The addition of respiratory muscle strength training to facilitate swallow and pulmonary rehabilitation following massive tissue loss and severe deconditioning: A case series.

INTRODUCTION: Impaired respiratory and swallow function in patients with intensive care unit-acquired deconditioning, such as associated with massive tissue loss, is not uncommon and can require prolonged rehabilitation. AIM: The aim of the study was to examine the effect of combined inspiratory and expiratory respiratory muscle strength training (RMST) on respiratory and swallow function in two critical care patients with marked deconditioning after massive tissue loss. METHODS: Case 1 was a 19-year-old male patient with 80% body surface area burns; case 2 was a 45-year-old man with group A streptococcus myositis necessitating quadruple amputation. Both required prolonged intensive care and mechanical ventilation. Both received routine intensive pulmonary and swallow rehabilitation before the trial; however, chronic aspiration and poor secretion clearance remained. At 25 and 26 weeks after initial injury, RMST was performed using EMST150 (expiratory) and Threshold IMT (inspiratory) devices, respectively. At baseline and throughout treatment, data collected included peak expiratory flow (PEF), anthropometry measures, aspiration risk (Penetration-Aspiration Scale [PAS]), pharyngeal clearance (Yale Pharyngeal Residue Scale), secretions (New Zealand Secretion Scale [NZSS]), and functional diet (Functional Oral Intake Scale [FOIS]) via endoscopy. RESULTS/DISCUSSION: At baseline, the PEF score of case 1 was 41% (predicted age-height norm) and the PEF score of case 2 was 14%, indicating severe expiratory compromise. Both had extreme energy requirements (3300 kcal/day; 3500 kcal/day). The baseline swallowing scores of case 1 and 2 were as follows: PAS, 8 and 8; Yale, 9 and 10; NZSS, 4 and 7; and FOIS, 1 and 1, respectively, indicating profound dysphagia. At week 3 of 7 of RMST, swallow function improved to allow both to commence oral intake, followed by tracheostomy decannulation. At weeks 10 and 11, full dysphagia resolution was achieved (FOIS = 7; PAS = 1, Yale = 2, NZSS = 0), with PEF at 70% and 48% predicted respectively. Both patients continued RMST, and at discharge from the acute facility, PEF was 84% and 80% predicted respectively. CONCLUSION: The addition of RMST assisted swallow and pulmonary rehabilitation in both cases and was clinically viable to deliver. Controlled validation trials are now required.

Whiplash-Associated Dysphagia and Dysphonia: A Scoping Review.

Swallowing and voice complaints after a whiplash injury have been observed and reported in several studies; however, variability in study design complicates current understanding of whether dysphagia and dysphonia should be recognised as potential adverse outcomes. A scoping review was conducted across six databases from 1950 to March 2019. A total of 18 studies were included for review. Data regarding study purpose, design, outcome measures, participant characteristics and outcomes reported were extracted. Level of evidence (LOE) was assessed by the American Speech-Language Language Association (ASHA)'s LOE system. All studies were exploratory, with 68% rated as poor (< 3) on quality ratings. Nearly half (n = 6) were single case reports. Only three studies investigated some type of swallow-related outcome specifically within the study aim/s. Incidence of swallow-related problems ranged from 2 to 29%, with unspecified complaints of "swallowing difficulty", "dysphagia" and fatigue and pain whilst chewing reported. Neither swallowing biomechanics nor the underlying pathophysiology of swallow or voice complaints was investigated in any study. Four case studies presented post-whiplash voice complaints; two of which described loss of pitch range. Others described hoarseness, loss of control and weak phonation. Most studies only mentioned swallow- or voice-related deficits when reporting a wider set of post-injury symptomatology and six did not describe the outcome measure used to identify the swallow and voice-related problems reported. The existing literature is limited and of low quality, contributing to an unclear picture of the true incidence and underlying mechanisms of whiplash-related dysphagia and dysphonia.

Self-reported Dysphagia and Pharyngeal Volume Following Whiplash Injury.

