The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina.

Mycobacterium tuberculosis (Mtb) causes nearly 10 millions of new tuberculosis disease cases annually. However, most individuals exposed to Mtb do not develop tuberculosis, suggesting the influence of a human genetic component. Here, we investigated the association of the rs2275913 SNP (G → A) from IL-17A and tuberculosis in Argentina by a case-control study. Furthermore, we evaluated in vitro the functional relevance of this SNP during the immune response of the host against Mtb and analyzed its impact on clinical parameters of the disease. We found an association between the AA genotype and tuberculosis resistance. Additionally, within the healthy donors population, AA cells stimulated with a Mtb lysate (Mtb-Ag) produced the highest amounts of IL-17A and IFN-γ, which further support the genetic evidence found. In contrast, within the tuberculosis patients population, AA Mtb-Ag stimulated cells showed the lowest immunological parameters and we evidenced an association between the AA genotype and clinical parameters of disease severity, such as severe radiological lesions and higher bacilli burden in sputum. Overall, our findings demonstrated that the AA genotype from the IL-17A rs2275913 SNP is positively associated with protection to active tuberculosis but related to higher disease severity in the Argentinean population.

Evolución de la pediatría en Atención Primaria / Evolution of pediatrics in Primary Health Care

No disponible

Intradermal ketorolac for reduction of epidural back pain.

Between 30 and 45% of all parturients receiving epidural laboring analgesia complain of postpartum back pain. Although long-term or chronic back pain has been reported, our study focuses on acute or short-term back pain that resolves within 72 h. The purpose of this randomized double-blind, placebo-controlled investigation was to determine if a ketorolac/lidocaine intradermal anesthesia combination could decrease post-epidural back pain. A total of 81 non-complicated parturients requesting epidural analgesia were approached for inclusion and randomized to receive either 3 mL of 1% lidocaine (control group) or 3 mL of 1% lidocaine with 6 mg ketorolac (experimental group) for dermal anesthesia. A 0-10 verbal numeric scale was used to assess pain at rest and with activity at 24 and 72 h. Demographics, mode of delivery, and duration of labor were noted. A chi2 test was used to analyse frequency data and a Student's t-test and generalized estimation equation were used to analyze ordinal and interval data. Demographics, mode of delivery and length of labor were similar between groups. Significantly lower verbal numeric scores were noted in the experimental group at the 24-h active measurements after vaginal delivery and at 24 and 72 h for both active and resting measurements after cesarean delivery. Based on these findings it can be recommended that intradermal ketorolac given at the time of epidural catheter placement may result in a reduction in post-epidural back pain in the parturient, especially in the event of cesarean delivery.

A randomized trial comparing povidone-iodine to a chlorhexidine gluconate-impregnated dressing for prevention of central venous catheter infections in neonates.

UNLABELLED: Neonates who require a central venous catheter (CVC) for prolonged vascular access experience high rates of catheter-related bloodstream infection (CRBSI). PURPOSE: A multicenter randomized clinical trial was undertaken to ascertain the efficacy of a novel chlorhexidine-impregnated dressing (Biopatch Antimicrobial Dressing) on the CVC sites of neonates for the prevention of catheter tip colonization, CRBSI, and bloodstream infection (BSI) without a source. Setting. Six level III neonatal intensive care units. Patients Studied. Neonates admitted to study units who would require a CVC for at least 48 hours. METHODS: Eligible infants were randomized before catheter placement to 1 of the 2 catheter site antisepsis regimens: 1) 10% povidone-iodine (PI) skin scrub, or 2) a 70% alcohol scrub followed by placement of a chlorhexidine-impregnated disk over the catheter insertion site. A transparent polyurethane dressing (Bioclusive Transparent Dressing) was used to cover the insertion site in both study groups. Primary study outcomes evaluated were catheter tip colonization, CRBSI, and BSI without an identified source. RESULTS: Seven hundred five neonates were enrolled in the trial, 335 randomized to receive the chlorhexidine dressing and 370 to skin disinfection with PI (controls). Neonates randomized to the antimicrobial dressing group were less likely to have colonized CVC tips than control neonates (15.0% vs 24.0%, relative risk [RR]: 0.6 95% confidence interval [CI]: 0.5-0.9). Rates of CRBSI (3.8% vs 3.2%, RR: 1.2, CI: 0.5-2.7) and BSI without a source (15.2% vs 14.3%, RR: 1.1, CI: 0.8-1.5) did not differ between the 2 groups. Localized contact dermatitis from the antimicrobial dressing, requiring crossover into the PI treatment group, occurred in 15 (15.3%) of 98 exposed neonates weighing

