The solitary pulmonary nodule on chest radiography: can we really tell if the nodule is calcified?

OBJECTIVE: This study was designed to assess the ability of radiologists to accurately detect calcification within a solitary pulmonary nodule with chest radiography. MATERIALS AND METHODS: Thirty-five solitary pulmonary nodules that were examined by both posteroanterior and lateral chest radiography and on thin-section CT were retrospectively identified. Fourteen radiologists blinded to the results of CT assessed the nodules for the presence or absence of calcification using chest radiographs alone. The radiologists then assigned one of six values on the basis of their confidence in that assessment. The accuracy and confidence values for each nodule were analyzed on the basis of the presence or absence of calcification as seen on CT. Receiver operating characteristic (ROC) curves were generated. RESULTS: The positive predictive value of a "definitely calcified" assessment was 0.93. Combining all levels of radiologists' confidence, the sensitivity of the chest radiograph in the detection of calcium was 0.50 and the specificity was 0.87. There was no difference in the confidence levels reported between the calcified and noncalcified nodules, and there was no correlation of nodule size with accuracy or confidence level. CONCLUSION: The ability of radiologists to detect calcium in a solitary pulmonary nodule by chest radiography was low, as defined by the ROC data. Of the "definitely calcified" nodules, up to 7% may not be calcified and may be potentially malignant. Without documentation of long-term stability, a low threshold for recommending CT may be appropriate.

Carcinogenesis and the plasma membrane.

Presented is a two-stage hypothesis of carcinogenesis based on: (1) plasma membrane defects that produce abnormal electron and proton efflux; and (2) electrical uncoupling of cells through loss of intercellular communication. These changes can be induced by a wide variety of stimuli including chemical carcinogens, oncoviruses, inherited and/or acquired genetic defects, and epigenetic abnormalities. The resulting loss of electron/proton homeostasis leads to decreased transmembrane potential, electrical microenvironment alterations, decreased extracellular pH, and increased intracellular pH. This produces a positive feedback loop to enhance and sustain the proton/electron efflux and loss of intercellular communication. Low transmembrane potential is functionally related to rapid cell cycling, changes in membrane structure, and malignancy. Intracellular alkalinization affects a variety of pH-sensitive systems including glycolysis, DNA synthesis, DNA transcription and DNA repair, and promotes genetic instability, accounting for the accumulation of genetic defects seen in malignancy. The abnormal microenvironment results in the selective survival and proliferation of malignant cells at the expense of contiguous normal cell populations.

The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia.

BACKGROUND: There has been an absence of controlled studies focusing specifically on neuroleptic treatment in the elderly schizophrenic population. Therefore, we conducted a 12-week double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients with chronic schizophrenia. METHOD: Forty-two elderly DSM-IV schizophrenic veterans were randomly assigned to clozapine or chlorpromazine and assessed for efficacy at baseline and at termination with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions scale (CGI). Side effects were also monitored. Medications were titrated, on the basis of clinical response and side effects, to a maximum dose of 300 mg/day of clozapine or 600 mg/day of chlorpromazine. RESULTS: The results suggest that both the chlorpromazine and clozapine groups improved their PANSS scores at termination compared with baseline, but the difference between the 2 groups was not statistically significant. The mean CGI scores reflecting severity of illness also demonstrated improvement in both groups over time. Both groups had similar incidences of side effects. One patient in each group had a life-threatening side effect. More patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients noted sedation. CONCLUSION: We concluded that both clozapine and chlorpromazine are effective treatments for psychosis and behavioral disturbances in geriatric schizophrenia. Both agents had similar incidences of side effects. With careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.

Computerized self-assessment of psychosis severity questionnaire [COSAPSQ] in schizophrenia: preliminary results.

We attempted to develop and validate a computer-driven patient self-rated questionnaire [COSAPSQ] which should provide a reliable, rapid, and inexpensive method to assess symptom severity in patients with psychosis in general and with schizophrenia in particular. After giving informed consent patients with DSM-IV schizophrenia or schizoaffective disorder were interviewed and rated on PANSS and CGI. Subsequently patients completed the COSAPSQ questionnaire (61 multiple choice questions) in the presence of an observer. The analysis of the first 29 rating sets showed that patients with CGI scores of 3-6 completed the questionnaire in a mean time of 21.6 minutes. One-way analysis of variance of COSAPSQ total scores by CGI ratings was highly significant (p < .001). COSAPSQ total scores correlated well with PANSS total, general and positive scores and with CGI (all r = 6-.7; p < .005). The next versions of the questionnaire will require some adjustments: overall fewer questions, improved assessment of negative symptoms, and improved graphic presentation.

Virtual bronchoscopy with perfluoronated hydrocarbon enhancement.