Difficulty swallowing has been reported following whiplash injury; however, the reasons remain poorly understood. A possible factor may be the observed changes in pharyngeal volume. The current exploratory study was designed to examine the prevalence of self-reported dysphagia after whiplash and the relationship with recovery status and change in pharyngeal volume. Data were available from a longitudinal study of adults with whiplash. Data included magnetic resonance imaging (MRI) of the cervical spine, the Dysphagia Handicap Index (DHI), and Neck Disability Index (NDI) collected over four timepoints (< 1 week, 2 weeks, 3 months, and 12 months post-injury). Initial cross-sectional analysis examined 60 patients with DHI data from at least one timepoint. A second, longitudinal analysis was conducted on 31 participants with MRI, NDI, and DHI data at both early (< 1-2 weeks) and late (3-12 months) timepoints. The pharynx was contoured on axial T2-weighted MRI slices using OsiriX image processing software and pharyngeal volume (mm3) was quantified. In the 60-patient cohort, prevalence of self-reported dysphagia (DHI ≥ 3) was observed in 50% of participants at least once in 12 months (M = 4.9, SD 8.16, range 0-40). In the longitudinal cohort (n = 31), mean total DHI significantly (p = 0.006) increased between early and late stages. There was no relationship (p = 1.0) between dysphagia and recovery status, per the NDI% score. Pharyngeal volume remained stable and there was no relationship between dysphagia and pharyngeal volume change (p = 1.0). This exploratory study supports the need for further work to understand the nature of dysphagia, extent of functional compromise, and the underlying pathophysiology post-whiplash.

Influence of Inhalation Injury on Incidence, Clinical Profile and Recovery Pattern of Dysphagia Following Burn Injury.

Inhalation injury is predictive of dysphagia post burns; however, the nature of dysphagia associated with inhalation burns is not well understood. This study describes the clinical profile and recovery pattern of swallowing following inhalation burn injury. All patients admitted 2008-2017 with confirmed inhalation burns on laryngoscopy and managed by speech-language pathology (SLP) were included. Initial dysphagia presentation and dysphagia recovery pattern were documented using the FOIS. Co-presence of dysphonia was determined clinically and rated present/absent. Persistent laryngeal/pharyngeal injury at 6 months was documented using laryngoscopy. Data were compared to published data from a large adult burn cohort. All patients with confirmed inhalation burns during the study period received SLP input, enabling review of 38 patients (68% male; m = 40.8 years). Percent Total Body Surface Area burn ranged 1-90%, 100% had head and neck burns, 97% required mechanical ventilation (mean 9.4 days), 18% required tracheostomy and 100% had dysphonia. Comparing to non-inhalation burn patients, the inhalation cohort had significantly (p < 0.01) higher dysphagia incidence (89.47% vs 5.6%); more with severe dysphagia at presentation (78.9% vs 1.7%); increased duration to initiate oral intake (m = 24.69 vs 0.089 days); longer duration of enteral feeding (m = 45.03 vs 1.96 days); and longer duration to resolution of dysphagia (m = 29.79 vs 1.67 days). Persistent laryngeal pathology was present in 47.37% at 6 months. This study shows dysphagia incidence in burn patients with inhalation injury is 16 times greater than for those without inhalation injury. Laryngeal pathology due to inhalation injury increases dysphagia severity and duration to dysphagia recovery.

Immunotherapy of a murine leukemia virus-infected, chemically induced murine sarcoma with antiviral antibodies.

Many murine tumor models associated with murine leukemia virus(es) (MuLV) have been successfully treated by passive administration of antiviral antibodies. There is a large body of virus-negative tumors, however, which are lowly antigenic and thus refractory to such approaches. Therefore, an investigation was done for determination of whether such tumors could be rendered susceptible to passive serum therapy by introduction of MuLV antigens onto the tumor cell surface. For this purpose a 3-methylcholanthrene-induced fibro-sarcoma from inbred C57BL/6J mice was chosen. Following infection of the tumor in vitro with Friend murine leukemia virus (F-MuLV), the tumor was found to be susceptible to treatment with a high-titered heterologous anti-F-MuLV gp71 antiserum. The specificity of the treatment was determined by conduction of the therapy on the uninfected parental tumor, in which case there was no effect. In addition, therapy could be initiated at time points when demonstrable tumors were present and successfully treated animals were resistant to rechallenge with the infected tumor. Thus conversion of a lowly antigenic virus-negative tumor to an MuLV-positive antigenic tumor rendered such growths susceptible to immunologic management.

