Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients.

BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.

Tryptophan depletion in patients with obsessive-compulsive disorder who respond to serotonin reuptake inhibitors.

METHODS: The effects of short-term tryptophan depletion were examined in 15 patients with DSM-III-R obsessive-compulsive disorder who had demonstrated symptom reduction following treatment with serotonin reuptake inhibitors. Patients received a 24-hour, low-tryptophan (160-mg/d) diet followed the next morning by a drink of 15 amino acids. A double-blind, placebo-controlled cross-over design was used. RESULTS: The diet and the amino acid drink reduced free plasma tryptophan levels by a mean of 84% 5 hours later. Short-term tryptophan depletion did not significantly change mean ratings of obsessions and compulsions. In contrast, mean depression ratings were significantly increased with tryptophan depletion compared with the control (tryptophan-supplemented) testing. CONCLUSION: Maintenance of serotonin reuptake inhibitor-induced improvement of obsessive and compulsive symptoms, unlike remission of depressive symptoms, may not depend on ongoing short-term availability of serotonin.

Effects of fluoxetine administration on mood response to tryptophan depletion in healthy subjects.

Short-term reduction in plasma tryptophan (tryptophan depletion) produces a relapse of depressive symptoms in 60% of previously depressed patients recently recovered with serotonin reuptake inhibitor treatment. Tryptophan depletion does not consistently increase depressive symptoms in unmedicated depressed patients or in depressed patients whose symptoms are remitted with a norepinephrine reuptake inhibitor. These data suggest that serotonin reuptake inhibitor treatment itself may confer vulnerability to the development of depressive symptoms during tryptophan depletion. In order to further investigate this possibility, six healthy individuals underwent double-blind placebo-controlled tryptophan depletion before and following six weeks of treatment with fluoxetine 20 mg/day. No increased vulnerability to the mood-lowering effects of tryptophan depletion occurred as a result of fluoxetine treatment. Additionally, fluoxetine treatment itself was not associated with changes in mood or quality of life in these healthy volunteers. These data indicate that serotonin reuptake inhibitor treatment alone does not produce the depressive effects of tryptophan depletion that are observed in serotonin reuptake inhibitor-treated depressed and obsessive compulsive disorder patients.

m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation.

Oral administration of the serotonin mixed agonist-antagonist meta-chlorophenylpiperazine (mCPP) at 0.5 mg/kg has been reported to exacerbate symptoms of obsessive-compulsive disorder (OCD). In an attempt to replicate these findings, double-blind behavioral and biochemical measures were obtained in 12 drug-free patients (9 men, 3 women) with OCD who received either oral mCPP (0.5 mg/kg), intravenous (IV) mCPP (0.1 mg/kg over 20 min), or placebo in random order on 3 separate test days. Neither oral nor IV mCPP had significant effects on the severity of OCD symptoms. The magnitude of the mCPP-induced plasma prolactin response and plasma mCPP levels were similar to those values obtained in other published studies in which mCPP exacerbated OCD symptoms. In contrast, both oral and IV mCPP were associated with significant increases in ratings of anxiety. These findings suggest that mCPP, whether administered by an oral or intravenous route (as a slow infusion), may not be a reliable probe for investigating obsessive-compulsive symptoms. It is possible, however, that more reproducible behavioral findings might be obtained by identifying susceptible subgroups of OCD or by including a behavioral exposure condition.

Addition of desipramine to serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to determine whether combined treatment with a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor, desipramine, effectively reduces obsessive-compulsive symptoms in patients who do not respond to SSRIs. METHOD: In a double-blind study, desipramine or placebo was added for 6 or 10 weeks to the treatment of 30 patients with obsessive-compulsive disorder whose symptoms were refractory to SSRI treatment (fluvoxamine, fluoxetine, or sertraline) alone. RESULTS: There were no significant differences between the adjunctive desipramine and placebo groups in obsessive-compulsive or depressive symptoms. CONCLUSIONS: These data suggest that clomipramine's possibly superior efficacy in the treatment of obsessive-compulsive symptoms may not stem from its capacity to inhibit reuptake of norepinephrine.

