Assessing in-session rumination and its effects on CBT for depression.

The study evaluated if rumination of patients during therapy (i.e., in-session rumination) relates to whether or not they do less well in CBT treatment. We developed a reliably assessed in-session rumination observational measure and evaluated its relationship to depression over the course of CBT. Rated sessions came from 63 treatment-naïve patients with major depressive disorder who participated in CBT in the PReDICT study (Dunlop et al., 2017). In-session rumination was operationalized as repetitive, negative, and passive talking about depressive topics. Trained undergraduates rated the intensity and duration of in-session rumination occurring during 57 initial therapy sessions (i.e., session one) and 45 sessions in the middle of treatment (i.e., session eight). The observational ratings were sufficiently reliable (all ICCs > 0.69). Mixed model results indicated that greater intensity of in-session rumination during the initial treatment session predicted higher levels of subsequent clinician-rated depressive symptoms (p < .023). Regression results indicated that greater intensity and duration of in-session rumination at session 8 significantly predicted higher clinician-rated symptoms at end of treatment (p's < 0.02). In-session rumination intensity and duration were not, however, related to subsequent self-reported depressive symptoms. The results support efforts to identify which patients might benefit from rumination-specific interventions.

[Celebration speech marking the 150th anniversary of the Vereniging Nederlands Tijdschrift voor Geneeskunde (Association Dutch Journal of Medicine)]. / Feestrede bij de viering van het 150-jarig jubileum van de Vereniging Nederlands Tijdschrift voor Geneeskunde.

The Nederlands Tijdschrift voor Geneeskunde (NTvG [Dutch Journal of Medicine]) celebrates its 150th anniversary this year. J. van der Meer and S.van 't Hofare the editors of a jubilee book issued to mark the occasion. Two earlier books, issued for the 50th and 100th anniversary of the journal, focused primarily on the history of the association of editors which publishes the NTvG. Unlike these books, a large portion of the current jubilee book is devoted to the history of medicine in the Netherlands in the last 50 years. Of greater importance is that the authors reflect on the relationship between the NTvG, the medical profession and society at large. This relationship has intensified since the 1960's. The NTvG has accomplished its goal of being a general medical journal, but lacks 'the voice of the patient' and editorial comments on current social issues. With respect to the physician-patient relationship, the Netherlands has succeeded more than other countries in diminishing the gap between these two partners. The way the Dutch have dealt with the issue of euthanasia is a clear example. But as to the role of the physician in society, the loss of position and authority, increasing professionalism and specialisation and reluctance to engage in social and ethical debate for fear of losing impartiality have caused the medical profession to assume a marginal position in society, even with respect to its own needs as a group of professionals. At present, there is a clear need for physician citizenship that engages in a broad spectrum of social responsibilities in a professional context.

An affordable, portable fluorescence imaging device for skin lesion detection using a dual wavelength approach for image contrast enhancement and aminolaevulinic acid-induced protoporphyrin IX. Part II. In vivo testing.

A fluorescence imaging prototype for skin lesion detection and diagnosis using aminolaevulinic acid (ALA) induced protoporphyrin IX (PpIX) was tested in vivo and in the clinic. The prototype was designed as an affordable, portable device to allow contrast enhanced imaging of skin lesions using either the dual excitation wavelength method or the dual emission wavelength method or both. In this study the prototype was tested first on an animal model. Topical application of ALA on defined spots on mouse skin gave PpIX fluorescence after about 3 hours of application. After successful in vivo testing the instrument was tested on basal cell carcinoma patients before ALA-PpIX photodynamic therapy. The patients were topically applied with ALA. After three hours the device was tested (immediately before treatment). The prototype showed good results in terms of contrast enhancement (elimination of unwanted background signals, e.g. autofluorescence) using either contrast enhancement method, both methods achieving similar results. The results achieved in this study, combined with the affordable design of the device, seem to allow cost-effective, contrast-enhanced imaging of skin lesions before or during photodynamic therapy using ALA induced PpIX.

A physical and transcript map of the MCOLN1 gene region on human chromosome 19p13.3-p13.2.