In vivo antigenic modification of tumor cells. II. Distribution of virus in sarcoma-bearing mice.

Murine leukemia viruses were previously demonstrated to be able to infect efficiently non-virus-expressing tumors in vivo. In the present study the infectivity and tissue distribution of Friend murine leukemia virus (F-MuLV) in normal and tumor-bearing C57BL/6J (B6) mice were examined. Two syngeneic fibrosarcoma-inducing cell lines were used: Cells from a 3-methylcholanthrene-induced fibrosarcoma syngeneic to B6 mice (MCA-FS) and cells from a Harvey murine sarcoma virus-transformed, nonproducer sarcoma syngeneic to B6 mice (H-NP) were described in the preceding study. Both cell lines lacked ecotropic viral expression. F-MuLV produced in vitro was rarely able to infect normal adult B6 tissue in vivo and lacked pathogenic potential. Adult animals receiving F-MuLV remained clinically normal during 20 months of follow-up and had no detectable viremia, although some had persistently infected thymuses and long bones. In animals receiving a single dose of F-MuLV given to superinfect either the MCA-FS or the H-NP induced tumors, virion antigens were found only in tumor tissue and not in the normal host organs studied. Infectious virus was abundant in tumors; occasionally, it was found in thymuses and long bones of animals bearing superinfected H-NP tumors but rarely in other organs. Localization of F-MuLV in MCA-FS tumors appeared to be more selective with rare contamination of host organs. The presence of a rescuable sarcoma genome in H-NP may explain the discrepancy between MCA-FS and H-NP tumors. The possibility of increasing the efficiency and selectivity of infection as well as the therapeutic application of this technique are discussed.

In vivo antigenic modification of tumor cells. I. Introduction of murine leukemia virus antigens on non-virus-producing murine sarcomas.

Murine oncovirus antigens represent excellent targets for immune recognition, and virus-associated tumors are generally susceptible to various immunotherapy protocols. Virus-negative tumors, however, are nonimmunogenic and refractory to immunologic control. Therefore, the feasibility of the introduction of antigens onto non-virus-expressing tumors in situ in inbred C57BL/6J mice by systemic administration of nononcogenic murine retroviruses was investigated. Two classes of murine fibrosarcomas were studied: a 3-methylcholanthrene-induced fibrosarcoma syngeneic to C57BL/6 mice (MCA-FS) and a Harvey murine sarcoma virus-transformed, nonproducer fibrosarcoma syngeneic to C57BL/6 mice (H-NP). Both were found to be devoid of infectious ecotropic murine leukemia virus (MuLV) or MuLV antigens. A single dose of Friend murine leukemia virus (F-MuLV) was used to superinfect MCA-FS- and H-NP-induced tumors in vivo and converted these tumors to a highly productive, virus-positive state. In vivo superinfected tumors were indistinguishable from their preinfected counterparts by competition radioimmunoassays for the virion's major envelope glycoprotein, gp71, and its group-specific antigen, p30, and by assays for infectious virus. Analysis of virus from tumor extracts proved that the antigenic specificity of the superinfected tumor was provided by F-MuLV administered systemically to the animals. Finally, an immunoperoxidase technique, applied to tumor cross sections, demonstrated the uniform appearance of viral antigens in the superinfected tumors.

Full thickness facial burns: Outcomes following orofacial rehabilitation.