Bone suture anchors versus the pullout button for repair of distal profundus tendon injuries: a comparison of strength in human cadaveric hands.

Avulsion or distal tendon laceration of flexor digitorum profundus (FDP) is classically repaired to the base of the distal phalanx via a pullout suture over a button. Bone suture anchors, used extensively in other surgical areas, have recently been proposed for reattachment of the FDP to the distal phalanx. The FDP tendons of the index, long, and ring fingers in 9 fresh frozen cadeveric hands were randomized to 1 of 3 repair techniques after simulated distal avulsion injuries. These were the pullout button using 3-0 monofilament nylon in a 2-strand Bunnell suture pattern, the 1.8 mm Mini QuickAnchor (Mitek Products, Norwood, MA) using 3-0 braided polyester in a 2-strand Bunnell suture pattern, and the Mitek micro anchor using 3-0 braided polyester with a modified 4-strand Becker suture pattern. Nine specimens were loaded to failure, noting maximum load and mode of failure. The 1.3 mm Micro QuickAnchor (Mitek) technique (69.6 +/- 10.8 N) was significantly stronger than the pullout button (43.3 +/- 4.8 N) or the Mini anchor technique (44.6 +/- 12.7 N). The Micro bone suture anchor provides a stronger tendon to bone repair than the pullout button or the Mini anchor. Given the disadvantages of the pullout button, the Micro bone suture anchor with the modified Becker technique is worth consideration as an alternative method to repair distal FDP avulsions.

The impact of nalmefene on side effects due to intrathecal morphine at cesarean section.

Nalmefene is a long-acting opioid antagonist that provides long-term relief from side effects of intrathecal morphine sulfate. A randomized, double-blind, placebo-controlled study was conducted to determine whether prophylactic nalmefene could decrease side effects of intrathecal morphine given during cesarean section, without affecting analgesia. Sixty parturients were given 0.25 mg of intrathecal morphine, 12.5 micrograms of fentanyl, and 11.25 to 15 mg of bupivacaine. A dose of 0.25 microgram/kg of nalmefene or placebo was given by intravenous piggyback immediately after delivery of the neonate. Nausea, vomiting, pruritus, and level of sedation were assessed for a 24-hour period using a 4-point ordinal scoring system. Pain was assessed by using a 0- to 10-point verbal analogue scale. A 5-point analgesic satisfaction survey also was completed. Subjects who received nalmefene required supplemental analgesia at a median of 6.00 hours after intrathecal morphine, compared with 14.12 hours in the placebo group (P = .037). No differences were found between the groups in the incidence of pruritus, nausea and vomiting, level of sedation, or analgesic satisfaction. We concluded that nalmefene at a dose of 0.25 microgram/kg does not decrease the incidence of side effects but increases the need for supplemental analgesics.

Induction of global anergy rather than inhibitory Th2 lymphokines mediates posttrauma T cell immunodepression.