Mutations in MCOLN1 have been found to cause mucolipidosis type IV (MLIV; MIM 252650), a rare autosomal recessive lysosomal storage disorder found primarily in the Ashkenazi Jewish population. As a part of the successful cloning of MCOLN1, we constructed a 1.4-Mb physical map containing 14 BACs and 4 cosmids that encompasses the region surrounding MCOLN1 on human chromosome 19p13.3-p13.2-a region to which linkage or association has been reported for multiple diseases. Here we detail the precise physical mapping of 28 expressed sequence tags that represent unique UniGene clusters, of which 15 are known genes. We present a detailed transcript map of the MCOLN1 gene region that includes the genes KIAA0521, neuropathy target esterase (NTE), a novel zinc finger gene, and two novel transcripts in addition to MCOLN1. We also report the identification of eight new polymorphic markers between D19S406 and D19S912, which allowed us to pinpoint the location of MCOLN1 by haplotype analysis and which will facilitate future fine-mapping in this region. Additionally, we briefly describe the correlation between the observed haplotypes and the mutations found in MCOLN1. The complete 14-marker haplotypes of non-Jewish disease chromosomes, which are crucial for the genetic diagnosis of MLIV in the non-Jewish population, are presented here for the first time.

Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.

Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the Drosophila transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.

Quantification of the selective retention of palladium octabutoxynaphthalocyanine, a potential photothermal drug, in mouse tissues.

Palladium octabutoxynaphthalocyanine (PdNc(OBu)8) is a potential photothermal therapy (PTT) agent, absorbing strongly in the near-infrared region with no ability to induce photodynamic-type sensitisation (unlike many related napthalocyanines). We report here on the application of high pressure liquid chromatography (HPLC) with near-infrared absorption detection for the determination of the tissue accumulation and clearance of PdNc(OBu)8 in a tumour-bearing mouse model (Balb/c mice with EMT6 carcinoma tumour). Due to its insolubility in aqueous-based solvents, the drug was delivered intraperitoneally in a Cremophor-containing vehicle. Good selective accumulation of the drug into the tumour versus muscle or skin is observed, with the best combination of selectivity and tumour concentration occurring at 24-72 h after drug administration. Clearance times are quite long. Comparison with other similar drugs as reported in the literature indicates that the Cremophor-containing vehicle is likely in large part responsible for the observed pharmacokinetic behaviour. This drug shows potential for PTT and will be investigated further for therapy in this animal model.

Catatonic signs in medical and psychiatric catatonias.

Patients with psychiatric catatonias vs those with medical catatonias may differ in catatonic phenomenology. To determine if these could be distinguished, the following methods were used: 1) a review of the literature; 2) a chart review; and 3) a prospective series. The literature review of 467 reports of medical catatonias yielded 240 cases that met research criteria. A chart review of 47 episodes of catatonia revealed a higher frequency of negativism in patients with medical catatonias. Prospective data obtained from rating scales revealed an increased frequency of echophenomena in patients with medical catatonias; however, no discriminate pattern of catatonic signs for medical catatonias arose. Overall, catatonic signs appear to share a similar distribution. These findings suggest that psychiatric and medical catatonias are indistinguishable based upon catatonic sign.

Family size, infections, and asthma prevalence in New Zealand children.

We conducted a prevalence case-control study to investigate the relation between family composition, infection, and development of asthma at age 7-9 years. Potential cases (399) and controls (398) were selected from the Wellington, NZ, arm of the International Study of Asthma and Allergies in Childhood, a population-based prevalence study. Further screening questions restricted cases to children with a diagnosis of asthma and current medication use (N = 233) and restricted controls to children without a history of wheezing and no diagnosis of asthma (N = 241). After controlling for confounders (including infections, atopy, and socioeconomic status), family size was strongly related to asthma. Having no siblings [prevalence odds ratio (POR) = 2.51; 95% confidence interval (CI) = 1.05-6.01] or one sibling (POR = 1.86; 95% CI = 1.14-3.03) was associated with an increased risk of asthma compared with having more than one sibling. Parent-reported rubeola infection (and possibly other similar viral exanthems) was independently associated with a decreased risk of asthma (POR = 0.48; 95% CI = 0.27-0.83), but reported pertussis infection (POR = 1.57; 95% CI = 0.58-4.24) and day care attendance in the first year of life (POR = 1.81; 95% CI = 0.93-3.51) were not strongly associated with increased risks of asthma.