PURPOSE: To document orofacial rehabilitation and outcomes after full thickness orofacial burn. METHODS: Participants included 12 consecutive patients presenting with full thickness orofacial burns. A group of 120 age-matched healthy participants was recruited for normative comparison. Non-surgical exercise was initiated within 48 h of admission and continued until wounds had healed, circumoral scar tissue had stabilised and functional goals were achieved to the best of the patient's ability. Outcomes were documented using vertical and horizontal mouth opening measures at start and end of treatment and therapy duration was recorded. RESULTS: At commencement of treatment, participants had significantly (p<0.001) reduced vertical and horizontal mouth opening range compared to controls. Average duration of orofacial contracture management was 550 days, with half requiring >2 years rehabilitation. By end of treatment, significant (p<0.01) positive improvement in vertical and horizontal mouth opening had been achieved, however measures had returned to lower limits of normal function and remained significantly (p<0.05) reduced compared to the control group. CONCLUSION: This study demonstrates that although positive gains can be achieved through non-surgical exercise after full thickness burn, the duration of rehabilitation is considerable and some degree of long term loss in functional mouth opening remains.

Orofacial contracture management outcomes following partial thickness facial burns.

PURPOSE: To examine clinical outcomes following non-surgical exercise for contracture management post partial thickness orofacial burn. METHODS: A cohort of 229 patients with partial thickness orofacial burn was recruited over 3 years. Orofacial contracture management combining exercise and stretching was initiated within 48h of admission and continued until functional goals were consistently achieved. A second cohort of 120 healthy controls was recruited for normative comparison. Vertical and horizontal mouth opening measures were recorded at the start and completion of orofacial intervention for patients and once only for controls. RESULTS: At commencement of intervention, participants with orofacial burns had significantly (p<0.001) reduced vertical and horizontal mouth opening. Treatment duration averaged 30.7 days (SD=52.3). Post treatment significant (p<0.001) improvements in vertical and horizontal opening were noted. At treatment conclusion, a significant (p<0.01) difference remained between the burns cohort and control group for vertical mouth opening, though horizontal mouth opening was now statistically comparable to the controls. CONCLUSION: This study supports positive outcomes following orofacial contracture management for patients with partial thickness orofacial burn. Despite this, some functional loss remained with patients demonstrating persistent reduced vertical mouth opening at conclusion of treatment compared to their healthy counterparts.

Functional speech outcomes after laryngectomy and pharyngolaryngectomy.

OBJECTIVE: To compare and contrast functional speech outcomes of patients having undergone total laryngectomy and pharyngolaryngectomy who use tracheoesophageal speech as their primary mode of communication. DESIGN: Group comparison design. SETTING: Adult acute tertiary care hospital. PATIENTS: Thirty patients who underwent total laryngectomy and 13 who underwent pharyngolaryngectomy with free jejunal interposition reconstruction. All patients used tracheoesophageal speech. INTERVENTION: Group comparisons across measures of speech intelligibility, voice quality, tracheoesophageal speech use, voice satisfaction and levels of perceived voice disability, handicap, and well-being/distress. MAIN OUTCOME MEASURE: The existence of any significant differences between the 2 groups on measures of intelligibility, voice quality, tracheoesophageal speech use, and voice satisfaction and levels of voice disability, handicap, and well-being/distress. RESULTS: Statistical comparisons confirmed reduced functional intelligibility (P<.05), reduced vocal quality (P<.01), and higher levels of disability (P<.05) in the pharyngolaryngectomy group. However, no significant difference was observed between the proportion of patients classified as "successful" tracheoesophageal speech users in either group. Low levels of handicap and high levels of patient well-being were recorded in both groups. CONCLUSION: Despite the perceptual differences in voice quality and intelligibility observed between the 2 groups, tracheoesophageal speech that is functional, effective, and perceived by the patients as satisfactory can be achieved after total laryngectomy and pharyngolaryngectomy with free jejunal interposition reconstruction.

Duration of dysphagic symptoms and swallowing outcomes after thermal burn injury.

Levels of swallowing disability, patterns of dysphagia rehabilitation and swallowing outcomes on discharge were retrospectively reviewed for 30 patients with thermal burn injury (with or without inhalation injury), referred to speech pathology services for dysphagia management. The average total surface burn area of the group was 50%. All patients were mechanically ventilated for an average of 24 days, with 80% of patients requiring subsequent tracheostomy. Initial dysphagia assessment occurred approximately 20 days after admission, whereas first safe oral intake was achieved by approximately 30 days. Supplementary nutrition and hydration was necessary for all patients. The time to achieve oral intake without supplementation was 53 days. Outcome measures revealed a significant improvement in swallowing function throughout the duration of inpatient stay, with 90% of patients discharged safely tolerating a normal diet, 6.7% of patients managing soft diet consistencies, and 3.3% managing soft puree consistencies on discharge.