Lack of efficacy of clozapine monotherapy in refractory obsessive-compulsive disorder.

OBJECTIVE: The authors assessed the efficacy of clozapine monotherapy for adults with treatment-resistant obsessive-compulsive disorder. METHOD: Twelve adults with refractory obsessive-compulsive disorder participated in a 10-week, open-label, systematic trial of clozapine. They were assessed with the Yale-Brown Obsessive Compulsive Scale, the Hamilton Depression Rating Scale, and the global improvement item of the Clinical Global Impression (CGI) scale. RESULTS: None of the 10 patients who completed the trial was a responder. No significant change was observed in obsessive-compulsive or depressive symptoms or in scores on the CGI global improvement item. CONCLUSIONS: These findings suggest that clozapine monotherapy is not effective for most adult patients with treatment-resistant obsessive-compulsive disorder.

Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder.

The authors found that buspirone added to the treatment of 33 patients with obsessive-compulsive disorder who were refractory to the serotonin reuptake inhibitor fluvoxamine was no better than placebo in reducing obsessive-compulsive, depressive, or anxiety symptoms. This finding suggests that addition of buspirone to ongoing fluvoxamine therapy is not an effective treatment strategy for most patients with obsessive-compulsive disorder.

Possible role of neuropeptides in obsessive compulsive disorder.

The most consistent finding in clinical research of obsessive compulsive disorder (OCD) is the significant treatment advantage of potent serotonin uptake inhibitors (SUIs) over other classes of antidepressant and antianxiety drugs. Clinical neurobiological studies of OCD, however, have yielded limited and inconsistent evidence for significant fundamental abnormalities in monoamine systems including serotonin, norepinephrine and dopamine. Furthermore, one-third to one-half of OCD patients do not experience a clinically meaningful improvement with SUI treatment. Investigation beyond the monoamine systems may be necessary in order to more fully understand the pathophysiology of obsessive-compulsive symptoms and develop improved treatments. Evidence from preclinical studies suggests that neuropeptides may have important influences on memory acquisition, maintenance and retrieval; grooming, maternal, sexual and aggressive behavior; fixed action patterns; and stereotyped behavior; these phenomena may relate to some features of OCD. In addition, extensive interactions have been identified in the brain between neuropeptidergic and monoaminergic systems, including co-localization among specific populations of neurons. The purpose of this review is to present the current knowledge of the role of neuropeptides in the clinical neurobiology of children, adolescents and adults with OCD focusing primarily on results from pharmacological challenge and cerebrospinal fluid studies. Where evidence exists, developmentally regulated differences in neuropeptide function between children and adolescents versus adults with OCD will be emphasized; these data are intended to underscore the potential importance of establishing the age of symptom onset (childhood versus adult) in individual patients with OCD participating in clinical neurobiological investigations. Likewise, where information is available, differences in measures of neuropeptides between patients with non-tic-related OCD versus tic-related OCD will be highlighted; these data will demonstrate the critical value of diagnostic precision, as these two particular subtypes of OCD may have different neurochemical underpinnings.

The role of central oxytocin in obsessive compulsive disorder and related normal behavior.

Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells, which project to widely distributed sites in the CNS as well as the neurohypophysis. Central OT affects a variety of cognitive, grooming, affiliative, sexual, and reproductive behaviors in animals. Obsessive Compulsive Disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with OT. Anecdotal data and a recently completed cerebrospinal fluid (CSF) study provide evidence that some forms of OCD are related to OT dysfunction. Based on these findings, we hypothesize: 1) that some forms of OCD are at the extreme end of a range of normal behaviors that are mediated by OT and related systems; and that 2) some normal cognitive, affiliative, and sexual behaviors contain elements that are similar to features of OCD. Alternative hypotheses are considered, and a series of predictions are presented concerning the relationship between central OT and the onset, course, treatment response, and response to challenge procedures seen in this form of OCD.

The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies.

