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The BZLF1 protein of Epstein-Barr virus (EBV) is a key immediate-early protein which has been shown to disrupt virus latency in EBV-infected B cells. We have generated a monoclonal antibody, BZ1, to BZLF1 which reacts in immunohistology, immunoblotting, and immunoprecipitation and which recognizes both the active, dimeric form and the inactive, monomeric form of the protein. Biopsies of oral hairy leukoplakia, an AIDS-associated lesion characterized by high-level EBV replication, were examined by immunohistochemistry using the BZ1 monoclonal antibody. A differentiation-associated pattern of BZLF1 expression was observed, BZ1 reacting with nuclei of the upper spinous layer of the lesion. This finding suggests that the BZLF1 promoter may be regulated by the degree of squamous differentiation. A comparison of in situ hybridization to EBV DNA and viral capsid antigen staining with BZ1 reactivity suggested that BZLF1 expression precedes rampant virus replication. The inability to detect EBV in the lower epithelial layers of oral hairy leukoplakia raises questions concerning the nature of EBV latency and persistence in stratified squamous epithelium.

The clinical manifestations of Sjõgren's syndrome (SS) and sarcoidosis can be identical. Of the 1600 patients whom we have evaluated for dryness of the mouth and eyes, 300 proved to have SS and 5 had sarcoidosis. The patients with sarcoidosis had combinations of salivary gland enlargement, elevated antinuclear antibody titers, reduced salivary flow rates, and keratoconjunctivitis sicca, findings typically associated with SS. Finding non-caseating granulomas in a labial salivary gland biopsy specimen may be the only way to definitively differentiate these two disorders.

In order to gain further understanding of the role of chemokines in healthy oral mucosa, we analyzed mRNA expression of the alpha (CXC)-family chemokines IL-8 and GROgamma as well as of the beta (CC)-family chemokines MIP-1alpha, MIP-1beta and MCP-1 in twenty young and healthy subjects with good oral hygiene. Twenty biopsies were taken from clinically healthy oral mucosa before surgical removal of impacted wisdom teeth. In addition, five biopsies from patients presenting with specific oral lesions were studied. RNA was purified, quantitated and utilized as substrate for competitive reverse transcription-polymerase chain reaction (RT-PCR). In healthy tissue, IL-8 and MCP-1 mRNA was constitutively expressed in all biopsies, whereas GROgamma, MIP-1alpha, and MIP-1beta were significantly lower. These findings suggest that IL8 and MCP-1 play a significant role in oral tissue homeostasis. The few samples from pathological conditions encourage exploring diseased tissue in more detail.

Liquid breathing has been in the medical literature for nearly 80 years and has been proposed as a means of improving gas exchange in patients with acute respiratory failure since the 1970s. There are many potential clinical applications of perfluorochemical (PFC) liquids that span many specialties in medicine. The ability to lower surface tension directed the initial clinical focus on neonatal therapy in the treatment of respiratory distress syndrome. The first clinical trial of PFC ventilation was performed in neonates in 1989. Additional trials using LiquiVent, a medical-grade PFC liquid, were initiated in 1993 in infants, children, and adults with severe respiratory distress. Based on the results of several studies during this time, it was concluded that the technique of liquid ventilation seemed to be safe, improve lung function, and recruit lung volume in patients from these various populations. More than 100 patients from preterm neonates to elderly patients with respiratory distress have been studied. In general, patients experience improvement in lung function and oxygenation, without adverse events. The results of such trials are encouraging and suggest the feasibility of this technique in the neonate with severe respiratory failure requiring respiratory support. Limitations of the technique include a limited understanding of how it works and its effectiveness in different patient populations. It has also become evident that there is a need for additional diagnostic and therapeutic instrumentation to expedite its implementation in the intensive care environment. This article discusses clinical experiences with liquid ventilation and highlights the technical needs to facilitate its implementation in respiratory care management.

A multidisciplinary approach using a neonatology independent physicians association, affiliated hospitals, a pediatric home care company, and a health maintenance organization was designed to promote earlier safe discharge of infants from intensive care. This pilot project involved 43 infants who received case management and early discharge home with home oxygen, monitoring, intravenous antibiotics, gavage feedings, phototherapy, or nutritional management for poor weight gain. A staff neonatologist remained the primary physician until the patient would have been discharged according to standard criteria. Two patients had unscheduled readmissions and all infants survived. This approach resulted in an estimated savings of 456 hospital days and $329,982; 89% of parents rated the care as good to excellent, and 83% were satisfied with the program and outcome. This study suggests that a prospectively designed program can be designed to promote safe earlier discharge of infants in intensive care.

Liquid breathing has been in medical literature for nearly 80 years and has been proposed as a means of improving gas exchange in critically ill infants since the 1970s. Extensive laboratory experience with perfluorochemical liquid ventilation has lead to clinical trials in infants, children, and adults. This article discusses the process and physiologic response to liquid breathing in neonates, and reviews some of the factors that need clarification prior to approval as a routine clinical therapy.