Impact of malocclusion and orthognathic reconstruction surgery on resonance and articulatory function: an examination of variability in five cases.

Articulatory patterns and nasal resonance were assessed before and 6 months after orthognathic reconstruction surgery in five patients with dentofacial deformities. Perceptual and physiological assessments showed disorders of nasality and articulatory function preoperatively, two patients being hyponasal, and one hypernasal. Four patients had mild articulatory deficits, and four had reduced maximal lip or tongue pressures. Operation resulted in different patterns of change. Nasality deteriorated in three patients and articulatory precision and intelligibility improved in only one patient and showed no change in the other four. Operation improved interlabial pressures in three patients, while its impact on tongue pressures varied, being improved in one case, deteriorating in one, and remaining unchanged in the other three. The variability in the results highlights the need for routine assessment of speech and resonance before and after orthognathic reconstruction.

Tongue-to-palate contact patterns and variability of four English consonants in an /i/ vowel environment.

Minimal data exist describing tongue-to-palate contact patterns and their variability in normal speakers of English. Consequently, the aims of the present study were to examine, using a comprehensive profile of data analysis, tongue-to-palate contact patterns and their variability in a group of ten normal speakers of English using the Reading Electropalatography3 (EPG3) system. Each speaker produced ten repetitions of the target words tea, leap, sea, and key following the carrier phrase 'I saw a ...'. Results revealed that the contact patterns produced exhibited similar characteristics to those described in earlier research. Additionally, the lateral approximant /i/ exhibited the highest degree of intra-subject variability with the alveolar fricative /s/ exhibiting the least. The results of this study are discussed in relation to existing normative data.

Older African American women's lived experiences with depression and coping behaviours.

Little is known about older African American women's lived experiences with depression. What does depression mean to this group? What are they doing about their depression? Unfortunately, these questions are unanswered. This study examined older African American women's lived experiences with depression and coping behaviours. The common sense model provided the theoretical framework for present study. Thirteen community-dwelling African American women aged 60 and older (M = 71 years) participated. Using qualitative phenomenological data analysis, results showed the women held beliefs about factors that can cause depression including experiences of trauma, poverty and disempowerment. Results also indicated the women believed that depression is a normal reaction to life circumstances and did not see the need to seek professional treatment for depression. They coped by use of culturally sanctioned behaviours including religious practices and resilience. It appears these women's beliefs about depression and use of culturally sanctioned coping behaviours might potentially be a barrier to seeking professional mental healthcare, which could result in missed opportunities for early diagnosis and treatment of depression among this group. Implications for research, educational and clinical interventions are discussed.

Dysarthria and dysphagia following treatment for a fourth ventricle choroid plexus papilloma.

The present case report describes the presence of a persistent dysarthria and dysphagia as a consequence of surgical intervention for a choroid plexus papilloma (CPP). WM was a nine year ten month old male who at the time of the present study was seven years post-surgery. A comprehensive perceptual and instrumental test battery was used to document the nature of the dysarthria incorporating all components of speech production including respiration, phonation, resonance, articulation, and prosody. The nature of the dysphagia was evaluated through the use of videofluoroscopic evaluation of swallowing (VFS). Assessments confirmed the presence of a LMN dysarthria, marked by deficits in phonation, respiration, and prosody. Dysphagia assessment revealed deficits in oral preparatory, oral and pharyngeal stages of the swallow. The presence of persistent dysarthria and dysphagia in this case has a number of important implications for the management of children undergoing surgery for fourth ventricle CPPs, in particular the need for appropriate treatment, as well as counselling prior to surgery of the possible negative outcomes related to speech and swallowing.

Differential modes of alaryngeal communication and long-term voice outcomes following pharyngolaryngectomy and laryngectomy.