Demonstration of the efficacy of serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors such as clomipramine in the treatment of obsessive compulsive disorder has fueled interest in the neurobiological basis of this illness. Results of treatment studies, investigations of biological markers, and pharmacologic challenges are reviewed and implications for a 5-HT theory of obsessive compulsive disorder discussed. While the nature of the dysregulation in serotonin transmission that may attend obsessive compulsive disorder has yet to be fully elucidated, evidence accumulates that 5-HT function in part modulates obsessive compulsive symptoms. Development of more specific probes and new brain imaging techniques will further enhance understanding of the pathophysiology of obsessive compulsive disorder.

Biological approaches to treatment-resistant obsessive compulsive disorder.

Biological approaches to the patient with treatment-resistant obsessive compulsive disorder are briefly reviewed. The most commonly employed strategy involves combining a potent serotonin reuptake inhibitor (SRI) (e.g., clomipramine or fluvoxamine) with another medication that may exert effects on the brain serotonin system. Open-label reports regarding the addition of tryptophan, fenfluramine, lithium, or buspirone to ongoing SRI therapy of obsessive compulsive disorder are encouraging. However, the anti-obsessive compulsive efficacy of SRI-lithium and SRI-buspirone combination therapy has not been confirmed in recent controlled trials. Preliminary evidence suggests that addition of neuroleptic may benefit SRI-refractory obsessive compulsive disorder patients who have a comorbid chronic tic disorder. Other biological approaches (e.g., electroconvulsive therapy and psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant obsessive compulsive disorder. Finally, an algorithm is proposed for those patients with obsessive compulsive disorder who fail to respond to an adequate trial with a potent SRI.

Acute tryptophan depletion: a method of studying antidepressant action.

Serotonin (5-HT) has been implicated in the pathophysiology of depressive syndromes and in the mechanism of antidepressant drug action. Rapid dietary depletion of tryptophan (TRP) provides a paradigm for studying the role of 5-HT in depressed patients. Drug-free depressed patients do not show mood changes during TRP depletion but about one third have a clinically apparent, transient improvement in mood on return to normal TRP intake. Depressed patients in clinical remission after 6 to 8 weeks of antidepressant therapy experience a transient depressive relapse during acute TRP depletion. The significance of these findings will be discussed. Tryptophan depletion in other psychiatric syndromes will also be reviewed.

Invasion of the mandible by squamous carcinomas of the oral cavity and oropharynx.

The radiologic and histologic features of mandibular invasion, and its clinical implications, are considered in a retrospective series of 111 patients with squamous carcinomas of the oral cavity and oropharynx treated by composite resection. Eighty percent of the entire group had either recurrent or advanced (T3, T4) local disease, and 33 patients (30%) had histologic evidence of mandibular invasion by tumor. Preoperative radiologic assessment was unreliable in cases in which infiltrating tumor was confined to the periosteum and superficial cortex-44% false negatives. The extent of bone invasion was found to correlate with the size of the tumor, but not with its histologic grade. The mandibular periosteum was not seen as a morphologically discrete "barrier" and infiltration occurred at various points along the mandibular body, mainly related to the course of the inferior dental canal. The gross and microscopic patterns of bone invasion appeared to be similar in irradiated and nonirradiated resections. The incidence and pattern of recurrent disease following composite resection was the same in the groups with and without mandibular invasion: in each group half the patients were dead from disease and one third alive and free of disease at 2 years. Mandibular invasion alone did not appear to influence prognosis in this series.

Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes.

The incidence, extent, and selected clinicopathologic correlations of transcapsular spread from metastatic tumor in the cervical lymph nodes have been investigated in 210 specimens obtained by radical neck dissection from 203 patients with squamous cell carcinomas of the head and neck. Transcapsular spread was detected in 137 of 159 (86 percent) positive specimens, and classified as macroscopic in 74 (54 percent) and microscopic in 63 (46 percent). Macroscopic transcapsular spread was seen most frequently in association with large nodal masses more than 3 cm in diameter (48 of 70 specimens, 69 percent), but also occurred in some specimens with smaller lymph nodes less than 3 cm in diameter (26 of 67 specimens, 39 percent). Anatomic structures most commonly invaded in areas of neck dissection with macroscopic spread from nodal metastases were skeletal muscle (39 dissections) and the adventitial coat of the internal jugular vein (27 dissections). Macroscopic transcapsular infiltration was associated with a high incidence (44 percent) of recurrent tumor in the ipsilateral neck, particularly within 12 months of surgery. Microscopic transcapsular growth was associated with a lower incidence (25 percent) of recurrent tumor in the ipsilateral neck but the difference did not reach statistical significance. Similar recurrence figures (32 percent) were found in the minority of patients whose nodal disease was intracapsular at the time of neck dissection. More precise definition of the morphologic extent of transcapsular spread could be important in clarifying its clinicopathologic correlations.