In patients with advanced human immunodeficiency virus (HIV) infection, aphthous ulceration of the mouth and oropharynx can become extensive and debilitating. Preliminary reports suggest that thalidomide may promote the healing of oral aphthous ulcers.We performed a double-blind, randomized, placebo-controlled study of thalidomide as therapy for oral aphthous ulcers in HIV-infected patients. The patients received a four-week course of either 200 mg of thalidomide or placebo orally once per day. They were evaluated weekly for the condition of the ulcers, their quality of life, and evidence of toxicity. Assays were performed for plasma tumor necrosis factor alpha (TNF-alpha), soluble TNF-alpha receptors, and HIV RNA.Sixteen of 29 patients in the thalidomide group (55 percent) had complete healing of their aphthous ulcers after four weeks, as compared with only 2 of 28 patients in the placebo group (7 percent; odds ratio, 15; 95 percent confidence interval after adjustment for group sequential testing, 1.8 to 499; unadjusted P0.001). Pain diminished and ability to eat improved with thalidomide treatment. The adverse effects noted with thalidomide included somnolence and rash (7 patients each), and 6 of the 29 patients discontinued treatment because of toxicity. Thalidomide treatment increased HIV RNA levels (median increase, 0.42 log10 copies per milliliter; increase with placebo, 0.05; P=0.04). With thalidomide treatment there were unexpected increases in the plasma concentrations of TNF-alpha and soluble TNF-alpha receptors.Thalidomide is an effective treatment for aphthous ulceration of the mouth and oropharynx in patients with HIV infection.

The decision to place an infant on extracorporeal membrane oxygenation (ECMO) is based on predictions of expected morbidity and mortality. One unknown factor is the relationship between pre-ECMO pulmonary dysfunction and on barotrauma and post-ECMO pulmonary sequelae. To determine whether placement of infants on extracorporeal membrane oxygenation (ECMO) early is associated with less subsequent pulmonary dysfunction than placing infants on EMCO later, we evaluated pulmonary function in 25 neonates prior to ECMO, when the infants had come off EMCO, and at the time of nursery discharge. Pulmonary resistance (R) and compliance (CL) were determined by a pneumotachograph and esophageal manometry, and functional residual capacity (FRC) was determined by a helium dilution method. Maximal expiratory flow (VmaxFRC) was determined by thoracic compression at the time of discharge. Infants were assigned to an early ECMO group (36 hours of age, n = 12), or a late ECMO group (36 hours of age, n = 13). When first evaluated, the early group had a higher oxygenation index than the late group (mean value, 63 versus 48), but initial pulmonary function measurements were not different between the two groups. In the early group mean CL increase from 0.20 to 0.36 ml/cmH2O/kg, FRC increased from 7 to 20 ml/kg, and mean R decreased from 107 to 61 cmH2O/L/sec between the initial study and immediately after ECMO. In the late group, only FRC increased from a mean of 8 to 20 ml/kg. CL and FRC increased from post-ECMO to discharge in both groups (mean CL from 0.36 to 0.76 ml/cmH2O/kg in the early group, and from 0.30 to 0.79 in the late group). Mean FRC increased from 20 to 26 ml/kg in the early group, and from 20 to 25 ml/kg in the late group. VmaxFRC was lower in the late than the early group at discharge (mean, 1.14 versus 1.58 L/sec; P0.05). While both groups of infants had minimal pulmonary dysfunction at discharge, the infants placed on ECMO early had evidence of slightly less airway dysfunction despite a higher initial oxygenation index than the infants placed on ECMO late.

To demonstrate that a period of partial liquid ventilation (PLV) with perflubron improves pulmonary function, without adverse events, in a select group of critically ill infants receiving extracorporeal life support (ECLS) with a high likelihood of mortality.This was an open-label, noncontrolled, phase I and II trial of PLV in two infants with congenital diaphragmatic hernia and four infants with acute respiratory distress syndrome (ARDS) who were failing to improve while receiving ECLS. PLV was performed by instilling and maintaining a functional residual capacity of sterile perflubron for 4 to 96 hours.Four infants were successfully weaned off ECLS for at least 3 days, and two infants (both with ARDS) are long-term survivors after PLV. All infants demonstrated lung recruitment and improved lung compliance, and there were no adverse events related to PLV.The study suggests that perflubron PLV is safe, improves lung function, and recruits lung volume in critically ill infants receiving ECLS. PLV therapy for infants with ARDS seems to have a great deal of promise. Based on this and other phase I and II trials, studies of PLV on selected full-term infants before ECLS have been initiated.

Three cases of Langerhans' cell histiocytosis (histiocytosis X) are reported in which the clinical presentations were (1) soft-tissue enlargements, (2) oral ulcerations, and (3) leukoplakia. Each case was without bone involvement at the time of diagnosis, and two patients were older than 60 years of age. Definitive diagnoses were aided with the use of immunohistochemistry.