Rodent fibroblast model for studies of response of malignant cells to exogenous 5-aminolevulinic acid.

All nucleated mammalian cells synthesize protoporphyrin IX (PpIX) when exposed to exogenous 5-aminolevulinic acid (ALA). The response to exogenous ALA under standard conditions (the ALA phenotype) is characteristic for each cell type. Significantly more PpIX accumulates in malignant and premalignant cells than in the normal cells from which they were derived. A rodent fibroblast model was developed to study the mechanisms responsible for this phenomenon. Exogenous ALA induced the accumulation of substantial concentrations of PpIX in fibrosarcoma cells, and in immortalized fibroblasts transfected with the oncogene c-myc, IGF-1 receptor, IGF-1 and its receptor, v-fos, v-raf, v-Ki-ras, v-abl, or polyomavirus middle T antigen with G418 resistance selection. Much lower concentrations of PpIX accumulated in primary fibroblast cultures, in immortalized fibroblast cell lines, and in immortalized fibroblasts transfected with the G418-resistance gene only. The mechanisms responsible for the increased accumulation of ALA-induced PpIX by transformed cells (the malignant ALA phenotype) therefore appear to be closely linked to the mechanisms responsible for malignant transformation. Identification of the nature of that linkage may lead to new approaches to cancer therapy.

Papillary endothelial hyperplasia presenting as a chest wall neoplasm.

Soft tissue hematomas generally resolve but may persist and develop into slow-growing, organized masses. These chronic expanding hematomas are characterized by a pseudocapsule and a predominantly necrotic central cavity, with foci of newly formed capillaries. These have been called chronic expanding hematomas or Masson's papillary endothelial hyperplasia. These lesions can mimic vascular neoplasms and must be considered in the evaluation of expanding soft tissue vascular malformations.

Effect of mammalian cell differentiation on response to exogenous 5-aminolevulinic acid.

Many different types of mammalian cells accumulate fluorescing and photosensitizing concentrations of protoporphyrin IX (PpIX) when exposed to exogenous 5-aminolevulinic acid (ALA) in vivo or in vitro. Most types of malignant cells accumulate substantially more ALA-induced PpIX than do the normal cells from which they arose. Most types of malignant cells also are less differentiated than their normal counterparts. We therefore considered the possibility that malignant cells demonstrate a malignant ALA phenotype (accumulate abnormally large amounts of PpIX when exposed to exogenous ALA) as a direct consequence of their less differentiated state. Human promyelocyte cell line HL-60 and mouse preadipocyte cell line 3T3 L1 were induced to differentiate by exposing them to inducing agents in vitro. The HL-60 cells accumulated less ALA-induced PpIX when differentiated, but the 3T3 L1 cells accumulated more. It appears then that changes in the ALA phenotype with changes in the state of differentiation are cell-type specific. The decreased accumulation of ALA-induced PpIX that accompanied differentiation of the promyelocytic leukemia cells may have clinical application for rapid quantitation of the response of myelocytic leukemia patients to differentiation therapy.

The Monitoring of ALA-Induced Protoporphyrin IX Accumulation and Clearance in Patients with Skin Lesions by In Vivo Surface-Detected Fluorescence Spectroscopy.

The method of surface-detected fluorescence has been used to monitor the emission intensity from 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in lesions and corresponding adjacent normal skin. Three types of lesions were examined: psoriatic plaques, actinic keratosis and basal cell carcinoma. This study included a total of 14 human volunteers on whom ALA-induced PpIX formation and clearance was monitored for a total of 48 h post-ALA application. Both an ALA dose-ranging study, as well as a comparison of results between normal and lesional tissue at a fixed ALA dose, were carried out. For the dose range examined (10-30%), there was no ALA dose dependency of the PpIX fluorescence for any of the lesions tested. Although all three lesions tested did show enhanced PpIX fluorescence as compared with normal skin, there was considerable lesion-to-lesion variability. Thick psoriatic plaques seem to give longer PpIX retention times than those of thin lesions. Limitations of the surface-detected fluorescence methodology are discussed.