Depressed mitogen-induced IL-2 and IFN-gamma responses after severe mechanical or thermal injury are postulated to result from an expansion of Th2 lymphocytes with concomitant excessive production of IL-4 and/or IL-10. Here, we simultaneously assessed proliferation and Th1 (IFN-gamma) versus Th2 (IL-10, IL-4) lymphokine production in trauma patients' isolated T cells stimulated in a costimulation sufficient, antigen presenting cell independent system (anti CD3 + anti-CD4). T cells with depressed proliferation and IL-2 production simultaneously lost IL-4, IL-10, and IFN-gamma protein and mRNA responses. Exogenous IL-12 addition did not restore IFNgamma responses, but exogenous IL-2 partially restored IL-4, IFN-gamma, and IL-10 production. Although initially partially restored by exogenous IL-2 or stimulation with PMA + ionomycin, patient T cells with persisting anergy progressively lost even these lymphokine and proliferative responses. Development of global T cell anergy was not a result of lost T cell viability or protein synthesis, since it corresponded to predominance of anergic T cells with upregulated expression of CD11b, but downregulated CD28 and CD3 expression. Thus, the subset of posttrauma patients whose isolated T cells become unresponsive experienced progressively worsening global anergy, mediated not by an increased production of Th2 lymphokines, but possibly by T cell incapacity to be activated through TCR triggering or Ca(2+) mobilization.

The effect of oral pyridostigmine bromide nerve agent prophylaxis on return of twitch height in persons receiving succinylcholine.

Prophylactic pyridostigmine is used for troops under threat of organophosphate exposure and can affect the neuromuscular blocking agent succinylcholine. The purpose of this study was to determine what effect pyridostigmine would have on neuromuscular blockade from succinylcholine. Thirty-nine subjects were enrolled in this double-blind, placebo-controlled investigation and assigned to either the pyridostigmine or the placebo group. All subjects were evaluated for pyridostigmine or placebo side effects and given an anesthesia induction that included the neuromuscular blocking agent succinylcholine. Neuromuscular blockade was measured by twitch height with a nerve stimulator. Interval data were analyzed using the chi 2 test and Student's t test. The pyridostigmine group demonstrated a prolonged recovery time to return of 25% (p = 0.003) and 75% (p = 0.028) of twitch height compared with the placebo group. No differences were noted for any other parameter measured. We conclude that the recovery from neuromuscular blockade after succinylcholine is prolonged while the intubating conditions remain unaffected.

Relationships between T lymphocyte apoptosis and anergy following trauma.

BACKGROUND: Severely injured trauma patients experience T cell depletion. A subset of these patients also develop T cell unresponsiveness (anergy), as characterized by the failure of their T cells to proliferate or to produce T lymphokines in response to a direct stimulus through the T cell receptor. We hypothesized that T cell apoptosis plays a role in the development of posttrauma T cell depletion and/or T cell anergy by deleting an activated T cell population. We found that moderately increased T cell depletion posttrauma is not innately deleterious or immediately responsible for anergy, but may predispose to later development of T cell anergy, possibly due to a more stringent requirement for activation of the remaining naive T cells. METHODS: A total of 30 blunt trauma and burn patients were assessed twice weekly for the following parameters: (1) clinical outcome expressed as severity of organ dysfunction as measured by the multiple organ dysfunction syndrome score, (2) proliferative response of highly purified T cells to anti-CD3/anti-CD4, (3) level of apoptosis as determined by flow cytometric analysis of propidium iodide-stained monocyte reduced peripheral blood mononuclear cells, either unstimulated or in response to mitogenic challenge or Fas (CD95) stimulation. RESULTS: A wide range of apoptosis levels are seen in the patients' T cells. Apoptosis is increased when all trauma patients' T cells are compared to T cells of normal volunteers. However, at the time a patients' T cells are anergic, there is no increased level of apoptosis. In fact, the point of maximum anergy (lowest proliferative response) correlates to diminished apoptotic response. Increased T cell apoptosis can be stimulated by anti-Fas antibody in trauma patients' responsive T cells but not in maximally anergic T cells. These data suggest that patients' T cell anergy is not an immediate result of apoptotic T cell depletion upon stimulation. However, patients who later develop T cell anergy have increased T cell apoptosis earlier in their clinical course than patients who never experience T cell anergy. CONCLUSIONS: Increased levels of apoptosis are not directly associated with negative trauma patient outcome nor the immediate cause of T cell anergy. However, unusually high levels of apoptosis and development of severe T cell depletion occurring before complete activation and expansion of the posttrauma T cell response may presage anergy and subsequent organ failure.