Patterns of vocal rehabilitation for 37 pharyngolaryngectomy patients and 55 total laryngectomy patients over a 5-year period were compared. An electrolarynx (EL) was introduced as the initial communication mode immediately after surgery for 98% of patients, with 30% of pharyngolaryngectomy and 74% of laryngectomy patients subsequently developing tracheoesophageal speech (TES) as their primary mode of communication. Follow-up with 14 of 37 pharyngolaryngectomy patients and 36 of 55 laryngectomy patients was conducted 1-6 years following surgery and revealed that 90% of the pharyngolaryngectomy patients maintained the use of TES in the long term compared to 69% of the laryngectomy group. Long-term outcomes relating to communication disability and handicap did not differ significantly between the two surgical groups, however the laryngectomy patients had significantly higher levels of wellbeing. Across the whole group of patients, statistical comparison revealed that patients using TES had significantly lower levels of disability, handicap and distress than EL users. Considering that lower levels of disability, handicap and distress are associated with TES, and the data supports that suitably selected patients can maintain functional TES in the long term, increased application of this form of communication rehabilitation should be encouraged where viable for the pharyngolaryngectomy population.

Real-time continuous visual biofeedback in the treatment of speech breathing disorders following childhood traumatic brain injury: report of one case.

The efficacy of traditional and physiological biofeedback methods for modifying abnormal speech breathing patterns was investigated in a child with persistent dysarthria following severe traumatic brain injury (TBI). An A-B-A-B single-subject experimental research design was utilized to provide the subject with two exclusive periods of therapy for speech breathing, based on traditional therapy techniques and physiological biofeedback methods, respectively. Traditional therapy techniques included establishing optimal posture for speech breathing, explanation of the movement of the respiratory muscles, and a hierarchy of non-speech and speech tasks focusing on establishing an appropriate level of sub-glottal air pressure, and improving the subject's control of inhalation and exhalation. The biofeedback phase of therapy utilized variable inductance plethysmography (or Respitrace) to provide real-time, continuous visual biofeedback of ribcage circumference during breathing. As in traditional therapy, a hierarchy of non-speech and speech tasks were devised to improve the subject's control of his respiratory pattern. Throughout the project, the subject's respiratory support for speech was assessed both instrumentally and perceptually. Instrumental assessment included kinematic and spirometric measures, and perceptual assessment included the Frenchay Dysarthria Assessment, Assessment of Intelligibility of Dysarthric Speech, and analysis of a speech sample. The results of the study demonstrated that real-time continuous visual biofeedback techniques for modifying speech breathing patterns were not only effective, but superior to the traditional therapy techniques for modifying abnormal speech breathing patterns in a child with persistent dysarthria following severe TBI. These results show that physiological biofeedback techniques are potentially useful clinical tools for the remediation of speech breathing impairment in the paediatric dysarthric population.

Mechanisms of dimethylbenzanthracene-induced immunotoxicity.

Traditional methods for toxicological assessment have implicated the immune system as a frequent target organ of toxic insult following chronic exposure to certain environmental chemicals, radiation or therapeutic drugs (xenobiotics). Immunotoxicity is expressed as autoimmunity, chemical hypersensitivity or immunosuppression. A tiered approach for characterizing chemical and drug-induced immunomodulation has been developed and validated in laboratory animals. Polycyclic aromatic hydrocarbons (PAH) have been studied because of their ubiquitous presence in the environment and carcinogenic potential. Since immunosuppression induced by PAH carcinogens has been implicated as an epigenetic mechanism in the outgrowth of initiated cells, this tiered approach was used to characterize the mechanism of PAH immunosuppressive capacity. Previously, studies in this laboratory have demonstrated that subchronic exposure of B6C3F1 mice to PAH carcinogens suppresses both humoral immunity (HI) and cell-mediated immunity (CMI), concurrently with decreased resistance to tumor challenge. The potent carcinogenic PAH, 7,12-dimethylbenz[a]anthracene (DMBA) was subchronically administered subcutaneously at 5, 50, or 100 micrograms/g of body weight. Natural killer (NK) cell tumor cytolysis, generation of cytotoxic T-cells (CTL), and lymphoproliferation to mitogens and allogeneic splenocytes in mixed leukocyte cultures (MLC) were quantitated 3-5 days after exposure to assess CMI. Mitogen and alloantigen-induced proliferation (MLC) of splenocytes was suppressed up to 90%. CTL and NK tumor cytolysis of radiolabelled target cells were similarly depressed up to 88 and 82%, respectively. Impairment of MLC or CTL responses correlated with increased susceptibility to challenge with PYB6 sarcoma cells. HI was measured by quantitating the number of antibody (IgM) plaque-forming cells (PFC) produced in response to T-cell dependent antigen challenge (sheep erythrocytes) and was similarly suppressed up to 95%. To understand the mechanism of PAH-induced immunotoxicity, splenocytes from DMBA-exposed mice were sensitized to alloantigens in the presence of interleukin-2 (IL-2) because there were indications that T-helper cell function was suppressed. In these preliminary studies, CTL suppression could be completely restored by the addition of the T-cell growth supporting lymphokine (IL-2) during the inductive phase of CTL generation, suggesting that DMBA exposure directly or indirectly induced deficits in T-helper cell function.