Detection of early stages of carcinogenesis in adenomas of murine lung by 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.

Administration of the heme precursor 5-aminolevulinic acid (ALA) leads to the selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in certain types of normal and abnormal tissues. This phenomenon has been exploited clinically for detection and treatment of a variety of malignant and nonmalignant lesions. The present preclinical study examined the specificity of ALA-induced porphyrin fluorescence in chemically induced murine lung tumors in vivo. During the early stages of tumorigenesis, ALA-induced PpIX fluorescence developed in hyperplastic tissues in the lung and later in early lung tumor foci. In early tumor foci, maximum PpIX fluorescence occurred 2 h after the administration of ALA and returned to background levels after 4 h. There was approximately a 20-fold difference in PpIX fluorescence intensity between tumor foci and the adjacent normal tissue. The specificity of ALA-induced fluorescence for hyperplastic tissues and benign tumors in lung during tumorigenesis suggests a possible use for this fluorochrome in the detection of premalignant alterations in the lung by fluorescence endoscopy. Two non-small cell lung cancer cell lines developed ALA-induced PpIX fluorescence in vitro. These lines exhibited a light-dose-dependent phototoxic response to ALA photodynamic therapy (PDT) in vitro. Because PpIX is a clinically effective photosensitizer for a wide variety of malignancies, these results support the possible use of ALA-induced PpIX PDT for lung cancer.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results.

5-Aminolevulinic acid (ALA), when added to many tissues, results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA is the only photodynamic therapy (PDT) agent in current clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and in human clinical studies has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. The current state of knowledge of the mechanisms of endogenous topical and systemic photosensitization using ALA, the results of published clinical trials, and possible methods of increasing the efficacy of endogenous photosensitization for ALA PDT are reviewed in this paper.

In vitro studies on the potential use of 5-aminolaevulinic acid-mediated photodynamic therapy for gynaecological tumours.

Results are reported on the sensitivity of various gynaecological tumour cell lines to 5-aminolaevulinic acid-induced protoporphyrin IX-sensitised photodynamic therapy (ALA-PDT) in vitro. All cell lines tested accumulated ALA-induced protoporphyrin IX (PpIX) and demonstrated good sensitivity to ALA-PDT. Localisation of PpIX in the mitochondria was demonstrated by fluorescence microscopy. Subcellular damage following ALA-PDT was observed using transmission electron microscopy. This damage was localised initially to the mitochondria, with damage to membranes and the nucleus and complete loss of intracytoplasmic organisation being observed subsequently. There was no apparent difference in ALA-PDT response between a multidrug-resistant ovarian carcinoma cell line and its parent line. These results indicate that ALA-PDT has potential for application to therapy of gynaecological malignancies.

Intrauterine 5-aminolevulinic acid induces selective endometrial fluorescence in the rhesus and cynomolgus monkey.

OBJECTIVES: To evaluate the selectivity of endometrial photosensitization after intrauterine 5-aminolevulinic acid administration in nonhuman primates, and to assess acute and chronic systemic toxicity after intravenous (i.v.) delivery of 5-aminolevulinic acid. METHODS: Ovariectomized cynomolgus monkeys (n = 19) aged 6-18 years and ovariectomized rheusus monkeys (n = 3) aged 9-14 years were used in these studies, 5-aminolevulinic acid at various doses was administered by a transfundal (n = 8), transcervical (n = 3), or i.v. (n = 11) route. Spectrophoto-fluorometric readings and fluorescence microscopy were used to assess 5-aminolevulinic acid-induced photosensitization of uterine tissues; respiration, heart rate, blood biochemistry, and behavior were used to evaluate potential acute and delayed systemic toxicity. RESULTS: Endometrial fluorescence was achieved in all animals after administration of 5-aminolevulinic acid. Characteristic spectrophotofluorescence peaks of protoporphyrin IX (PpIX) in the endometrium but not myometrium confirmed selective endometrial PpIX production from 5-aminolevulinic acid. A transient (less than 1 week) increase in serum aspartate aminotransferase was observed after systemic instillation of 5-aminolevulinic acid in dosages 24-50-fold greater than that required to induce endometrial photosensitization after intrauterine injection. CONCLUSIONS: The endometrium but not myometrium in nonhuman primates is capable of converting 5-aminolevulinic acid into protoporphyrin IX. At large doses, systemic 5-aminolevulinic acid causes a transient increase in the serum aspartate aminotransferase level. No other evidence of acute or delayed systemic toxicity was observed.

