation. Recipients of subconjunctival, but not AC or VC, implants developed retina-specific delayed hypersensitivity. Alternatively, mice bearing AC and VC implants of neonatal neural retina developed retina-specific anterior chamber associated immune deviation. It is concluded that retinal autoantigens are expressed on developing neural retinal tissues and these antigens are highly immunogenic when retinal grafts are placed at conventional body sites. When similar grafts are placed in immune privileged compartments of the normal eye, they enjoy significant survival. Circumstantial evidence indicates that intraocular retinal grafts are protected and maintained in part by the emergence of systemic retinal auto-antigen-specific immune suppression.


Localization of vasoactive intestinal peptide (VIP) messenger RNA (mRNA) in amacrine cells of rat retina.

We detected vasoactive intestinal peptide (VIP) messenger RNA (mRNA) in the rat retina using an in situ hybridization technique and a 35S-labelled cDNA probe. VIP mRNA was present in the cells of the inner nuclear layer (INL). The VIP mRNA-positive cells showed a distribution similar to that of the VIP-like immunoreactive amacrine cells. This observation suggests that VIP mRNA undergoes transcription in the VIP-immunoreactive amacrine cells.


Widespread Candida folliculitis in a nontoxic patient.

We present a case of widespread Candida folliculitis in a nontoxic, immunocompetent woman. Predisposing factors included obesity and use of systemic antibiotics and topical steroids. Diagnosis was made through potassium hydroxide and Gram's stain examination of the pustular contents. The patient was treated with oral ketoconazole and topical econazole, with resolution of the eruption in six weeks. We suggest that temperature played a role in the follicular location of the lesions.


Multiple symmetrical lipomatosis.

We report a patient with multiple symmetrical lipomatosis, which is an unusual subgroup of lipomatous disease. This entity is described along with a brief review of the literature on this disease and associated disorders.


Nodular vasculitis associated with propylthiouracil therapy.

Cutaneous vasculitis is a rare complication of propylthiouracil therapy. We describe a patient who presented with lower extremity subcutaneous nodules, hemorrhagic bullae, and necrotic ulcers during treatment with this agent. Examination of a skin biopsy specimen revealed nodular vasculitis. This type of vasculitis has not been described in association with propylthiouracil therapy before. Nodular vasculitis not associated with the drug is characterized by a chronic protracted course, whereas in the patient reported the lesions rapidly regressed when use of the drug was discontinued.


Coexistent oral cryptococcosis and Kaposi's sarcoma in acquired immunodeficiency syndrome.

As experience with the acquired immunodeficiency syndrome has grown during the last decade, it has become important to recognize interactions between the opportunistic infections and malignancies that complicate the course of patients with acquired immunodeficiency syndrome. Our recent experience as described in this paper reveals that Kaposi's sarcoma and cryptococcal infection can associate in such a manner. The first reported case of oral Cryptococcus neoformans infection within a Kaposi's sarcoma lesion in a patient with acquired immunodeficiency syndrome is described. Based on the clinical course of this patient, it is an important consideration that the sarcoma may have harbored and even protected the fungus during systemic amphotericin B therapy.