Immunological studies in B6C3F1 mice following exposure to ethylene glycol monomethyl ether and its principal metabolite methoxyacetic acid.

Exposure to glycol ethers has been associated with adverse effects in laboratory animals including thymus atrophy and mild leukopenia. These effects may involve depletion of immunoresponsive cells. This study examined possible alterations in immune function and host resistance of B6C3F1 mice following exposure to ethylene glycol monomethyl ether (EGME) or its principal metabolite, methoxyacetic acid (MOAA). EGME and MOAA were administered by gavage to mice in 10 doses over a 2-week period at total dosages of 250, 500, and 1000 micrograms/g of body weight. Following exposure, immunopathology, humoral immunity, cell-mediated immunity, macrophage function, and host resistance to Listeria monocytogenes bacterial challenge were examined. A 48% reduction in thymus weight was observed at the intermediate and high doses of both chemicals. No significant alterations in immune function or host resistance to L. monocytogenes were observed in animals exposed to either EGME or MOAA.

Persistent suppression of humoral and cell-mediated immunity in mice following exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene.

Carcinogen-induced immunosuppression has been implicated as an epigenetic mechanism in promoting the outgrowth and metastasis of neoplastic cells. It has previously been reported that the complete carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) suppresses both humoral immunity (HI) and cell-mediated immunity (CMI) 3-5 days following exposure. Since persistent systemic immunosuppression may be more relevant in tumor outgrowth, assays quantitating HI and CMI, including those functions involved in tumor resistance, were performed 4 and 8 weeks following exposure to tumorigenic doses of DMBA. Adult B6C3F1 female mice were administered DMBA dissolved in corn oil subcutaneously at 5, 50 and 100 micrograms/g body weight in ten equal doses over 2 weeks (corn oil = vehicle control). The number of splenocytes producing IgM antibody to the T-dependent antigen, sheep erythrocytes, was suppressed up to 95% and 98% at 4 and 8 weeks, respectively. The IgG response was similarly depressed 75% and 98% at 4 and 8 weeks, respectively. Lymphoproliferation of splenocytes in response to the mitogens LPS, PHA and Con A were depressed up to 88%, 78% and 83% at 4 weeks and 63%, 63% and 67% respectively, at 8 weeks. In addition, alloantigen-induced proliferation of splenocytes in a one-way mixed lymphocyte culture was suppressed up to 90% at 8 weeks. The ability to generate cytotoxic T-lymphocytes (CTL) in vitro against P815 tumor cells was depressed at both time periods (88% and 60%, respectively) as was natural killer (NK) cell cytolysis of YAC-1 tumor targets (84% and 55%, respectively). The immunosuppression noted in these parameters was similar to that observed within 3-5 days following DMBA dosing. The persistent immunosuppression induced by the PAH carcinogen DMBA, including CTL and NK cell tumoricidal functions, may represent an important epigenetic mechanism contributing to tumor outgrowth or metastasis by this class of agents.