The intratracheal administration of a perfluorocarbon liquid during continuous positive-pressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency. Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known.We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed. Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity. Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours.Ten infants received partial liquid ventilation for 24 to 76 hours. In the other three infants, partial liquid ventilation was discontinued within four hours in favor of high-frequency ventilation, which was not permitted by the protocol, and the data from these infants were excluded from the analysis. Within one hour after the instillation of perflubron, the arterial oxygen tension increased by 138 percent and the dynamic compliance increased by 61 percent; the mean (+/- SD) oxygenation index was reduced from 49 +/- 60 to 17 +/- 16. Chest radiographs showed symmetric filling, with patchy clearing during the return from partial liquid to gas ventilation. There were no adverse events clearly attributable to partial liquid ventilation. Infants were weaned from partial liquid to gas ventilation without complications. Eight infants survived to 36 weeks' corrected gestational age.Partial liquid ventilation leads to clinical improvement and survival in some infants with severe respiratory distress syndrome who are not predicted to survive.

Advanced ventilation therapies for the sick neonate, such as nitric oxide and liquid ventilation, may be effective in treating the sick neonate. Both techniques are discussed in terms of their current merit for treatment and what impact they may have on nurses caring for the sick neonate.

Evidence of surfactant inactivation by meconium has led to the use of exogenous surfactant therapy in the management of meconium aspiration syndrome (MAS). Liquid assisted ventilation has been shown to improve the cardiopulmonary function in lungs with high surface tension. We compared exogenous surfactant therapy with liquid assisted ventilation in the management of experimental acute meconium aspiration injury. Thirty-two newborn lambs were ventilated at peak inspiratory pressures of 13-16 cm H2O, positive end expiratory pressure of 3-4 cm H2O, fractional inspired oxygen concentration (FiO2) of 1.0, and a respiratory frequency range between 30 and 35 breaths/min. Baseline arterial blood gases, pulmonary function, and arterial blood pressure measurements were taken. All lambs were given 2-3 ml/kg of an unfiltered 25% meconium solution. Lambs were then randomized into either gas-ventilated meconium control, or one of three treatment groups: 1) surfactant; 2) partial liquid ventilation (PLV); or 3) total liquid ventilation (TLV) for 4 hours after meconium injury. All treated groups demonstrated a significant increase in arterial oxygenation (P0.05); surfactant and PLV-treated lambs demonstrated significantly decreased arterial PCO2 (P0.05). Compliance in all groups increased compared with injury values; compliance of the TLV group increased more than in all other treatment groups (P0.05). In addition, lung histology of the TLV group demonstrated clear, intact alveolar epithelium and homogeneously expanded alveoli, while no such improvement was evident in the other groups. These data suggest roles for both exogenous surfactant therapy and liquid assisted ventilation techniques in the management of MAS.

Therapeutic management of respiratory distress syndrome, pneumonia, and pulmonary hypertension includes delivery of biologically active agents to the neonatal lung. However, mechanical abnormalities of the lung, intrapulmonary shunting, ventilation-perfusion mismatching, and elevated surface tension impede effective systemic or intratracheal delivery of agents to the lung during conventional gas ventilation. The objective of this study was to test the hypothesis that perfluorochemical (PFC) liquid ventilation can be used for pulmonary administration of vasoactive drugs (PAD) and to compare these responses to those elicited with intravascular (IV) administration during tidal liquid ventilation.Cardiovascular responses of 16 preterm and neonatal lambs to randomized doses of acetylcholine, epinephrine, and priscoline were studied. Physiologic gas exchanged and acid-base balance were maintained using previously described tidal liquid ventilation techniques. In subgroups of animals, the distribution pattern of carbon 1- and choline 14-labeled dipalmitoylphosphatidylcholine (14C-DPPC) in saline and the responses to priscoline after hypoxia-induced pulmonary hypertension and hypoxemia administered during liquid ventilation were studied.Dose-response curves for PAD and IV administration demonstrated progressive, dose-dependent, cholinergic responses to acetylcholine (decreased mean systemic arterial pressure [MAP] and heart rate), sympathomimetic responses to epinephrine (increased MAP and heart rate), and alpha-adrenergic blockade responses to priscoline (decreased MAP and mean pulmonary arterial pressure). Compared with IV administration, PAD of priscoline resulted in a significantly greater decrease in pulmonary relative to systemic arterial pressure; this response was potentiated by hypoxia, reduced pulmonary pressures to near normal values, and improved oxygenation. The 14C-DPPC in saline was distributed relatively homogeneously throughout the lung by PAD, with 80% of the lung pieces receiving amounts of 14C-DPPC with +/-20% of the mean value.This study demonstrates that vasoactive agents can be delivered to the lung directly by PAD during PFC liquid ventilation. The inherent advantages of this method relate to the physical properties of PFC liquid ventilation as a vehicle (respiratory gas solubility, low surface tension-enhancing distribution, and inertness precluding interaction) and physiological properties of the lung as an exchanger.

