Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss.

BACKGROUND: The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol. METHOD: Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded. RESULTS: Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. CONCLUSIONS: Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area.

Usefulness of sonication procedure in mesh infection diagnosis associated with hernia repair.

BACKGROUND: The use of prosthetic meshes is a common practice in hernia repair surgery. However, infection can appear as an important complication where antibiotic selection must be directed by the etiology of the infection. In recent years, sonication has appeared as an important tool for the diagnosis of many biomaterial-associated infections. Here, we evaluated our experience with this methodology for the diagnosis of mesh infection. METHODS: We retrospectively reviewed the microbiological records between 2015 and 2019 looking for sonicated meshes in the microbiology laboratory. All samples were processed according to the sonication protocol described by Esteban J et al. (J Clin Microbiol. 2008 Feb; 46 (2): 488-92). RESULTS: 26 samples were processed during the study period. 21 of them gave a positive result for culture (11 polymicrobial and 10 monomicrobial ones). Staphylococcus aureus and Candida albicans were the commonest monomicrobial isolates (4 cases each). There were five cases of mixed gut microbiota. The median (interquartile range) UFC count was > 100,000 (50,000- > 100,000) CFU/mL. CONCLUSION: Sonication is a useful technique for the diagnosis of mesh infection.

Chronological milestones to guide drug change. When should clinicians switch antidepressants?

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received placebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

Brachytherapy after laser recanalization versus external beam radiotherapy after laser recanalization versus laser alone in inoperable oesophagocardial cancer: a controlled pilot study.

PURPOSE: To compare the results of combined laser/radiation therapy with laser treatment alone, and to evaluate the potential benefit of brachytherapy vs. external beam radiotherapy after laser recanalization in patients with dysphagia due to oesophagocardial cancer. PATIENTS AND METHODS: Twenty patients with grade 4 malignant dysphagia caused by oesophagocardial cancer underwent Nd: YAG laser desobstruction up to grade 0-1. Ten of them were referred afterwards for external beam radiotherapy at a dose of 30 Gy for 10 sessions, while the remaining were administered endocavitary afteloading brachytherapy at a dose of 2x7.5 Gy. Twenty preselected patients (to maximally match the above group), who successfully underwent laser re-establishment of the continuity, served as controls to the groups described. Criteria for evaluation were: mean interval to re-stenosis, mean number of additional laser procedures needed, mean survival and Karnofski's performance status (PS). Patients were followed to death. Statistical analysis was carried out with the Student's t-test. RESULTS: It was found that laser plus brachytherapy increased almost 3 times the interval to re-stenosis and decreased almost 2 times the need of additional laser usage in comparison to laser alone. It was also found that laser plus brachytherapy is statistically superior option to laser plus external beam radiotherapy. CONCLUSION: Laser plus brachytherapy has the potential to become a single modality-single session treatment for the relief of dysphagia in patients with stage IV oesophagocardial cancer.

A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical depression.

OBJECTIVE: The atypical subtype of depression appears to be both well validated and common. Although monoamine oxidase inhibitors are effective in treating atypical depression, their side effects and prescription-associated dietary restrictions reduce their suitability as a first-line treatment. The objective of this study was to estimate the efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the treatment of major depression with atypical features. METHOD: One hundred fifty-four subjects with DSM-IV major depression who met the Columbia criteria for atypical depression were randomly assigned to receive fluoxetine, imipramine, or placebo for a 10-week clinical trial. Imipramine was included because its known efficacy for treatment of atypical depression helped to calibrate the appropriateness of the study group. RESULTS: In both intention-to-treat and completer groups, the effectiveness of both fluoxetine and imipramine was significantly better than that of placebo. The two medications did not differ from each other in effectiveness. Significantly more patients dropped out of treatment with imipramine than with fluoxetine. Before treatment, patients on average rated themselves as very impaired on psychological dimensions of general health and moderately impaired on physical dimensions, compared with population norms. The self-ratings of patients who responded to treatment essentially normalized on these measures. CONCLUSIONS: Despite earlier data that SSRIs might be the treatment of choice, fluoxetine appeared to be no better than imipramine in the treatment of atypical depression, although fluoxetine was better tolerated than imipramine.

Postprandial cholecystokinin release and gastric emptying in patients with bulimia nervosa.

This study was designed to investigate the biological underpinnings of the observed deficit in satiety in patients with bulimia nervosa. Eight women with bulimia nervosa and 10 age- and weight-matched control subjects consumed three laboratory meals consisting of 200, 400, and 600 g of a radiolabeled liquid meal. For 1 h after each meal, blood samples were obtained at 10-min intervals for measurement of cholecystokinin concentration and gastric emptying was measured. Subjects also completed perceptual rating scales at 10-min intervals. Compared with control subjects, patients with bulimia nervosa showed a blunting of postprandial cholecystokinin release, particularly with larger meal sizes, as well as delayed gastric emptying. Increasing meal size was associated with increased desire to binge eat in patients but not in control subjects. These data lend support to a model in which increased gastric capacity, perhaps resulting from repeated binge eating, gives rise to delayed gastric emptying and blunted postprandial cholecystokinin release, leading to an impaired satiety response, which tends to perpetuate the illness.

