Polygraphy vs. polysomnography: missing osas in symptomatic snorers--a reminder for clinicians.

PURPOSES: The purposes of this study are to investigate the usefulness of polygraphy (PG) in diagnosing obstructive sleep apnea (OSA) in sleepy/tired snorers compared to polysomnography (PSG) and, further, to search for suspected respiratory arousals in the PG. METHODS: One hundred eighty-seven adults suffering from sleepiness/tiredness and snoring had undergone ambulant PG and were considered to be normal, using American Academy of Sleep Medicine's 2007 hypopnea criteria A. After approximately 7 months, in-lab PSG was performed using hypopnea criteria B, where arousals are also recognized. Validated questionnaires (Hospital Anxiety and Depression Scale, self-rated general health) were answered. In a subgroup, the sensitivity and specificity were calculated for flow limitation index (FLI) and flattening index (FlatI) in PG compared with the respiratory distress index (RDI) in PSG. RESULTS: Despite the normal PG, at PSG, the median RDI was 11.0 (range, 0-89.1). One hundred sixty-eight out of one hundred seventy-eight (90%) were found to have at least mild OSA and 119/187 (64%) with moderate-severe OSA according to the RDI values. The sensitivity and specificity were low (<70%) for FLI and FlatI. Forty-nine percent of the patients rated anxiety at borderline or pathological levels, 35% rated corresponding depression levels, and 45% rated poor or fair general health. CONCLUSIONS: PG was insufficient to rule out OSA when the respiratory events were mainly associated with arousals. Almost half of these patients experience low general health and psychiatric problems. We recommend a full-night PSG when PG is "normal", and patients have symptoms of snoring and sleepiness/tiredness.

Erythromelalgia? A clinical study of people who experience red, hot, painful feet in the community.

We recruited a population of people who clinically suffer from the symptoms of erythromelalgia, red, hot, painful feet made worse by heat and improved by cooling, to better characterise this population and measure their quality of life (QOL). Ninety-two individuals completed the QOL surveys, and 56 individuals were clinically assessed. There was a 3 : 1 ratio of females to males with an average age of 61 years. The estimated prevalence of people who had clinical symptoms of erythromelalgia in the Dunedin community was 15/100,000. Only 27% of people had received a diagnosis for their symptoms despite seeking medical attention. People in the study population had worse quality of life than the general New Zealand population (P < 0.001). In the majority of participants symptoms had a mild-moderate effect on their quality of life. The results of this study indicate that the number of people who have clinical symptoms of erythromelalgia is much greater than is commonly accepted and that the majority of these individuals go unrecognised by the medical profession despite seeking help. They have significantly diminished QOL with the majority of people having mild-to-moderate symptoms.

Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.