A retrospective review of the medical records of 492 children perinatally exposed to the human immunodeficiency virus (HIV) compared the prevalence of orofacial soft-tissue manifestations in HIV-infected and noninfected children, identified risk factors for occurrence of orofacial lesions in HIV-infected children, and investigated specific orofacial lesions as indicators of progression of HIV disease. Application of eligibility criteria and the Centers for Disease Control classification of pediatric HIV infection resulted in selection of a study group of 91 HIV-positive children and a control group of 185 HIV-seronegative children who had seroreverted. Analysis of oral lesions showed that 67% of the study group and 8% of the control group had oropharyngeal candidiasis (OPC), 4% of the study group and 0% of the control group had parotid enlargement, and 3% of the study group and 0% of the control group had herpes simplex; all three differences were significant at P0.04. No statistically significant association was found between OPC and the risk factors of gender, ethnicity, or mode of delivery (vaginal versus cesarean). However, OPC was associated significantly with all progression markers examined: failure to thrive, use of antiretroviral agents, lower CD4 counts, and development of acquired immunodeficiency syndrome (AIDS). Orofacial manifestations are common in pediatric HIV infection and may serve as markers of infection and predictors of progression of HIV disease to AIDS.

To determine whether fatal pulmonary hypoplasia, as assessed by functional residual capacity (FRC), can be distinguished from other reversible causes of respiratory failure in infants with congenital diaphragmatic hernia (CDH).In the present study, 25 term neonates having CDH without other anomalies (mean birth weight +/- SD, 3.25 +/- 0.50 kg) were enrolled prospectively into a protocol evaluating pulmonary function. Lung compliance (CL) and FRC were measured before diaphragmatic repair and compared with the highest oxygenation index (OI) and lowest PaCO2, also obtained preoperatively. Pulmonary function assessment was repeated after diaphragm repair on postoperative days 3 and 7. CL was determined by esophageal manometry and pneumotachography, and FRC was determined by helium dilution.Fifteen infants (60%) survived to hospital discharge. Eighteen (72%) required extracorporeal membrane oxygenation (ECMO) for support, and of these, 8 (44%) survived. PaCO2 was similar preoperatively in infants grouped as survivors without ECMO, survivors with ECMO, and nonsurvivors. In nonsurvivors (all of whom received ECMO), the preoperative OI was significantly higher (51 +/- 21), CL was less (0.11 +/- 0.04 mL/cm of water per kg), and FRC was smaller (4.5 +/- 1.0 mL/kg) than in the survivors who required ECMO (26 +/- 18, 0.18 +/- 0.08 mL/cm of water per kg, and 12 +/- 5 mL/kg, respectively), as well as in the survivors without ECMO, (6 +/- 2, 0.32 +/- 0.16 mL/cm of water per kg, and 15.8 +/- 4 mL/kg, respectively). The group surviving with ECMO had a higher OI than the infants surviving without ECMO. All nonsurviving infants had FRCs of less than 9.0 mL/kg preoperatively. In contrast, only 2 of the 15 survivors had preoperative FRCs less than 9 mL/kg.The results of this study suggest that preoperative assessment of FRC may predict fatal pulmonary hypoplasia in most infants with CDH.

Accurate monitoring of respiratory status is of vital importance for the bedside nurse caring for the critically ill neonate. Pulmonary function testing can be utilized to effectively diagnose and quantitate lung disease in infants. Data obtained can be integrated into the nursing assessment and facilitate appropriate nursing interventions. The case studies provided in Part III of this series illustrate the utility of such testing in neonates with a range of illnesses and different diagnostic and therapeutic dilemmas. Case study one is an infant with chronic lung disease complicated by bronchospasm, case study two is an infant with bronchomalacia, and case study three demonstrates fine tuning of the ventilator in an infant with respiratory distress syndrome. Every study describes the usefulness of pulmonary function testing on a specific patient, each with different pulmonary pathology. These case studies, and the discussion in parts I and II of this series, illustrate the value of integrating pulmonary function data with ongoing clinical assessment to optimize the care of the sick or convalescing neonate. Tests ordered on a routine and/or as-needed basis will provide detailed information on the infant's pulmonary status that may be readily available at the infant's bedside. The neonatal nurse's involvement in requesting, performing, and interpreting these tests may enhance the treatment of the infant in intensive care.