Comparison of the length of stage II labor and incidence of forceps and cesarean delivery after epidural infusion of 0.125% bupivacaine with 2 mu/mL fentanyl as compared with 0.0625% bupivacaine with 2 mu/mL fentanyl.

A large, retrospective chart review was conducted to analyze the length of stage II labor and instrumental and cesarean-section delivery rates in nulliparous women who received either 0.0625% bupivacaine with 2 mu/mL fentanyl or 0.125% bupivacaine with 2 mu/mL fentanyl. Data collected included length of stage II labor, incidence of operative or instrumental delivery rates, concentration of bupivacaine used, and demographic data. Demographics obtained included maternal age, weight, and height, as well as neonatal gestational age, weight, and Apgar scores. Further investigated were additional analgesic requirements of supplemental boluses of local anesthetic between the groups. No differences in demographics were noted between the groups. Instrumental delivery rates were similar between the groups with an incidence of 17.5% in the 0.125% bupivacaine group versus a 15% incidence in the 0.0625% bupivacaine group. Cesarean delivery rate was 17% in the 0.125% bupivacaine group versus a 21% ratio in the 0.0625% bupivacaine group. Duration of stage II labor was noted to be prolonged in the 0.125% bupivacaine group but was not statistically significant. Based on this data, it can be concluded that the use of 0.125% bupivacaine with 2 mu/mL fentanyl does not cause a statistically significant increase in instrumental or cesarean delivery rates, nor does it have a detrimental effect on length of stage II labor.

Oral care in the adult intensive care unit.

BACKGROUND: Nurses have not been formally trained in assessing the oral status of patients in intensive care units, and no oral care protocols for these patients are available. OBJECTIVES: To assess the oral status of patients in an intensive care unit, evaluate the effects of a defined oral care protocol on the oral health status of patients in an intensive care unit, and compare oral assessments of a dental hygienist with those of intensive care nurses. METHODS: A nonequivalent comparison group, longitudinal design with repeated measures was used. In phase 1, oral assessment data on the comparison group were collected by a dental hygienist. In phase 2, nurses were instructed in oral assessment and an oral care protocol. In phase 3, the oral care protocol was implemented in the treatment group, and oral assessment data were collected separately by the dental hygienist and by nurses. RESULTS: The mean inflammation score was significantly lower (t test P = .03) in the treatment group (mean, 3.9; SEM, 3.0) than in the comparison group (mean, 12.4; SEM, 2.2). Although not significant, the mean scores of the treatment group were also lower than those of the comparison group on scales of candidiasis, purulence, bleeding, and plaque. Correlations between scores for individual items on the oral assessment tool obtained by the dental hygienist and those obtained by nurses were all greater than 0.6386. CONCLUSION: Implementation of a well-developed oral care protocol by bedside nurses can improve oral health of patients in the intensive care unit.

Meperidine utilization and compliance with Agency for Health Care Policy and Research guidelines in a tertiary care hospital.