PURPOSE: To define the maximum tolerated dose (MTD) and the nature of the toxicities associated with gemcitabine given as a short infusion to patients with non-small cell lung cancer (NSCLC). Secondary objectives were to monitor immunologic response, clinical response, and survival. PATIENTS AND METHODS: Thirty-two patients diagnosed with advanced inoperable NSCLC and performance status of 0 or 1 participated in this study. Patients consisted of 22 males and 10 females whose median age was 62 years (range 32-79). Gemcitabine was administered as a 30 min infusion once weekly for 3 weeks followed by 1 week of rest. Patients were enrolled at six gemcitabine dose levels ranging from 1000 to 3500 mg/m2. Patients completed a median of four cycles (range 1-17). Responses were evaluated after every two cycles. RESULTS: Toxicity was evaluated in all 32 patients. The MTD was not reached as gemcitabine was well tolerated at all dose levels. Grade 4 toxicity occurred in three (9%) patients: pulmonary and lymphocytopenia in one patient each, and both neurocortical and cardiac in one patient. Grade 3 toxicity was found in a total of 20 (63%) patients: pulmonary in 10 (31%) patients; pain in 6 (19%) patients; liver toxicity in 6 (19%) patients; leukopenia and lymphocytopenia in 5 (16%) patients each; anemia, nausea, and cardiac toxicity in 3 (9%) patients each; proteinuria and infection in 2 (6%) patients each; and hemorrhage in 1 (3%) patient. Of the 29 patients evaluable for response, seven objective responses were achieved: six at the 2200 mg/m2 dose level and one at the 2800 mg/m2 dose level. The distribution of responses differed significantly by dose (P = 0.0124 by the exact chi-square test for independence). The overall response rate was 24.1% (95% CI, 10.3-43.5%). At 6 h post-infusion, there was a significant increase in spontaneous tumor necrosis factor (TNF) release and stimulated interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte counts (CD3+, CD8+, and CD16+ lymphocytes) and resting and stimulated superoxide production by formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate, and opsonized zymosan (OPS-Z). At 24 h post-infusion, there were significant decreases in total lymphocyte count, lymphocyte subsets (CD3+, CD4-, CD8+, CD56+, CD19+), and in resting and stimulated superoxide production by fMLP and OPS-Z. There also appeared to be an association between the levels of spontaneous TNF release and the severity of both gastrointestinal (GI) and pulmonary toxicities. CONCLUSION: Gemcitabine given as a short infusion was well tolerated at the dose levels of 1000-3500 mg/m2. The MTD was not reached. Toxicities appeared to be cumulative with multiple cycles. Gemcitabine appears to have activity against NSCLC. Although there was a differential dose-response rate among dose levels, increasing the gemcitabine dose beyond 2200mg/m2 did not show increased clinical response. Gemcitabine appears to modulate the immune response, which may in turn mediate both response and toxicity, although no statistically significant correlation between immune and clinical response was detected.

Heavy snorer's disease: a progressive local neuropathy.

"Heavy snorer's disease" is defined as progression from heavy snoring to obstructive sleep apnoea syndrome (OSAS). Apart from significant weight gain, the aetiology underlying progression to a collapse of the upper airways during inspiration and sleep remains unclear. Previous studies have shown that nocturnal respiratory disturbances became worse, even in some OSAS patients who did not gain weight. The patency of the upper airways depends on the balance between the negative intrapharyngeal pressure developed during inspiration and its counteraction by dilating muscles. The reflexogenic dilation is probably mediated by afferent nerve endings in the pharyngeal mucosa. Chronic vibration of a tissue may cause neuronal damage. Therefore, the hypothesis that snoring per se might cause progressive pharyngeal nerve lesion has been tested in a series of studies from the Karolinska Institute, Stockholm, which, along with other studies, will be reviewed here. In these studies it was found that a majority of patients with heavy snoring and different degrees of respiratory disturbance had signs of pharyngeal afferent and efferent (motor) nerve lesions. These lesions may cause the collapse of upper airways in OSAS. Since it is not known which "heavy snorer" will develop OSAS, early effective prevention and or treatment of snoring is called for.

Cytokine production and bone mineral density at the lumbar spine and femoral neck in premenopausal women.

Cytokines such as interleukin-1 (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45-52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1beta, IL-6, and TNF-alpha by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1beta, IL-6, and TNF-alpha, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r = -0.30 to r = -0.13. Trends of greater spinal bone loss were observed in women with "high" (>/=75th percentile) cytokine production of stimulated IL-1beta and IL-6 (IL-1beta: "high" = -1.56% +/- 0.70 versus "low" (<75th percentile) = -0.56% +/- 0.35, P = 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1beta and IL-6 (IL-1beta: high = 3.39% +/- 1.16 versus low = -0. 85 +/- 0.58, P = 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites.

Natural killer cells and natural killer cell activity in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is associated with insidious and persistent immunologic abnormalities that have proved difficult to reproduce. The heterogeneity of CFS, the variable quality of immunologic assays and their performance, along with an almost complete absence of longitudinal studies of cellular immune abnormalities in CFS may explain this difficulty. However, in a significant proportion of cases, low levels of natural killer (NK) cell activity have been reported. This article will explore the mechanisms responsible for low NK cell activity, discuss the relation between levels of NK cell activity and health/disease, describe new findings on NK cell-brain interactions, and put forth a specific hypothesis for the role of NK cells in the pathogenesis of CFS.