Pulmonary function testing is an important diagnostic tool in neonatal intensive care. These tests provide a detailed assessment of an infant's pulmonary status that can be used in several ways: to monitor the progression of lung disease, to streamline ventilator management, and to assess the infant's response to new treatments, such as surfactant replacement therapy or bronchodilators. In some settings, these tests are performed by specially trained nurses, and the results are available immediately for planning nursing care. This relatively noninvasive and low-risk assessment can be performed on all infants, whether on mechanical ventilation or breathing spontaneously. A comprehensive pulmonary function evaluation can be performed at the bedside in less than 60 minutes and is generally well tolerated. In this article, the determination of pulmonary "vital signs" tidal volume, minute ventilation, respiratory rate, pulmonary compliance, resistance, resistive work of breathing, and functional residual capacity-are discussed. The esophageal balloon technique for measuring dynamic pulmonary mechanics and energetics, as well as the helium dilution technique for measuring functional residual capacity, are described.

As the scope of the acquired immunodeficiency syndrome (AIDS) epidemic grows to include increasingly larger proportions of heterosexual adults and children, there has also been a change in the severity of human immunodeficiency virus (HIV)-related periodontal conditions at one San Francisco clinic. The cases of HIV-associated gingivitis, now called linear gingival erythema, HIV-associated periodontitis (or necrotizing ulcerative periodontitis), and necrotizing stomatitis have been less severe, despite an increase in overall HIV caseload. No clear basis for this trend has been established, but possible explanations include: biased population samples, increased immunosuppression as the disease matures, use of antimicrobial therapy, or a change in patient demographics. Several studies have failed to identify a single causative organism. This article presents a review of HIV-related periodontal complications and points out that the condition can be treated with local and systemic antibiotics and that dental professionals throughout the world can expect a tremendous increase over the next several years in HIV-infected patients with special clinical complications.

Oral traumatic granulomas are reactive mucosal lesions that are characterized by an intense mononuclear infiltrate (usually with eosinophils) that may mimic neoplasia. These pseudoneoplastic infiltrates were evaluated with the use of lineage-associated antibodies (CD3, OPD4, L26, KP1, XIIIa, S-100, HPCA-1, HHF-35). We determined that the large distinguishing mononuclear cells were either CD68-positive macrophages or factor XIIIa-positive dendrocytes (the oral counterparts to dermal dendrocytes). S-100-positive connective tissue cells occasionally contributed to this infiltrate. Also abundant in the infiltrate were smaller CD3-positive T-lymphocytes. Double-staining confirmed that there were separate populations of CD68-positive macrophages and XIIIa-positive dendrocytes. Because some XIIIa dendrocytes coexpressed CD68, phagocytosis may be one of the functions of dendrocytes.

Recurrent oral herpes simplex virus lesions are common in both immunocompetent and immunocompromised persons. In contrast, cytomegalovirus-associated intraoral lesions are rarely seen, even in the immunocompromised host. We report a case of concurrent oral herpes simplex virus and cytomegalovirus infection, appearing as an ulcerative lesion of the labial mucosa in a patient with acquired immunodeficiency syndrome. Herpes simplex virus type 1 was shown to be present in the lesion by culture tests, histopathologic examination, immunohistochemistry findings and a direct immunofluorescence assay, and cytomegalovirus by histopathologic examination and immunohistochemistry findings. We deduce that the lesion was due to concurrent herpes simplex virus-1 and cytomegalovirus infection. The patient responded well to 2 weeks of treatment with a high dose of acyclovir.

Oral lesions were included in some of the first descriptions of the acquired immunodeficiency syndrome (AIDS), and it has become clear in the ensuing years that these lesions may represent some of the earliest signs of infection with the human immunodeficiency virus (HIV), may be of prognostic significance in the subsequent development of AIDS, and may, if not treated, produce significant morbidity. Understanding oral lesions may shed light on the other manifestations of HIV disease. Oral examination is an important part of any physical examination, and nowhere is this more important than in the case of suspected HIV infection.

In the clinical setting, nasal cannulas are frequently used to deliver supplemental oxygen to neonates and are not believed to affect the general respiratory status. In contrast, it was hypothesized that clinical changes associated with nasal cannula gas flow may be related in part to the generation of positive end-distending pressure. To test this hypothesis, alterations in esophageal pressure were quantified as an indication of end-distending pressure and thoracoabdominal motion was quantified as an indication of breathing patterns in 13 preterm infants at gas flow levels of 0.5, 1, and 2 L/min delivered by nasal cannula with an outer diameter of either 0.2 or 0.3 cm. Changes in esophageal pressure were assessed by esophageal balloon manometry. Ventilatory patterns were assessed from thoracoabdominal motion by using respiratory inductive plethysmography. Thoracoabdominal motion was quantitated as a phase angle (theta); larger values represent greater asynchrony. The 0.2-cm nasal cannula did not deliver pressure or alter thoracoabdominal motion at any flow. In contrast, the 0.3-cm nasal cannula delivered positive end-distending pressure as a function of increasing levels of gas flow (r = .92) and reduced thoracoabdominal motion asynchrony. The mean pressure generated at 2 L/min was 9.8 cm H2O. These data demonstrate that nasal cannula gas flow can deliver positive end-distending pressure to infants and significantly alter their breathing strategy. This finding raises important concerns about the indiscriminate therapeutic use, size selection, and safety of nasal cannulas for the routine delivery of oxygen in preterm infants.