The Agency for Health Care Policy and Research (AHCPR) established guidelines for the use of meperidine (demerol), a common inpatient analgesic. These guidelines define standards of care for acute and chronic cancer pain management and address many of the problems with meperidine and its metabolite, normeperidine. The purpose of this study was to determine whether meperidine was prescribed in compliance with AHCPR guidelines, whether patients exhibited any adverse reactions to meperidine, and to determine the analgesic efficacy of meperidine. Three hundred inpatient charts were reviewed and identified meperidine as the primary analgesic in 157 nonobstetric inpatients. Age, sex, weight, dosing interval, route of administration, duration of meperidine use, serum chemistry values, primary diagnosis, associated medical conditions, and medications concurrently being taken with meperidine were the parameters analyzed. An interview was conducted to ascertain medical and drug history, chronicity of pain syndromes, analgesic drug history, and analgesic efficacy. A visual analog scale for pain (range = 0 to 10) and an analgesic satisfaction survey (range = 1 to 5) were used. Of 157 patients, 124 (79.8%) were in conflict with AHCPR guidelines. The most frequent conflict was found to be suboptimal dosing regimen and treatment of chronic pain. Often concurrent analgesics were given with the meperidine to achieve adequate analgesia. Higher analgesic satisfaction scores were noted when meperidine was given with concurrent analgesics. Meperidine also was administered to patients in renal failure or with medications contraindicated with meperidine use. No significant adverse effects were noted with meperidine use in this sample population other than an increased incidence of confusion in the elderly population.

Intrathecal opioids for the control of pain experienced during labor and in the post-cesarean section period.

Since the discovery of opiate receptors in the brain and spinal cord, considerable research has been performed to include intrathecal opioids for the control of pain. No area has used this knowledge more than the practice of obstetrical anesthesia. Intrathecal opioids have been shown to be very effective in controlling the pain experienced in the first stage of labor but have been ineffective in controlling second-stage labor pain. Intrathecal opioids, especially morphine sulfate, provide long-term analgesia but are associated with a high number of side effects. Research studies have attempted to determine the optimal dose of intrathecal opioids to provide the greatest amount of analgesia with the lowest incidence of side effects. Intrathecal morphine sulfate has been shown to be effective in controlling first-stage labor pain but has been shown to be the most efficacious in controlling the pain experienced in the post-cesarean section period. This article reviews the current literature and provides background of information to understand these developments.

Both T-helper-1- and T-helper-2-type lymphokines are depressed in posttrauma anergy.

BACKGROUND: We have previously shown that an intrinsic postinjury T-cell dysfunction defined as lack of proliferative response to direct stimulation through the T-cell receptor, referred to here as "anergy," occurs in a subgroup of patients with severe trauma and is associated with organ failure. It has been suggested recently that a dominance of T-helper-2 (Th2) lymphokine production might be responsible for immunosuppression and associated with poor patient outcome. Here, we hypothesize that anergy is associated with global failure of T lymphokine (T LK) production, suggesting that poor outcome is not the result of an excess of immunosuppressive T LK (i.e., interleukin (IL)-10) but rather results from lost T-cell regulatory networking. METHODS: Purified T cells from 37 severely injured trauma patients were cultured and stimulated with alphaCD3/alphaCD4, and proliferation was assessed at 72 hours. Anergy is defined as occurring when the patient's T-cell proliferation to alphaCD3/alphaCD4 is less than 50% of the simultaneously run normal proliferation. Culture supernatants were assessed for T LK production by enzyme-linked immunosorbent assay. Clinical severity was measured by the multiple organ dysfunction syndrome (MODS) and Acute Physiology and Chronic Health Evaluation III scores. RESULTS: Anergy occurred in 20 of 37 patients, and it usually appeared at greater than 5 to 7 days after injury. There was a global reduction of T LK production during T-cell anergy (IL-2, 2.5%; interferon (IFN)gamma, 30.5%; IL-4, 11.8%; and IL-10, 16.9%) compared with increased or unchanged T LK production during the nonanergic state (IL-2, 83%; IFNgamma, 230%; IL-4, 110%; and IL-10, 307.9%; p < 0.01). There was a significant direct correlation between depressed IL-4 and depressed IFNgamma (r = 0.620, p < 0.001), indicating a diminished LK production of both types of T-helper cells (Th1 and Th2). Decreased IL-2 and IL-10 levels were also specifically correlated to each other during the anergic state (r = 0.91, p < 0.001). The average MODS score for patients during anergy was significantly higher (7.6) than their MODS score in the absence of anergy (4.0, p = 0.01). When IL-2 and IL-10 were measured simultaneously, a predominance of Th2 LK (IL-10) production would result in an IL-10/IL-2 ratio greater than 1. We found, however, that this ratio was not greater than 1 in 80% of assays in which T cells were anergic (p = 0.01). CONCLUSION: During T-cell anergy there is not a predominance of Th2 lymphokine production but rather a global depression of the T-cell lymphokine profile. Both depressed T-cell proliferation and depressed LK production correlate to poor clinical outcome.