RATIONALE AND OBJECTIVES: Bronchoscopic computed tomography (CT) is limited by machine resolution and air-soft-tissue contrast. The objective of this study was to determine whether improving the contrast by using the contrast agent perflubron (PFOB) in the lung would improve the bronchoscopic CT technique and permit visualization of small airways. MATERIALS AND METHODS: Bronchoscopic CT was performed in an anesthetized 8-week-old New Zealand white rabbit before and after the endotracheal administration of PFOB. RESULTS: Bronchoscopic CT performed with PFOB permitted navigation of bronchi as small as 0.8 mm in diameter, which are much smaller than those that can be navigated without PFOB. CONCLUSION: In this example, the use of perfluorochemicals with bronchoscopic CT enhanced the capabilities of virtual bronchoscopy.

Limitations of controlled augmentation trials in schizophrenia.

To assess the empirical basis for add-on augmentation treatments in schizophrenia, this study examined the experimental design components of pharmacologic augmentation trials in schizophrenia and compared them to conventional requirements. A search covering a 5-year period (1988-1992) identified 13 double-blind, placebo-controlled, parallel, add-on neuroleptic augmentation drug trials. The mean number of subjects per trial was 34.5, and the mean number of outcome measures examined was 25.0. The probability for a significant finding by chance was 63%. Mean effect size required to achieve conventional statistical power was 1.6. Mean statistical power (for effect sizes of .5-1.0) was .1-.4. The mean number of subjects actually required for power of .80 was 58-216. The majority of the 13 trials included too few patients and employed too many outcome measures to conclusively prove or disprove therapeutic efficacy. Conclusions drawn from such trials with less than 40-100 subjects or more than one hypothesis must remain tentative at best.

Early response to clozapine in schizophrenia.

Forty schizophrenic patients were treated with clozapine for 5 weeks. Patients were then classified as treatment responders or nonresponders according to a priori established criteria. After only 1 week of treatment, the responders showed a significant decrease on the Brief Psychiatric Rating Scale (BPRS) total score and the psychosis and tension subscale scores. Higher BPRS scores at baseline and larger improvements in BPRS scores after the first week predicted a more favorable outcome in this trial and yielded good classification accuracy.

A longitudinal study of Alzheimer's disease: measurement, rate, and predictors of cognitive deterioration.

OBJECTIVE: This study measured the annual rate of cognitive change in patients with Alzheimer's disease and determined the effects of clinical variables on that rate. It also compared the ability of two cognitive scales to measure change over the entire range of dementia severity. METHOD: The cognitive subscale of the Alzheimer's Disease Assessment Scale and the Blessed test for information memory and concentration were given to 111 patients with Alzheimer's disease and 72 nondemented elderly comparison subjects at 6-month intervals for up to 90 months. Longitudinal changes in scores on the cognitive subscale were measured with several different methods of data analysis. RESULTS: For the patients with Alzheimer's disease, the annual rate of change in cognitive subscale scores showed a quadratic relationship with dementia severity in which deterioration was slower for mildly and severely demented patients than for patients with moderate dementia. Gender, age at onset, and family history of dementia had no effect on the rate of cognitive deterioration. The comparison group showed a slight improvement in cognitive performance over time. All data analytic methods gave similar results. The cognitive subscale of the Alzheimer's Disease Assessment Scale was more sensitive to change in both mild and severe dementia than was the Blessed test. CONCLUSIONS: These results suggest that cognitive deterioration is slow during the early and very late stages of Alzheimer's disease and more rapid during the middle stages. No clinical variables other than degree of cognitive impairment and previous rate of cognitive decline predicted rate of deterioration. These results have implications for treatment trials and attempts to identify subgroups.

Utility of a perfluorochemical liquid for pulmonary diagnostic imaging.

The use of neat perfluorochemical liquid (PFC) as an alternative respiratory medium has gained increasing attention for assessment and treatment of the immature or injured lung. In vitro and in vivo plain film and computed tomographic (CT) studies were performed on small and large animals to evaluate the use of perfluorooctylbromide (perflubron) as a bronchographic contrast agent and to quantitate the distribution and elimination of this fluid from the lung following total liquid ventilation or during gas breathing after tracheal instillation of small quantities of this liquid. The results demonstrate the utility of a highly radiopaque PFC liquid in combination with diagnostic imaging techniques to visualize small airways anatomy, identify regional and gravity dependent differences in distribution/elimination of the fluid, ventilation, and track PFC liquid following therapeutic application.

Perfluorochemical liquid as a respiratory medium.