Infections with Geotrichum species, although rare, are sometimes seen in immunocompromised hosts. We report a case of oral geotrichosis in a patient seropositive for human immunodeficiency virus who had erythematous mandibular and maxillary gingiva but was otherwise free of any active systemic disease. Geotrichum candidum was shown by both culture and histopathology to be present in the lesion and was deduced to be the causative organism. The patient responded well to several weeks of treatment involving oral topical administration of nystatin vaginal tablets.

Individuals who are infected with human immunodeficiency virus (HIV) are known to have a high incidence of autoantibodies. In this study, serum samples from 100 individuals with HIV infection were tested for granulocyte antibodies (red cell antibodies, lymphocytotoxic antibodies, circulating immune complexes, and serum immunoglobulin G levels) by granulocyte agglutination (GA) and granulocyte immunofluorescence (GIF) assays. Granulocyte antibodies were detected in 66% of serum samples by GIF and in 21% of serum samples by GA. None of the positive sera reacted with granulocyte antigens of known specificity. Antibodies that reacted with red cell antigens other than ABO were detected in only three serum samples, but lymphocytotoxic antibodies were detected in 62% of patients. All serum samples were tested by immunoblotting with granulocyte plasma membranes. Only two samples were found to be positive; one sample reacted with a 58 kd protein and one reacted with a 55 kd protein, but neither serum sample immunoprecipitated any protein from granulocytes that were labeled at the cell surface with iodine 125. Since immune complexes that are bound to granulocyte membranes can be detected by GIF, circulating immune complex levels were measured in all 100 samples. Immune complexes were increased in GIF-reactive serum samples compared with GIF-nonreactive serum samples (23.3 +/- 19.5 micrograms Eq/ml [mean +/- SD] vs 9.6 +/- 8.1 micrograms Eq/ml, p less than 0.001) but not in GA-reactive serum samples compared with GA-nonreactive sera (24.4 +/- 21.3 micrograms Eq/ml versus 16.9 +/- 16.0 micrograms Eq/ml, p = 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

We examined 142 biopsy specimens of smokeless tobacco-associated oral mucosal lesions from 133 professional baseball players. Four types of epithelial change were observed in the specimens: hyperparakeratosis, hyperorthokeratosis, pale surface staining, and basal cell hyperplasia. These types of epithelial change were associated with the type of smokeless tobacco used (snuff or chewing tobacco) but not with the duration (years) or amount (hours per day) of use. The thickness of hyperkeratosis in a specimen correlated directly with the amount of smokeless tobacco use. The use of snuff was more frequently associated with development of oral mucosal lesions than was the use of chewing tobacco, and snuff appeared to cause a greater variety and severity of epithelial change than did chewing tobacco.

A set of definitions and diagnostic criteria for the more common oral features of human immunodeficiency virus infection were prepared as the result of a consensus reached by a group of dental and medical clinicians, epidemiologists, and other experts. These are intended for use in epidemiologic surveys, where the presumptive diagnoses are recommended, and in clinical care, pathogenesis and therapy studies, where the definitive diagnoses are appropriate.

Human immunodeficiency virus (HIV) associated salivary gland disease is defined as the presence of enlargement of one or more major salivary glands and/or diminished salivary function in an HIV infected individual. It has a number of similarities to, as well as differences from, Sjögren's syndrome (SS). We studied the sialochemistry of stimulated parotid saliva of 11 patients with HIV associated salivary gland disease and bilateral parotid gland enlargement, and compared these findings with those of 15 HIV negative controls, 13 HIV positive individuals with no salivary gland involvement and 18 individuals with SS. The patients with HIV associated salivary gland disease had a significant decrease in the level of salivary protein, with increases in salivary IgA, lysozyme and albumin compared to the HIV negative controls. There were no changes in concentration of electrolytes. The sialochemistry among the patients with HIV associated salivary gland disease was unrelated to the degree of immune suppression and did not change over a 6 month period. The observed changes were similar to those of SS but less pronounced. The similar clinical, histologic and sialochemical features of HIV associated salivary gland disease and SS suggest that these conditions share common pathogenetic mechanisms, which may be modified in the former by the HIV infection.

