The significance of angiogenesis in malignant pheochromocytomas

The purpose of this study was to investigate tumor angiogenesis in a series of benign and malignant pheochromocytomas and to determine whether there is a correlation between angiogenesis and the presence of distant metastases. In this study, the CD31 monoclonal antibody was selected to measure intratumoral microvessel density. Nineteen patients with malignant pheochromocytomas and nineteen patients with benign pheochromocytomas who underwent operation were studied. In order to quantify intratumoral microvessel density, the total number of pixels of CD31-positive reactivity was assessed and expressed as a percentage of the total tissue area in the analyzed field. Analysis of variance revealed a statistically significant correlation between malignancy and intratumoral microvessel density (p=0.0009). Although there was a considerable variability in the intratumoral microvessel density from tumor to tumor within both the benign and the malignant group, a percentage of more than 28.5% anti-CD31 stained area was found only in malignant tumors. In conclusion, this study shows that the mean intratumoral microvessel density in malignant pheochromocytomas is increased approximately two-fold as compared with benign tumors. However, the clinical significance of this prognostic marker is rather weak, because only 4 of the 19 malignant pheochromocytomas had microvesel density higher than this threshold of 28.5%.     

Atypical diaphyseal femoral fractures—new aspects

Post menopausal osteoporotic fractures are a major public health concern worldwide with oral bisphosphonates favored for their prevention and treatment. Recent interest has centered on clinically observed, unusually sited femoral diaphyseal fractures, particularly attributed to alendronate. Their imaging presentations on routine radiographs, alternate imaging modalities, and associated pitfalls in nine fractures in six patients are selectively illustrated by seven fractures in four patients that serve to emphasize the following: (1) Bisphosphonates other than alendronate have been used for treating various bone diseases in children and men as well as osteoporotic women. (2) Effects may differ with each bisphosphonate’s route of administration and prolongation of activity, despite discontinuation. Prior investigations and theoretical mechanisms of bisphosphonates as a class rather than with a specific alendronate association are reviewed to provide a broader basis for evaluating their recently observed clinical and radiographic complications.     

Prolonged treatment of Salmonella enterica serovar Typhimurium with commercial disinfectants selects for multiple antibiotic resistance, increased efflux and reduced invasiveness

OBJECTIVES: To study how disinfectants affect antimicrobial susceptibility and phenotype of Salmonella enterica serovar Typhimurium SL1,344. METHODS: Wild-type strain SL1,344 and its isogenic gyrA mutant were passaged daily for 7 days in subinhibitory concentrations, and separately for 16 days in gradually increasing concentrations of a quaternary ammonium disinfectant containing formaldehyde and glutaraldehyde (QACFG), an oxidizing compound blend (OXC), a phenolic tar acids-based disinfectant (TOP) and triclosan. The MICs of antimicrobials and antibiotics for populations and representative isolates and the proportion of cells resistant to the MICs for the wild-type were determined. Expression of acrB gene, growth at 37 degrees C and invasiveness of populations in Caco-2 intestinal epithelial cells were assessed. RESULTS: QACFG and triclosan showed the highest selectivity for variants with reduced susceptibility to chloramphenicol, tetracycline, ampicillin, acriflavine and triclosan. Populations treated with the above biocides had reduced invasiveness in Caco-2 cells, and altered growth kinetics. Resistance to disinfectants was observed only after exposure to gradually increasing concentrations of triclosan, accompanied with a 2000-fold increase in its MIC. Growth in OXC and TOP did not affect the MICs of antibiotics, but resulted in the appearance of a proportion of cells resistant to the MIC of acriflavine and triclosan for the wild-type. Randomly selected stable variants from all populations, except the one treated with TOP, over-expressed acrB. CONCLUSIONS: In vitro exposure to QACFG and triclosan selects for Salmonella Typhimurium cells with reduced susceptibility to several antibiotics. This is associated with overexpression of AcrAB efflux pump, but accompanied with reduced invasiveness.     

Barriers to Implementation of Treatment Guidelines for ADHD in Adults With Substance Use Disorder

Objective: Attention deficit hyperactivity disorder (ADHD) is common among adult patients with a substance use disorder, yet often goes undetected. This is a qualitative study to explore implementation barriers to a guideline developed in Belgium for the recognition and treatment of ADHD in adult patients with substance use disorder and to gain a better understanding of the strategies to overcome these barriers.

Methods: Focus groups were conducted with caregivers and patients to explore experiences with comorbid substance use disorder and ADHD. The barriers reported in these focus groups became the subject of further study in focus groups with addiction professionals (physicians, psychiatrists, and psychologists) who had tried the guideline and with psychiatrists specializing in addiction but without experience with ADHD.

Results: Our analysis revealed a number of barriers to the implementation of this guideline, including lack of information from the family, pressure from patients and caregivers to make an ADHD diagnosis, and the potential for abuse of ADHD medication. Furthermore, diagnostic instruments for ADHD have not been validated in people with substance use disorder. Although patients with ADHD are usually treated in an outpatient setting, patients with ADHD comorbid with substance use disorder are difficult to identify in an outpatient setting for various reasons. Finally, there is a lack of specific ADHD expertise in substance use treatment organizations.