Dysfunction of natural killer activity in a family with chronic fatigue syndrome.

A family was identified with 5 of 6 siblings and 3 other immediate family members who had developed chronic fatigue syndrome (CFS) as adults. All 8 met criteria for the CFS case definition as recommended by the Centers for Disease Control and Prevention. Sixty-eight blood samples were obtained over a period of 2 years from 20 family members (8 affected, 12 unaffected) and 8 normal controls. All blood samples were tested for NK activity in 4-h 51Cr-release assays and for the number of circulating CD3-CD56(+) and CD3-CD16(+) by flow cytometry. NK activity of the affected immediate family members (cases, n = 8) was significantly lower (P = 0.006, two-sided) than that of the concurrently tested normal controls. The results for unaffected family members were intermediate between these two groups, and the pairwise comparison of unaffected family members to either cases or controls showed no statistically significant difference (P = 0.29, two-sided). No differences were seen between the groups in the absolute number of CD3-CD56(+) or CD3-CD16(+) lymphocytes in the peripheral blood. Familial CFS was associated with persistently low NK activity, which was documented in 6/8 cases and in 4/12 unaffected family members. In the family with 5 of 6 siblings who had documented CFS, 2 of their offspring had pediatric malignancies. Low NK activity in this family may be a result of a genetically determined immunologic abnormality predisposing to CFS and cancer.

Evaluation of the vascular reaction in pharyngeal mucosa.

The patency of the upper airways during inspiration is maintained by reflexogenic muscular dilation, mediated by afferent nerves. Our hypothesis is that a local disturbance in these nerves might explain the increased tendency of upper airways to collapse in patients with obstructive sleep apnea. The vascular reaction in the mucosal microcirculation is regulated by afferent nerves. To investigate this, we developed the laser Doppler perfusion monitoring method and electrical nerve stimulation for investigations of the soft palatal mucosa in non-snoring subjects. A 12 cm probe with integrated bipolar electrodes and a special probe-holder were designed. The bandwidths 12 and 24 kHz were compared and the latter was better able to detect a high blood-flow. A dose response relation was found between the voltage stimulation level and percentage increase in blood-flow. Three series of stimuli (40 V) in 10 subjects caused reproducible vascular reactions. In conclusion, this method seems to be safe, tolerable and valuable for investigations of patients with obstructive sleep apnea or other pharyngeal disorders, e.g. dysphagia, in the search for local nerve lesions.

Habitual snorers and sleep apnoics have abnormal vascular reactions of the soft palatal mucosa on afferent nerve stimulation.

A local disturbance in the afferent nerves involved in the reflexogenic dilation of the upper airways (UAs) could contribute to the increased collapsibility seen in patients with obstructive sleep apnea (OSA). Laser Doppler perfusion monitoring, combined with electrical stimulation, is a method for investigating the afferent nerve regulation of the microcirculation. It was used in the mucosa of the soft palate in 35 patients with various degrees of UA obstruction and in 13 control subjects, all nonsmoking men. In a majority of snorers and patients with mild OSA, stimulation induced an exaggerated vasodilation, compared with controls. In contrast, in patients with severe OSA, the vasodilation was significantly reduced, compared with controls. These signs of disturbances in the microcirculation support the hypothesis of a local progressive afferent nerve lesion in heavy snorers with or without OSA.

Histological indications of a progressive snorers disease in an upper airway muscle.