A method to quantify rater bias in antidepressant trials.

Some studies indicate that the blind in clinical trials of the efficacy of antidepressant drugs is less than perfect. It has been suggested that, as a consequence of this incomplete blind, biased raters inflate efficacy and that, in fact, these drugs are relatively ineffective. However, in the literature, we could find no prior attempt to quantify rater bias and, thus, measure its contribution to claims of antidepressant efficacy. We used the distribution of SCL-90 (Symptom Check List) depression scale scores to derive a patient-based effect size, and contrasted this with the clinician-based effect size. We propose the difference between these two effect sizes (patient self-rating and clinician-derived) to be an indirect measure of bias. If patients had a prodrug bias, this method would be invalid. However the response rate from studies with active placebo suggest a patient prodrug bias is unlikely. The effect sizes derived from patient self-ratings are smaller than those derived from clinician ratings. This allows for the possibility that some clinician ratings were biased. However, quantifying the effect of bias suggests that it was insufficient to invalidate the original study conclusions based on clinician ratings, because the proportion of responders, based on patient self-ratings, differed significantly between the two drugs and placebo. Their 95% confidence intervals (CI) did not overlap. This analysis allows that some clinician ratings may be biased. However, the extent of bias appears insufficient to alter conclusions based on clinician ratings regarding efficacy of antidepressant drugs in this trial. Application of our approach in other trials is necessary to establish generalizability.

Predictors of relapse during fluoxetine continuation or maintenance treatment of major depression.

BACKGROUND: The goal was to examine predictors of relapse during continuation/maintenance treatment of major depression that had remitted following 12 to 14 weeks of fluoxetine therapy. METHOD: The study utilizes data collected in a collaborative clinical trial including patients with DSM-III-R major depression at 5 university-affiliated outpatient psychiatry clinics. Three hundred ninety-five patients who remitted with fluoxetine therapy were randomly assigned to 1 of 4 treatments: fluoxetine for 14 weeks followed by placebo for 36 weeks, fluoxetine for 38 weeks followed by placebo for 12 weeks, fluoxetine for 50 weeks, or placebo for 50 weeks. Cox proportional hazard models were used to identify predictors of time to relapse. RESULTS: In addition to the previously reported longitudinal pattern of response during acute treatment, neurovegetative symptom pattern was a predictor of fluoxetine benefit compared with placebo. Greater chronicity predicted poorer survival, which was not differential by treatment. The most robust advantage of fluoxetine was seen for patients with endogenous vegetative symptoms, chronic depression, and acute treatment response characterized by onset in the third week or later and persistence of response once attained. CONCLUSION: Both nonspecific pattern of response and neurovegetative symptoms characteristic of atypical depression were predictive of lack of fluoxetine efficacy in continuation/ maintenance treatment. These findings have importance for both clinical management and analyses of future maintenance trials.

Psychological versus pharmacological treatments of bulimia nervosa: predictors and processes of change.

This article extends the acute outcome findings from a study comparing psychological and pharmacological interventions for bulimia nervosa (B.T. Walsh et al., 1997) by examining 3 additional domains: predictive factors, therapeutic alliance, and time course of change. One hundred twenty women were randomized to cognitive-behavioral therapy (CBT), supportive psychotherapy (SPT) plus antidepressant medication or a placebo, or a medication-alone condition. Results indicate that high baseline frequencies of binge eating and vomiting, as well as a positive history of substance abuse or dependence, are negative prognostic indicators. Although a greater overall therapeutic alliance may increase the likelihood of remission, symptom change over the course of treatment may have as much of an impact on patient ratings of alliance as the reverse. CBT was significantly more rapid than SPT in reducing binge eating and vomiting frequencies.

Two cases of radiation-induced cancers 20 years after treatment of first malignancies.

Studies on radiation-induced breast and thyroid cancers have demonstrated that age at exposure is a major determinant of risk, with the greatest risk being for those irradiated as children and adolescents. In measuring the outcome of treatment, the ability to provide toxicity-free survival and minimal risk of second cancer may in future be regarded as important as achieving disease-free survival or local control. Herein we present two cases of secondary cancer with good treatment outcome that occurred 20 years after treatment for primary malignancies in childhood.

Forming first impressions of others in schizophrenia: impairments in fast processing and in use of spatial frequency information.