We investigated the prevalence of HIV-associated periodontal disease in an AIDS clinic in San Francisco. Patient recruitment occurred over 6 months with 90% patient participation. In 136 patients, three forms of periodontal disease were recorded: HIV-associated gingivitis (HIV-G), HIV-associated periodontitis (HIV-P), and conventional non-HIV-associated periodontal disease. Diagnosis was based on defined clinical criteria established before the study began. For the HIV-associated diseases, two sets of diagnostic criteria were used. One consisted of clinical signs that included bleeding on probing, pocket depth, and attachment loss; and the other consisted of the same signs but did not require probing (the measurement of the depth of the gingival sulcus). Using the first set of these criteria, HIV-G was diagnosed in 42 patients [31%; 95% confidence interval (CI) 23 to 39%] and HIV-P in 5 (4%; 95% CI 1 to 7%). Using the second set, 68 patients were diagnosed with HIV-G (50%; 95% CI 42 to 58%) and 8 with HIV-P (6%; 95% CI 2 to 10%). All other categories of periodontal disease that were non-HIV-associated were diagnosed in 60 (44%) of patients. These results indicate that while the prevalence of HIV-P is low, the prevalence of HIV-G and conventional periodontal disease among HIV-infected individuals is high and should be considered in the dental care of these patients.

Candidiasis is the most common oral fungal infection seen in association with HIV infection. It may present in a number of clinical forms, including pseudomembranous and erythematous candidiasis. To determine whether erythematous candidiasis, like the pseudomembranous form, is predictive of the development of AIDS, we reviewed the records of 169 HIV-seropositive patients seen at clinic of the Oral AIDS Center, University of California, San Francisco who were diagnosed with pseudomembranous or erythematous (or both) forms of oral candidiasis at their first examination. Kaplan-Meier analysis showed a rapid rate of progression to AIDS (median, 25 months) and to death (median, 43.8 months) in all three groups. We conclude that erythematous candidiasis is as serious a prognostic indicator as pseudomembranous candidiasis. Because the erythematous form is more difficult to recognize and hence is underdiagnosed, efforts should be made to teach non-dental clinicians who care for HIV-infected patients to diagnose and treat this lesion.

Oral lesions are frequently seen in association with all stages of infection with the human immunodeficiency virus (HIV). Many of these lesions occur as the first clinical sign of HIV infection. These lesions include candidiasis, hairy leukoplakia, warts, ulcers, and an aggressive form of periodontal disease. Careful oral examination may reveal lesions that alter Centers for Disease Control staging.

The authors investigated the life cycle of Epstein-Barr virus (EBV) in keratinocytes of oral hairy leukoplakia by combining immunohistochemistry. DNA in situ hybridization, and lectin histochemistry with electron microscopy. Diffuse-staining components of the EBV early antigen complex (EA-D), EBV 150-kd capsid antigen (VCA), EBV membrane antigen (gp350/220), and double-stranded DNA were labeled with monoclonal antibodies. An EBV-DNA probe was used to locate EBV DNA. Wheat-germ agglutinin (WGA) was employed to distinguish Golgi-associated compartments. The authors found EBV proteins and EBV DNA only in keratinocytes with apparent viral assembly. In situ hybridization showed EBV DNA in free corelike material and in electron-dense cores of mature nucleocapsids. Monoclonal antibodies to nonspecific double-stranded DNA attached to the same structures and to marginated chromatin. Components of EA-D were dispersed throughout the nuclei but accumulated near condensed chromatin and in 'punched-out' regions of the chromatin. Epstein-Barr virus 150-kd capsid antigen was found only in the nuclei, where it appeared preferentially on mature nucleocapsids. As yet unexplained arrays of intranuclear particles that remained unlabeled with all EBV-specific probes reacted intensely with an antiserum against common papillomavirus antigen. Gp350/220 was detectable in various cellular membrane compartments and was highly concentrated on EBV envelopes in peripheral Golgi-associated secretory vesicles. It was less abundant on the extracellular EBV, indicating that viral membrane antigen partly dissociates from the mature virus. Combined lectin-binding histochemistry and electron microscopy demonstrated for the first time that EBV is processed in the Golgi apparatus, which eventually releases the virus by fusion with the plasma membrane. These results provide insight into the biologic events that occur during complete EBV replication in vivo.

This study was conducted to characterize the recurrent aphthous ulcers (RAU) found in association with human immunodeficiency virus (HIV) infection, to examine evidence for increased severity of the ulcers with HIV disease, and to determine whether increased severity is associated with abnormalities of peripheral blood lymphocyte subsets. Seventy-five HIV-seropositive patients with RAU were followed for up to 2 years, and lymphocyte subsets were analyzed in 42. Minor, herpetiform, and major ulcer types were seen, but unexpectedly, 66% of the patients had the usually uncommon herpetiform and major types. These types were temporally associated with symptomatic HIV disease. Patients with major RAU were significantly more immunosuppressed than those with minor or herpetiform RAU in that they had fewer CD4 and CD8 lymphocytes (p less than 0.05). The lesion of RAU is considered to represent a local breakdown in immunoregulation. The systemic immune imbalance seen with HIV disease may amplify the local defect and lead to more severe ulcers.