The etiology of upper airway collapsibility in patients with snoring and obstructive sleep apnea (OSA) remains unclear. Local muscular abnormalities, including neurogenic lesions, could be a contributory factor. The aim of this study was to histologically evaluate the hypothesis of a progressive snorers disease. Biopsies of palatopharyngeal muscle were obtained from 21 patients with habitual snoring and different degrees of upper airway obstruction (10 patients with OSA) and 10 nonsnoring control subjects. Morphological abnormalities, including neurogenic signs (e.g., type grouping), were blindly quantified. The degree of abnormality was significantly increased in patients compared with control subjects. The individual score of abnormalities was significantly correlated to the percentage periodic obstructive breathing but not to oxygen desaturation index. Analyses of the individual fiber-size spectra demonstrated a significantly increased number of hypertrophied and/or atrophied fibers in patients compared with controls. The subjects were also divided into three groups according to their type of nocturnal breathing, i.e., nonsnorers, patients with < 20%, and patients with > or = 45% obstructive breathing. These groups correlated significantly with the degree of abnormality and pathological fiber-size spectra. In conclusion, these results support the hypothesis of a progressive local neurogenic lesion, caused by the trauma of snoring, as a possible contributory factor to upper airway collapsibility.

Abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers.

Habitual snoring precedes obstructive sleep apnea (OSA), but the pathophysiological mechanisms behind progression are still unclear. The patency of upper airways depends on a reflexogen mechanism reacting on negative intrapharyngeal pressure at inspiration, probably mediated by mucosal receptors, i.e., via afferent nerve endings. Such nerves contain a specific nerve protein, protein-gene product 9.5 (PGP 9.5) and in some cases substance P (SP) and calcitonin gene-related (CGRP). Biopsies of the soft palatial mucosa were obtained from non-smoking men ten OSA patients, 11 habitual snorers and 11 non-snoring controls. The specimens were immunohistochemically analyzed for PGP 9.5, SP and CGRP. As compared to controls, an increased number of PGP-, SP- and CGRP-immunoreactive nerves were demonstrated in the mucosa in 9/10 OSA patients and 4/11 snorers, in addition to varicose nerve endings in the papillae and epithelium. Using double staining methodology, it could be shown that SP- and CGRP-like immunoreactivities (LIs) often coexisted in these fibres, as did CGRP- and PGP 9.5-LIs. The increased density in sensory nerve terminals are interpreted to indicate an afferent nerve lesion. Our results support the hypothesis of a progressive neurogenic lesion as a contributory factor to the collapse of upper airways during sleep in OSA patients.

Comparison of europium and chromium release assays: cytotoxicity in healthy individuals and patients with cervical carcinoma.

Natural killer (NK) and lymphokine-activated killer (LAK) cell activities were measured in peripheral blood obtained from healthy women to compare a standard 51Cr release assay with a nonradioactive europium (Eu3+) release assay based on time-resolved fluorescence. The two types of cytotoxicity assays were first compared in paired determinations performed on 28 samples of peripheral blood mononuclear cells obtained from healthy women who had normal pap smears or no biopsy evidence of cervical squamous intraepithelial lesions (SIL). Target cells (NK-sensitive K562 and NK-resistant Raji cell lines) were labeled with Eu3+ only, 51Cr only, or both labels and compared in cytotoxicity assays using fresh or interleukin 2 (IL-2)-activated effector cells. Spontaneous release in the Eu3+ release assay was comparable to that observed in the 51Cr release assay, but maximum Eu3+ release always exceeded that of 51Cr. In 4-h assays, specific release of Eu3+ from target cells was more rapid than that of 51Cr, consistently resulting in 30 to 40% higher levels of activity. However, a significant linear correlation (P < 0.001) was observed between cytotoxicity levels based on measurements of Eu3+ and 51Cr release in 4-h assays. The Eu3+ release assay was then used to measure NK and LAK activities in the peripheral blood of women with cervical SIL or cervical squamous cell carcinoma (SCC). Mean NK activity of women with advanced SIL (121 lytic units [LU]) or SCC (93 LU) was found to be similar to that of controls (101 LU) or patients with normal cervical biopsies (90 LU), as was the ability to generate IL-2-stimulated NK activity. However, LAK activity during 18 h of incubation in the presence of IL-2 was reduced in patients with cervical SCC (P < 0.05) compared with that in normal controls. Results of 51Cr assays performed in parallel with patient samples gave comparable results. Advantages of EU3+ release assays for routine evaluation of cytotoxicity are discussed.