The serotonin hypothesis of obsessive compulsive disorder.

The above studies investigating the responsivity of the 5-HT system to provocation provide some support for the hypothesis drawn from the results of pharmacologic treatment trials and studies of biological markers that dysregulation of the 5-HT system may be involved in the pathogenesis of OC symptoms. While results of several studies document blunting of neuroendocrine responses to 5-HT agonists, only one study suggests a small increase in responsiveness compared to healthy controls. Combined with neurophysiologic data suggesting net increases in 5-HT functioning following treatment with SRIs, these results suggest that the primary deficit in OCD is not one of increased 5-HT responsivity. Exacerbation of OC symptoms sometimes observed during mCPP challenge is not entirely consistent with this hypothesis and additional studies are required to clarify the significance of these findings. However, behavioral hypersensitivity coupled with neuroendocrine hyposensitivity to serotonergic stimulation might characterize the serotonergic dysfunction accompanying OCD. The complexity of the 5-HT system, and the likelihood that behavioral and neuroendocrine responses are mediated by different receptor subtypes makes this hypothesis entirely plausible. The efficacy of SRIs in the treatment of OCD remains the firmest evidence of serotonergic involvement in this condition. Results of challenge studies in OCD also suggest a possible dysregulation in 5-HT function, although the precise nature of this disturbance remains elusive. Neuroendocrine responses to 5-HT agonists generally are consistent with a tendency toward hyposensitivity in OCD. Behavioral results, while more mixed, indicate a hypersensitivity to 5-HT agonists. Further refinement in dependent and independent variables used in challenge studies may clarify remaining questions.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic laparotomy in suspected malignant lymphoma.

The place of laparotomy in the initial diagnosis of malignant lymphoma is investigated by reviewing a group of 25 patients with suspected lymphoma referred for diagnostic laparotomy. Intra-abdominal malignancy was found in 11 patients, although only 7 of these had a malignant lymphoma. A positive alternative diagnosis was made in a further 8 of the remaining 14 patients, but 6 patients remained undiagnosed following laparotomy. A scheme for the investigation of patients with suspected malignant lymphoma is therefore proposed. Patients with an abdominal mass other than a palpable liver or spleen should undergo early laparotomy, while those with no abdominal mass should undergo an extensive screening programme, appropriate to the mode of presentation and similar to that used in the investigation of a pyrexia of unknown origin, in which diagnostic laparotomy is used only as the final step.

Salvage mastectomy after failed breast-conserving therapy for carcinoma of the breast.

The indications, technique and complications of salvage mastectomy in 25 patients with local recurrence after breast-conserving therapy for carcinoma of the breast have been reviewed. Two patients required myocutaneous flaps to repair the defect, and six patients (24%) suffered wound infection or breakdown. Subsequent local relapse occurred in a total of five patients, two of whom died with uncontrolled chest wall skin nodules.

The primary management of breast cancer: is breast conservation feasible for all patients?

A consecutive series of 411 patients with primary breast cancer treated by a consistent policy of breast conservation, regardless of tumour size, location, clinical stage or histological subtype, is reported. Actuarial 5-year survival was 84% for UICC Stage I, 73% for Stage II and 47% for Stage III/IV. The incidence of local recurrence at 5 years was 13% for Stage I, 12% for Stage II, and 26% for Stage III/IV. The probability of salvage mastectomy at 5 years was 5% for Stage I, 8% for Stage II, and 15% for Stage III/IV. Of local recurrences, 40% were managed with further breast conservation. Primary treatment with breast conservation results in satisfactory local control rates, 5-year survival and cosmesis, but the prevention, diagnosis and treatment of local recurrence within the conserved breast requires further evaluation.