Role of cerebellum in adaptive modification of reflex blinks.

We investigated the involvement of the cerebellar cortex in the adaptive modification of corneal reflex blinks and the regulation of normal trigeminal reflex blinks in rats. The ansiform Crus I region contained blink-related Purkinje cells that exhibited a complex spike 20.4 msec after a corneal stimulus and a burst of simple spike activity correlated with the termination of orbicularis oculi activity. This occurrence of the complex spike correlated with trigeminal sensory information associated with the blink-evoking stimulus, and the burst of simple spike activity correlated with sensory feedback about the occurrence of a blink. Inactivation of the inferior olive with lidocaine prevented all complex and significantly reduced simple spike modulation of blink-related Purkinje cells, but did not alter orbicularis oculi activity evoked by corneal stimulation. In contrast, both acute and chronic lesions of the cerebellar cortex containing blink-related Purkinje cells blocked adaptive increases in orbicularis oculi activity of the lid ipsilateral but not contralateral to the lesion. These data are consistent with the hypothesis that the cerebellum is part of a trigeminal reflex blink circuit. Changes in trigeminal signals produce modifications of the cerebellar cortex, which in turn, reinforce or stabilize modifications of brainstem blink circuits. When the trigeminal system does not attempt to alter the magnitude of trigeminal reflex blinks, cerebellar input has little or no effect on reflex blinks.

Preoperative depletion of C3 improves the survival of guinea pig-to-rat cardiac xenograft recipients.

Rat strains with congenitally reduced total hemolytic complement activity do not reject cardiac xenografts hyperacutely. Prolongation of graft survival in the guinea pig-to-C6-deficient PVG rat donor/recipient combination has been observed. However, experience with this model has been complicated by a high postoperative mortality from respiratory distress. The authors hypothesized that placement of the xenograft resulted in local activation of complement, which contributed to remote pulmonary injury leading to respiratory dysfunction. To test this hypothesis, an attempt was made to reduce early complement component activation with the use of an antibody to rat C3 in C6-deficient PVG recipients. Six of eight untreated C6-deficient PVG recipients died in the immediate postoperative period with vigorously beating heart grafts, whereas only 2 of 14 C6-deficient recipients pretreated with anti-rat C3 antibody died within 24 h postoperatively. Although pretreatment with anti-C3 antibody improved survival of recipients, the duration of cardiac xenograft survival was similar whether the recipients were pretreated or not. The use of anti-C3 antibody in C6-deficient rats is a valid approach to studying xenotransplantation in the absence of hyperacute rejection and has an additional advantage in that it does not require the use of expensive reagents such as cobra venom factor.

Only a subset of trauma patients with depressed mitogen responses have true T cell dysfunctions.