UPPP for habitual snoring: a 5-year follow-up with respiratory sleep recordings.

Fifty-six men who underwent uvulopalatopharyngoplasty (UPPP) because of habitual snoring without preoperative obstructive sleep apnea (OSA), according to respiratory sleep recordings, were interviewed concerning persistent snoring and excessive daytime sleepiness (EDS). Renewed recordings were made in 53 of them at a median time of 63 months postoperatively. Median preoperative oxygen desaturation index (ODI) was 0; the median postoperative index was 1. Median duration of the preoperative obstructive respiratory pattern was 8% of total sleeping time, and the median duration postoperatively was 17%. (Significant individual increases were P = .0005 and P = .004, respectively.) Six patients answered to OSA criteria postoperatively. Weight increases were significantly correlated to increases in both ODI and obstructive respiratory pattern and to persistent snoring. Preoperatively 51 of 56 patients reported EDS, and 73% of the patients were improved or cured. From snoring, 87% reported improvement or cure. No patient had any serious sequelae of UPPP. Uvulopalatopharyngoplasty is a safe and effective treatment for habitual snoring, but it does not give absolute protection from development of OSA.

In vitro cytokine production by normal human peripheral blood mononuclear cells as a measure of immunocompetence or the state of activation.

Measurements of cytokine levels in serum may not adequately reflect the cytokine-producing potential of immune cells because of the short half-lives of cytokines and the presence of various inhibitors in human sera. In vitro cytokine production by peripheral blood mononuclear cells (PBMCs) can be an important and reliable measure of immunocompetence. Also, spontaneous in vitro release of cytokines by PBMCs may serve as a measure of their activation in vivo. In the present study, normal ranges for the in vitro production by PBMCs of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), IL-2, and gamma interferon (IFN-gamma) were established; the feasibility of using cryopreserved PBMCs for assays of in vitro cytokine production was evaluated; and spontaneous (unstimulated) versus induced production of cytokines by fresh and cryopreserved PBMCs from healthy donors was compared. Supernatants obtained from paired fresh and frozen PBMCs were quantitated for IL-1 beta, TNF-alpha, IL-2, and IFN-gamma by using enzyme-linked immunosorbent assay or a radioimmunoassay standardized against World Health Organization cytokine standards. Fresh or cryopreserved PBMCs activated with lipopolysaccharide produced comparable levels of IL-1 beta. However, the mean levels of stimulated production of TNF-alpha, IFN-gamma, and IL-2 were significantly higher in cryopreserved versus fresh PBMCs (P < or = 0.0004). Correlations between the level of production of each cytokine by fresh versus cryopreserved in vitro-stimulated PBMCs were statistically significant, although of moderate magnitude. Spontaneous cytokine release by fresh versus cryopreserved cells was not significantly different.

Cytokine production and serum levels in systemic sclerosis.

Serum levels of various cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL1-beta), and interleukin 2 (IL2), and of soluble IL2 receptors (sIL2R) were determined in 30 patients with definite systemic sclerosis (SSc). Spontaneous and lipopolysaccharide-or mitogen-induced production of the cytokines, TNF-alpha, IL1-beta, and IFN-gamma, by peripheral blood mononuclear cells (PBMNC) of these SSc patients was measured by immunoassays. The patients were divided into three groups: 12 with limited cutaneous disease (lcSSc), 7 with diffuse cutaneous disease (dcSSc) < 3 years duration, and 11 with dcSSc > 3 years duration. None were treated with cytotoxic drugs or biologic response modifiers. Sera of patients with SSc had elevated sIL2R levels, and only low levels of IL2 (1-2 U/ml) were detected in 10/29 sera tested. Spontaneous production of TNF-alpha and IL1-beta by PBMNC of patients with SSc (829 pg/ml +/- 215 SEM and 728 pg/ml +/- 186, respectively) was significantly higher than that by normal PBMNC obtained from 30 volunteers (25 +/- 10 and 34 +/- 6 pg/ml, respectively) and tested at the same time as patients' PBMNC. The largest increases in spontaneous release of TNF-alpha or IL1-beta were seen in patients with early dcSSc. No significant difference in spontaneous IFN-gamma production by patient or control PBMNC was detected. On the other hand, the mean level of mitogen-induced IFN-gamma production by PBMNC was significantly depressed in patients with SSc (103 U/ml +/- 18 vs 255 +/- 33 U/ml in controls). In vitro-induced production of TNF-alpha or IL1-beta by patients' PBMNC was comparable to that of normal PBMNC. These data indicate that in vivo-activated PBMNC of patients with SSc spontaneously secrete excessive amounts of fibrogenic cytokines, which are involved in modulation of connective tissue synthesis.