The use of perfluorochemical (PFC) liquids to facilitate or support respiration has been under study for several decades. The low surface tension and high respiratory gas solubility of liquid PFC enable adequate oxygenation and carbon dioxide removal at low insufflation pressures relative to gas ventilation in the immature or injured lung. Because liquid ventilation homogeneously inflates the lung and improves V/Q matching it has been studied as a vehicle for delivering biologically active agents to the lung tissues and systemic circulation. More recently, we have shown the utility of highly opaque PFC liquids as a high resolution computed tomographic (HRCT) bronchographic contrast agent either during LV or gas breathing after tracheal instillation of small quantities of PFC. As a result of extensive experimental work in premature animals as well as lung injury models, liquid PFC ventilation has been recently implemented as an investigational therapy for severe respiratory distress in human infants. This manuscript summarizes the physiological principles and applications of LV as well as the results of initial investigational clinical studies in human neonates with severe respiratory distress.

Early response to haloperidol treatment in chronic schizophrenia.

This study examined the time-course of treatment response to haloperidol in chronic schizophrenia. Furthermore the predictive value of baseline psychopathology and early therapeutic changes for the identification of the eventual treatment outcome was examined. After a two-week drug-free period forty-three chronic schizophrenic patients were treated with haloperidol for five weeks. Psychopathology was assessed on the last drug-free day and on the third and eighth day from the initiation of treatment, and then at weekly intervals. At the end of the study based on a priori criteria patients were classified as responders or non-responders to haloperidol. Seventeen patients met criteria for treatment response at the end of five weeks of treatment, while 26 did not. Already by the third day of treatment, in the responders there was a significant decrease in total BPRS and in the subscales scores for psychosis, tension and anergia, but not for hostility-suspiciousness and depression. These decreases represented approximately half of the eventual improvement obtained by the end of the study. Discriminant function analysis showed that severity of symptoms at baseline and improvement by day 3 correctly classified overall outcome in 72% of the cases.

Effect of neuroleptic medication on cerebrospinal fluid monoamine metabolite concentrations in schizophrenia. Serotonin-dopamine interactions as a target for treatment.

OBJECTIVE: This study examined the effect of neuroleptic treatment on indexes of dopamine and serotonin function in schizophrenic patients. We hypothesized that neuroleptic treatment would be effective by changing dopamine and serotonin function and/or by altering their interaction. DESIGN: Lumbar cerebrospinal fluid (CSF) concentrations of the metabolites of dopamine (homovanillic acid, [HVA]) and serotonin (5-hydroxyindoleacetic acid, [5-HIAA]) were measured after a minimum drug-free period of two weeks and again after five weeks of treatment with haloperidol, 20 mg/d orally. Psychiatric symptoms were rated within one day of CSF sampling. PATIENTS: Sixteen schizophrenic and three schizoaffective male inpatients. RESULTS: Neuroleptic treatment significantly raised HVA concentrations and significantly increased the ratio between HVA and 5-HIAA. The increase in HVA was not related to symptomatic improvement, whereas the increase in the HVA/5-HIAA ratio was significantly correlated with reduction in overall symptomatology. CONCLUSIONS: These findings suggest that the increase in HVA is relative to 5-HIAA, and not the absolute increase in HVA, that is related to symptomatic improvement. This, in turn, suggests that changing dopamine function relative to serotonin function, rather than changing dopamine per se, is associated with the therapeutic effect of haloperidol. Exploring serotonin-dopamine interactions in schizophrenia may be more informative than examining each system in isolation.

Predictors of response to neuroleptic treatment in schizophrenia.

Baseline symptom severity, early reduction in symptom severity, initial subjective response to neuroleptic treatment, the degree of brain atrophy, and early changes in pHVA levels appear to predict treatment outcome in schizophrenic patients. Computerized EEG results, neuropsychological and neurophysiologic tests, and baseline pHVA concentrations require further examination. Only a limited proportion of variance in treatment response, however, could be explained by either of the nine predictors alone or combined. Therefore, further research is necessary to discover yet unidentified determinants of treatment response. Future studies should test the validity and reliability of these five promising predictors in large groups of male and female patients, employ high standards for assessment reliability of clinical parameters, and use absolute rating scores on psychopathology as well as functional scales for the definition of good and poor treatment response. Furthermore, the statistical approach for data analysis should take in consideration the need for appropriate corrections when multiple correlations are performed and should test the extent to which these predictors are interdependent.

Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia.

Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA), is an indirect tool to assess changes in dopamine turnover. Levels of pHVA have been reported to decrease during treatment with conventional antidopaminergic, neuroleptics, with the decrement correlating with symptomatic improvement in schizophrenic symptoms. Clozapine, an atypical neuroleptic, is the only drug proved to be effective in treatment-refractory patients. However, the mechanism mediating this unique efficacy has not been fully elucidated. This study examined the effect of clozapine on pHVA concentrations in schizophrenic patients. Since clozapine potently binds to alpha 2-adrenergic receptors, plasma norepinephrine (pNE) concentrations were also measured. Twenty-eight treatment-refractory schizophrenic patients (24 men, 4 women) were treated with clozapine (up to 600 mg/day) for 5 weeks, after a minimum 1-week drug-free period. Symptomatology and pHVA and pNE concentrations were measured at the last drug-free day and weekly for 5 weeks. Fourteen patients responded to clozapine treatment, while an equal number did not. Mean pHVA concentrations did not significantly change during treatment with clozapine. Although clozapine tended to lower pHVA concentrations in treatment responders, the effect was small and not significant. Clozapine treatment significantly raised pNE concentrations, but this did not differentiate responders from nonresponders to clozapine. These findings suggest that clozapine's effect on DA turnover is small and that clozapine may be effective in treatment-refractory schizophrenia by mechanisms other than, or in addition to, dopamine receptor blockade. However, since about one-third of NE is metabolized into HVA, the clozapine-induced increase in pNE may have overshadowed a possible lowering effect of clozapine on pHVA.

A pilot study of oral physostigmine plus yohimbine in patients with Alzheimer disease.

Effective symptomatic treatment of Alzheimer's disease (AD) may require a combination of agents that augment cholinergic as well as noradrenergic neurotransmission. We conducted a pilot study of physostigmine plus oral yohimbine challenge in AD. Ten patients were enrolled in a 12-day double-blind protocol. Each patient received placebo q2h while awake for 5 days, followed by physostigmine 2 mg q2h while awake for 7 days. During each of these drug conditions, yohimbine challenges were administered at oral doses of 10 and 20 mg in a placebo-controlled manner. There was no significant improvement in Alzheimer's Disease Assessment Scale test performance for six patients for whom complete cognitive data were obtained for the 6 challenge days. Nine patients tolerated the protocol with no clinically significant changes in blood pressure, pulse, or electrocardiogram (ECG), and no cardiovascular, gastrointestinal, or autonomic toxicity. One patient complained of chest discomfort associated with tachycardia, a modest rise in blood pressure, and had t-wave inversion in a single precordial lead. These signs and symptoms resolved within a few hours. Serial ECG tracings and cardiac enzymes revealed no evidence of myocardial injury. This pilot study did not reveal major cognitive improvement with this regimen, but underscores the importance of careful cardiovascular monitoring during future combined cholinergic-noradrenergic therapies in AD.

High-resolution computed tomographic bronchiolography using perfluoroctylbromide (PFOB): an experimental model.

The use of perfluoroctylbromide (PFOB), a liquid ventilatory agent, was evaluated as a computed tomographic contrast agent to visualize small airway anatomy to the level of the centrilobular bronchiole, normally not visible on high-resolution computed tomography (HRCT). A freshly excised neonatal lamb heart-lung preparation was tracheally intubated, suspended in a saline bath, and mechanically ventilated with gas. After obtaining HRCT control images with suspended respiration using continuous positive airway pressure, 30 ml of perfluorocytlbromide was instilled into the trachea and repeat scans were obtained. These images demonstrated PFOB filling and distending the airways to the level of the centrilobular bronchioles and their first order branches. There was only minimal spillage into air spaces, allowing excellent anatomic detail of the bronchiolar structures. A liquid ventilatory agent, PFOB is a superb candidate as a bronchographic contrast agent due to its promotion of gas exchange, low toxicity, low surface tension, radiopacity, and vaporized excretion via the lung. It has great potential to evaluate small airway disease when used in conjunction with HRCT.

Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects.

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.

Deterioration on the Blessed test in Alzheimer's disease: longitudinal data and their implications for clinical trials and identification of subtypes.

One hundred eleven patients with probable Alzheimer's disease (AD) were given the Blessed test (BT) of information, memory, and concentration (scored 0-33) at 6-month intervals over periods of 6-96 months. For each patient, the change in the total BT score between pairs of visits at 6- and 12-month intervals was measured. Mean deterioration scores over 6 and 12 months were 2.2 (SD = 3.2) and 4.1 (SD = 4.1) points, respectively. There was no significant correlation between degree of dementia on the BT and the rate of deterioration. Gender, age of onset, and family history had no significant effect on the rate of deterioration. The implications of the results for treatment trials and investigations of clinical heterogeneity are discussed.

Nocturnal growth hormone secretion in schizophrenic patients and healthy subjects.

Plasma growth hormone concentrations were measured at hourly intervals between 10 p.m. and 8 a.m. the next morning in 15 drug-free chronic schizophrenic male inpatients and 14 healthy males. Growth hormone secretion was significantly lower in the patients as compared with the controls. Growth hormone release peaked around 1 a.m. in the controls, but a growth hormone peak was absent in the patient group. Increased dopamine activity, increased serotonin activity, or both could explain the absence of a nocturnal growth hormone surge in the schizophrenic patients.