Fluorescence and photosensitization of experimental endometriosis in the rat after systemic 5-aminolevulinic acid administration: a potential new approach to the diagnosis and treatment of endometriosis.

OBJECTIVE: Our purpose was to evaluate and compare the conversion of 5-aminolevulinic acid into the endogenous photosensitizer protoporphyrin IX in experimentally induced endometriosis and in other normal tissues in a rat model. STUDY DESIGN: Fluorescence of experimental endometriotic lesions, uterus, peritoneum, bowel mesentery, bladder, eye, skin, and skeletal muscle was assessed 3 hours after either intravenous, oral, or intrauterine administration of 5-aminolevulinic acid with use of spectrophotofluorometry. In another experiment the fluorescence of surgically induced endometriosis and adjacent normal peritoneum was evaluated every 15 minutes after 5-aminolevulinic acid administration to assess the time course of protoporphyrin IX production. RESULTS: In the rat endometriosis model intralesional and systemic 5-aminolevulinic acid produced fluorescence within implants showing viable endometrial cells. Treatment with 5-aminolevulinic acid produced low-intensity fluorescence in peritoneum, bowel mesentery, and eye. Relatively intense fluorescence was seen in skin, bladder, and uterus. No fluorescence was observed in skeletal muscle. The intensity of fluorescence varied with the dosage and route of administration of 5-aminolevulinic acid. Fluorescence intensity of protoporphyrin IX was significantly greater in implants than in adjacent normal peritoneum between 2 and 4 hours after treatment. CONCLUSIONS: Protoporphyrin IX fluorescence in experimentally induced endometriosis lesions after intravenous and oral delivery of 5-aminolevulinic acid was significantly greater than the fluorescence detected in adjacent normal peritoneum.

Flow cytometric technique for quantitating cytotoxic response to photodynamic therapy.

A simple flow cytometric technique for rapid measurement of multilog cytotoxic responses to photosensitization of cellular systems is described. This technique is particularly useful for cell lines with a low colony-forming efficiency, for which a nonclonogenic assay is required. The assay separates cell-sized objects from cellular debris by gating on forward scatter versus side scatter, identifies viable cells by positive calcein AM and negative ethidium homodimer-1 staining and measures cell concentration relative to an internal standard of polystyrene beads. Large numbers of cells can be analyzed rapidly. Two patient-derived small cell lung cancer cell lines, NCI-H209 and SV-E, were used to test the technique. Photordiation survival curves of the response of these cell lines to 5-aminolevulinic acid-induced protoprophyrin IX photosensitization correlated with the extent of photosensitizer accumulation. There was good agreement between the results obtained using the tritiated thymidine incorporation assay and the flow cytometric cytotoxicity assay. The technique can be used to measure cytotoxic responses to photosensitization of cell lines regardless of their plating efficiencies.

Mania due to general medical conditions: frequency, treatment, and cost.

OBJECTIVE: Mania due to general medicine conditions may occur in patients in a variety of settings. METHODS: We reviewed the charts of patients admitted to an adult psychiatric service over a nine-year period (Jan. 1985 to Dec. 1993). Patients were diagnosed with Organic Affective Syndrome (ICD-9 code 293.83) in 241 episodes (N = 227 patients). There were forty-seven manic or mixed episodes in forty patients (0.72% of all admissions). RESULTS: When DSM-IV criteria for Mood Disorder due to a General Medical Condition manic or mixed type (MDGMC) was applied, we found twenty-five patients with twenty-seven episodes (N = 30 treatment trials). Irritable mood predominated in twenty-seven (90%) of the thirty trials. CONCLUSIONS: Treatment included anticonvulsants in 63 percent, neuroleptics 63 percent, and lithium 40 percent. Favorable responses to anticonvulsants were seen; however combination therapy was used more frequently. Further research in this area is needed.