Lymphokine-activated killer cell and natural killer cell activities in patients with systemic sclerosis.

OBJECTIVE: To determine the ability of T lymphocytes and natural killer (NK) cells from patients with systemic sclerosis (SSc) to respond to cytokines and to generate immune effector cells. METHODS: The numbers and percentages of peripheral blood T and NK cells were examined by 2-color flow cytometry, and NK and lymphokine-activated killer (LAK) cell function were measured in 4-hour 51Cr-release assays, in 34 patients with SSc. The patients were categorized into 3 subgroups: 10 had diffuse cutaneous disease of less than or equal to 3 years disease duration, 11 had diffuse cutaneous SSc of greater than 3 years duration, and 13 had limited cutaneous disease. RESULTS: Baseline and activated NK and T cell numbers and NK activity were normal in SSc patients. However, mean LAK activity was significantly depressed in all SSc subgroups. CONCLUSION: Decreased LAK cell function, despite normal numbers of circulating T and NK cells, indicates that SSc patients have poor ability to produce effector cells in response to interleukin-2.

Antibiotic prophylaxis in major head and neck surgery when clean-contaminated wounds are established.

The case reports of 26 consecutive patients undergoing major head and neck surgery establishing direct wound communication between skin and mucosa of the oral cavity or the pharynx were analysed with respect to postoperative wound infections. All but two of the patients were perioperatively administered benzylpenicillin or benzylpenicillin in combination with tinidazole. The frequencies of wound infections were 23-25% when only severe infections as fistulation, pus-formation were taken into account, but 59-75% when also mild infections, not likely to impair the healing, were considered. The most frequently isolated pathogen in the wound infections was beta-lactamase producing Staphylococcus aureus. It is concluded that antibiotic prophylaxis reduces the risk of severe wound infections by approximately 50%. Antimicrobial prophylaxis can only be regarded as an important complement to good surgical techniques.

In vitro effects of an acyltripeptide, FK565, on NK-cell activity, LAK-cell generation and cytokine production by human mononuclear cells.

In vitro effects of an immunostimulatory acyltripeptide, FK565, on natural killer (NK)-cell activity, lymphokine-activated killer (LAK)-cell generation and cytokine production of normal human peripheral blood mononuclear cells (MNC) were studied. FK565 used at concentrations ranging from 0.1 to 100 micrograms/ml enhanced NK-cell activity only if adherent MNC were removed. The optimal NK-cell enhancing dose was 2 micrograms/ml FK565. At the same range of concentrations, FK565 activated adherent MNC to induce suppression of NK-cell activity in autologous non-adherent MNC preparations. FK565 also potentiated both the generation of LAK-cell activity in the presence of 1000 U/ml of interleukin 2 (IL2) and the effector phase of LAK cells generated at the IL2 concentration of 50 U/ml. The synergistic interaction of IL2 and FK565 on LAK-cell activity was observed for all drug concentrations used. The effects of FK565 on cytotoxic cells could not be attributed to IL2, interferon gamma or tumor necrosis factor-alpha, because FK565 alone had no detectable influence on in vitro production of these cytokines by MNC. The ability of FK56 to modulate effector cells of natural antitumor immunity indicates that it may have promise as a biological response modifier in humans.