Many studies have demonstrated depressed mitogenic responses in trauma/burn patients' peripheral blood mononuclear cells (PBMC). However, data attributing the relative contribution of secreted inhibitory factors versus a true T cell dysfunction to these depressed mitogenic responses have been conflicting. We have characterized the T cell dysfunctions in posttrauma mitogen depression by simultaneously assessing patient T cell proliferation in the phytohemagglutinin-stimulated PBMC and in the purified T cell population induced with anti-CD3 + anti-CD4. Patients' samples showed three distinct patterns or progressive phases of T cell responses: (i) normal or elevated T cell proliferation in both the whole PBMC and the isolated T cell population (phase I); (ii) depressed T cell proliferation in the PBMC but normal, or even elevated, proliferation in the isolated T cell population (phase II); and (iii) depressed T cell proliferation in both the PBMC and the isolated T cell population (phase III). Patients whose T cells exhibited only a phase I response experienced no major complications with a positive clinical outcome. Patients whose T cell alterations progressed to phase II experienced infectious episodes and some complications, but all had positive clinical outcomes. In contrast, patients whose T cells progressed to phase III dysfunction had severe clinical complications (multiple organ failure), with a negative clinical outcome (80% mortality). Patients whose T cells had a phase I or phase II response pattern had no true T cell dysfunctions in the absence of monocytes. However, patients whose T cells had a true T cell dysfunction (phase III) response pattern were at high risk for mortality. Thus, a true T cell dysfunction, though occurring in only a minority of trauma patients, is predictive of clinical outcome.

Intrathecal opioids plus bupivacaine: an option to prolong analgesic efficacy when using the combined spinal-epidural technique--a case report.

Providing analgesia in the latent phase of labor can be challenging. Many obstetricians and nurse midwives believe that epidural analgesia initiated too early in the course of labor can prolong labor and result in fetal malpresentation, thus increasing the need for instrumentation. Many practitioners therefore use the combined spinal-epidural technique with intrathecal opioids during the early portion of first stage labor and initiate epidural analgesia only in the active phase of labor. However, the use of intrathecal opioids has been shown to be less than efficacious in meeting the analgesic needs in a large segment of the patient population, thus requiring initiation of epidural analgesia after only 1 to 2 hours. A case is reported in which the combined spinal-epidural technique was utilized in a primigravida patient. An intrathecal dose of 15 micrograms of sufentanil was given with a dilute concentration of bupivacaine at the initiation of analgesia. Analgesia was provided for approximately 5 hours before epidural analgesia was required. The patient delivered by spontaneous vaginal delivery without instrumentation or adverse sequelae to mother or infant.

A membrane TNF-alpha/TNFR ratio correlates to MODS score and mortality.

This study hypothesizes that post-trauma elevated membrane-associated tumor necrosis factor-alpha (mTNF) and decreased TNF receptor shedding may be more related to development of multiple organ dysfunction syndrome (MODS) than elevated secreted TNF-alpha. We also address several of the possible reasons for the previous conflicting reports in studies correlating trauma patients sera TNF-alpha levels to their clinical outcome. These are 1) the lack of an objective quantitative score of clinical illness severity, 2) the lack of multiple TNF-alpha measurements in one patient to allow for trend analysis, 3) the lack of analysis of membrane-associated as well as secreted TNF-alpha levels, 4) the lack of concomitant analysis of soluble TNF-alpha receptors which may bind TNF-alpha in the serum, and 5) the possible requirement for more than one dysfunction in monocyte (M phi) TNF-alpha production and regulation to initiate pathology. Here, the MODS score was used to quantitate patients' illness severity over the length of their intensive care unit (ICU) stay. Patients' and normals' monocytes (stimulated and unstimulated) were assessed for production of secreted as well as membrane-associated TNF-alpha (sTNF and mTNF) and for shed p75 TNF-alpha receptor (TNFR) levels. These parameters of M phi TNF-alpha production and regulation were correlated to the MODS score as an indicator of clinical outcome. There was no correlation between sTNF and MODS score (p = .9025). There was a correlation between increased mTNF (p = .057) or decreased TNFR shedding (p = .0021) to increased MODS, but this lacked specificity. However, when the stimulated M phi production of mTNF and TNFR are expressed as the mTNF/TNFR ratio, an increased ratio correlates with high specificity to development of organ failure (p = .0002). These data indicate that a dual deregulation in M phi TNF-alpha production reflects increasing mTNF-alpha levels concomitant to decreased M phi shedding of neutralizing TNFR and correlates with the development of MODS.