Forty anal paraffin-embedded tissue specimens from 24 subjects were studied for the presence of human papillomavirus (HPV) types 6, 11, 16, 18, 31, and 33, herpes simplex virus (HSV), Epstein-Barr virus, and cytomegalovirus DNA by using the polymerase chain reaction. These tissues ranged from histologically normal to invasive squamous cell carcinoma. HPV DNA was detected in the invasive anal cancer tissues of 11 of 13 subjects. HPV types were segregated by histopathological severity, with HPV 16 associated exclusively with high grade anal intraepithelial neoplasia and invasive cancer. HPV types 6 and 11 were associated with condyloma and low grade anal intraepithelial neoplasia. HPV DNA in situ hybridization studies confirmed the presence of HPV DNA in the invasive cancer tissues of 6 of 12 subjects. HPV DNA in these tissues was highly focal and primarily associated with invasive cell nests that demonstrated the greatest degree of squamous differentiation. HSV DNA was detected only in association with advanced disease, being found in the cancer tissues of 5 of 13 subjects, and in 3 of 4 subjects with high grade anal intraepithelial neoplasia, but was not detected by in situ hybridization. Epstein-Barr virus and cytomegalovirus DNA were not detected in the 40 tissue specimens. We conclude that HPV infection may play an important role in the pathogenesis of anal cancer. The association between HSV infection and high grade anal disease suggests that HSV infection may also play a role in disease progression.

The efficacy of desciclovir, an analog of acyclovir, in eliminating lesions of oral hairy leukoplakia (HL) and suppressing Epstein-Barr virus (EBV) infection was evaluated in a double-blind, placebo-controlled study of 14 patients. Patients were randomized to receive either the active drug, 250 mg three times a day for 14 days, or placebo. In all eight patients receiving desciclovir, lesions of HL were either completely resolved or significantly reduced during the treatment period, whereas lesions in patients receiving placebo showed no change. The histological features of HL were significantly diminished in patients on desciclovir, and cytochemical, in situ hybridization, and ultrastructural studies showed that EBV infection was eliminated or dramatically reduced in the desciclovir group only. Four patients on desciclovir reported side effects, but none required withdrawal from the study. The reappearance of HL in all eight subjects on desciclovir within 1-4 months after therapy was discontinued suggests the need for additional study.

MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop an autoimmune disease characterized by anti-DNA antibodies, immune-complex glomerulonephritis, and massive proliferation of a distinct population of T cells. The proliferating T cells have the phenotype Thy-1.2+, T200+, Lyt-1+,2-,3-, but Thy-1.2 and Lyt-1 are expressed in abnormally low density. These cells appear to function as helper cells, and neonatal thymectomy prevents both lymphoproliferation and autoimmunity, which suggests that autoimmunity in MRL/lpr mice is secondary to T cell proliferation. We therefore attempted to reduce lymphoproliferation by treating MRL/lpr mice with a single injection of rat monoclonal antibody (MAb) to Thy-1.2 (30-H12, IgG2b). Mice were treated at 8 wk, before the onset of overt disease. We found that MRL/lpr mice were resistant to depletion of circulating T cells (CTC) by anti-Thy-1.2; 0.6 mg of antibody totally depleted CTC from normal mice, but had little or no effect on CTC in MRL/lpr mice. However, treatment with 6 mg of MAb against Thy-1.2 reduced CTC in MRL/lpr mice by over 70%. Moreover, this single treatment markedly reduced the proliferation of CTC over the ensuing 3 mo, despite clearance of the anti-Thy-1.2 from the circulation within 3 wk. Treated mice maintained better renal function than untreated controls, as assessed by levels of blood urea nitrogen (BUN), although anti-DNA antibodies were not significantly reduced. The effect of anti-Thy-1.2 was specific; treatment with rat MAb to the common leukocyte antigen T200 produced only a transient effect on circulating lymphocytes and did not reduce renal disease. The prolonged effects of a single injection of anti-Thy-1.2 suggest that the MAb produces a sustained alteration in immune regulation. The improvement in renal disease is in accord with evidence that autoimmune disease in MRL/lpr mice is T cell dependent. Monoclonal anti-lymphocyte antibodies may be useful in the treatment of autoimmunity.

Neutralizing antibody to Herpes simplex virus type 1 (HSV-1), type 2, and measles virus was measured in the serum of patients with oral cancer, patients with oral leukoplakia, and in control subjects who were smokers and nonsmokers. Significantly higher titers to HSV-1 were found in controls who smoked than in controls who did not smoke. Patients with untreated oral cancer had HSV-1 neutralizing titers similar to those of the controls who smoked, but those with later stage tumors had higher titers than those with earlier stage tumors. In patients who were tumor free after treatment for oral cancer, higher antibody titers to HSV-1 were associated with longer survival times. No association was found between clinical status and antibody to measles virus. The data are consistent with a role for both HSV-1 and smoking in the pathogenesis of oral cancer.