Conclusions: Despite the availability of an approved guideline for recognizing and treating adult ADHD in patients with a substance use disorder, underdiagnosis and inadequate treatment still persist. As in general substance use treatment, medication only plays a supportive role in the treatment of substance use disorder with comorbid ADHD. An integrated approach and further improvements in the competence of practitioners may help to reduce the resistance to diagnosing ADHD in substance use treatment centers. Practitioners who specialize in addiction medicine and therapists without medical education view the problem from different perspectives and therefore each group needs specific information and training. Targeted interventions need to be developed to keep these patients in treatment.     

Psychosocial Functioning and Depressive Symptoms Among HIV-Positive Persons Receiving Care and Treatment in Kenya,Namibia, and Tanzania

In sub-Saharan Africa, the prevalence of depressive symptoms among people living with HIV (PLHIV) is considerably greater than that among members of the general population. It is particularly important to treat depressive symptoms among PLHIV because they have been associated with poorer HIV care-related outcomes. This study describes overall psychosocial functioning and factors associated with depressive symptoms among PLHIV attending HIV care and treatment clinics in Kenya, Namibia, and Tanzania. Eighteen HIV care and treatment clinics (six per country) enrolled approximately 200 HIV-positive patients (for a total of 3,538 participants) and collected data on patients’ physical and mental well-being, medical/health status, and psychosocial functioning. Although the majority of participants did not report clinically significant depressive symptoms (72 %), 28 % reported mild to severe depressive symptoms, with 12 % reporting severe depressive symptoms. Regression models indicated that greater levels of depressive symptoms were associated with: (1) being female, (2) younger age, (3) not being completely adherent to HIV medications, (4) likely dependence on alcohol, (5) disclosure to three or more people (versus one person), (6) experiences of recent violence, (7) less social support, and (8) poorer physical functioning. Participants from Kenya and Namibia reported greater depressive symptoms than those from Tanzania. Approximately 28 % of PLHIV reported clinically significant depressive symptoms. The scale-up of care and treatment services in sub-Saharan Africa provides an opportunity to address psychosocial and mental health needs for PLHIV as part of comprehensive care.     

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.     

Remarks on the Philosophy of Mental Disorder†

Objective: Practitioners working with offenders who have set fires have access to very few measures examining fire-specific treatment needs (e.g., fire interest, fire attitudes). In this article we examine the new Four Factor Fire Scales (Ó Ciardha et al., 2015), which may be used by practitioners to examine fire-specific treatment needs for offenders who have set deliberate fires. We present a standardized scoring procedure when using these scales, as well as an associated scoring template for practitioner use. Method: Norm data are based on male and female firesetters (n = 378) and nonfiresetters (n = 187) recruited from 19 prison establishments (including six female establishments, one young offender institution) and 12 secure mixed-gender mental health settings. Results: We present a full overview of all data we have collected to date relating to the Four Factor Fire Scales across prison, mental health, and young offending participants. For each population, we present mean scores as well as associated cutoff scores and reliable change indices to aid practitioners in their interpretation of scores. Conclusions: The Four Factor Fire Scales provide professionals working in the area with a robust template for administering, scoring, and interpreting the fire-specific factors currently identified as playing a role in deliberate firesetting behavior. Strengths and limitations of the measure are discussed.     

Absence of evidence for allelic loss or allelic gain for ERCC1 or for XPD in human ovarian cancer cells and tissues

We have previously reported on mRNA expression of ERCC1, XPA and XPD in human ovarian cancer cells and tissues. Several factors can influence mRNA expression for any given gene. Alterations in gene copy number for ERCC1 and/or XPD have been reported to occur in malignant glioma specimens. Human ovarian cancer cell lines and tissues were therefore examined for evidence of altered gene copy number in selected genes within the nucleotide excision repair (NER) pathway. Six ovarian cancer cell lines were studied: A2780, A2780/CP70, SKOV3, MCAS, QvCar3 and Caov4. Cellular sensitivity to cisplatin varies by more than 1 log between some of these cells. In each of these cell lines, the genes examined included ERCC1, XPA, XPB, XPD, XPG, CSB and p53. Genomic DNA was also extracted from ovarian cancer specimens taken from 22 patients and assessed for evidence of allelic loss and/or allelic gain for ERCC1 and XPD. Twelve of the clinical specimens were from patients with platinum-sensitive tumors and ten were from patients with platinum-resistant tumors. In no case could we demonstrate a reproducible variation in gene copy number in any cell line. Among the human tissues studied, there was one case of allelic gain out of 22 specimens. We therefore conclude that alterations in gene copy number is not a common event in human ovarian cancer. Other mechanisms must be invoked to explain differences in mRNA expression for these genes.