Individuals form first impressions of others all the time, which affects their social functioning. Typical adults form threat impressions in faces with neutral expressions quickly, requiring less than 40 ms. These impressions appear to be mediated by low spatial frequency (LSF) content in the images. Little is known, however, about mechanisms of first impression formation in schizophrenia. The current study investigated how quickly individuals with schizophrenia can form consistent impressions of threat compared with controls and explored the mechanisms involved. Patients and controls were presented intact, LSF- or high spatial frequency (HSF)-filtered faces with durations that varied from 39 to 1703 ms and were asked to rate how threatening each face was on a scale from 1 to 5. In order to assess the speed of impression formation for intact faces, correlations were calculated for ratings made at each duration compared to a reference duration of 1703 ms for each group. Controls demonstrated a significant relation for intact faces presented for 39 ms, whereas patients required 390 ms to demonstrate a significant relation with the reference duration. For controls, LSFs primarily contributed to the formation of consistent threat impressions at 39 ms, whereas patients showed a trend for utilizing both LSF and HSF information to form consistent threat impressions at 390 ms. Results indicate that individuals with schizophrenia require a greater integration time to form a stable "first impression" of threat, which may be related to the need to utilize compensatory mechanisms such as HSF, as well as LSF, information.

A baseline inhalation toxicity model for narcosis in mammals.

This paper presents the results of an analysis of the rodent inhalation literature and the development of a quantitative structure-activity relationships (QSAR) model for 4-hour LC50 as baseline toxicity to complement the baseline toxicity model for aquatic animals. We used the same literature review criteria developed for the ECOTOX database which selects only primary references with explicit experimental methods to form a high-quality database. Our literature review focused on the primary references reporting a 4-hour exposure for a single species of rodent in which the chemical had been clearly tested as a vapour and for which the exposure concentrations were not ambiguous. An expert system was used to remove reactive chemicals, receptor-mediated toxicants, and any test that produced symptoms inconsistent with non-polar narcosis. The QSAR model derived for narcosis in rodents was log LC50 = 0.69 x log VP + 1.54 which had an r(2) of 0.91, which is significantly better than the baseline toxicity model for aquatic animals. This simple model suggests that there is no intrinsic barrier to estimating baseline toxicity for in vivo endpoints in mammalian or terrestrial toxicology.

The physicochemical basis of QSARs for baseline toxicity.

The physico-chemical properties relevant to the equilibrium partitioning (bioconcentration) of chemicals between organisms and their respired media of water and air are reviewed and illustrated for chemicals that range in hydrophobicity. Relationships are then explored between freely dissolved external concentrations such as LC50s and chemical properties for one important toxicity mechanism, namely baseline toxicity or narcosis. The 'activity hypothesis' proposed by Ferguson in 1939 provides a coherent and compelling explanation for baseline toxicity of chemicals in both water- and air-respiring organisms, as well as a reference point for identifying more specific toxicity pathways. From inhalation studies with fish and rodents, narcosis is shown to occur at a chemical activity exceeding approximately 0.01 and there is no evidence of narcosis at activities less than 0.001. The activity hypothesis provides a framework for directly comparing the toxic potency of chemicals in both air- and water-breathing animals. The activity hypothesis is shown to be consistent with the critical body residue concept, but it has the advantage of avoiding the confounding effect of lipid content of the test organism. It also provides a theoretically sound basis for assessing the baseline toxicity of mixtures. It is suggested that since activity is readily calculated from fugacity, observed or predicted environmental abiotic and biotic fugacities can be used to evaluate the potential for baseline toxicity. Further, models employing fugacity or activity can be used to improve the experimental design of bioassays, thus possibly reducing unnecessary animal testing.

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.

BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

[Activities of glutamate-oxalate and glutamate-pyruvate transaminases, alkaline phosphatase and lactate dehydrogenase in the serum of lambs weaned at different ages]. / Izsledvane aktivnostta na glutamat oksalat i glutamat piruvat transaminazite, alkalnata fosfataza i laktatdekhidrogenazata v seruma na agneta, otbiti na razlichna vuzrast.

Experiments were carried out with 32 lambs weaned at different age and fed a dry milk replacer as well as with 20 control lambs nursed by their ewes. All lambs were divided into three groups. Those of the first one were weaned at the age of 5 days, those of the second group - at 15 days, and those of the third group - at 20 days. Blood was sampled at the beginning of the test and then for a second and a third time at a 15-day interval in order to study the serum glutamate-oxal-acetate transaminase (SGOT), the serum glutamate pyruvate transaminase (SGPT), the alkaline phosphatase (AP), and the lactate dehydrogenase (LDH). It was established that at the first study in the beginning of the experiment SGOT and SGPT were at a higher level in the test animals than in the control ones. AP was found to rise in both groups with the advancement of age. Lowest values in the activity of LDH were recorded with the two groups at the age of 5 days. No differences were established between the values of LDH in the test and control groups in all investigations. The rise of SGOT and SGPT in the test lambs spoke of adaptation of the enzymes as a result of changes in the metabolic pattern with the lambs of different feeding.