Psychiatric disorders,acne and systemic retinoids: comparison of risks

Background: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids.

Materials and methods: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest.

Results: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin.

Conclusion: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations.     

Effects of the venom and the dermonecrotic toxin LiRecDT1 of Loxosceles intermedia in the rat liver

Brown spider bites cause dermonecrotic lesions and systemic manifestations known as loxoscelism. The Loxosceles intermedia venom contains many active proteins, as phospholipase D. There are reports of increased levels of hepatic transaminases in humans with loxoscelism, but detailed studies about the action of the Loxosceles intermedia venom on the liver functions are lacking. The aim of this study was to investigate the effects of the venom and the dermonecrotic recombinant toxin 1 (LiRecDT1) in the liver of Wistar rats injected subcutaneously with venom (80 μg) or toxin (80 μg). After 6 and 12 h the liver immunofluorescence was positive for venom and toxin. Hepatocytes from the venom group were tumefacted and apoptotic. There was leucocyte infiltration in the portal region combined with a high degree of steatosis in 12 h. In the toxin group the histological alterations were less severe. Plasma levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyl-transferase were significantly elevated only in the venom group in 6 h. Hepatic metabolism was modified: the venom, but not LiRecDT1, reduced gluconeogenesis and ureagenesis from alanine and glycogen accumulation. These results show that the venom is hepatotoxic and that the dermonecrotic toxin is only partly responsible.     

Monoclonal antibody to human high-molecular-weight kininogen recognizes its prekallikrein binding site and inhibits its coagulant activity

We developed a mouse monoclonal antibody (MoAb 115-21) to human high- molecular-weight kininogen (HK) that recognizes its prekallikrein binding site (residues 565 through 595 of HK). The corresponding synthesized 31-amino acid peptide (peptide IV) was recently shown to retain native HK's prekallikrein binding property. The same peptide bound factor XI also, although less avidly. Our MoAb recognizes purified HK, peptide IV, and the light chain moiety of HK (where the peptide IV resides), as shown by enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments. The apparent dissociation constant for the HK and MoAb 115-21 interaction was 2.2 nmol/L. It does not recognize low-molecular-weight kininogen (LK) with which HK shares its heavy chain moiety or any antigens in human plasma congenitally deficient in kininogens. The binding of MoAb 115-21 to purified light chain of HK was competitively inhibited by peptide IV. In addition, the antibody inhibits HK-dependent clotting activity of normal human plasma and dextran sulfate-mediated activation of prekallikrein in plasma and retards cleavage of HK in normal plasma after contact activation with dextran sulfate. Also, purified Fab fragments of MoAb 115-21 inhibited the HK-dependent coagulant activity and dextran sulfate-mediated prekallikrein activation in normal plasma. Since the kd for HK-MoAb 115- 21 interaction is ten times lower than that of HK-prekallikrein, our data suggest that binding of MoAb 115-21 to HK's peptide IV site increases the free prekallikrein concentration in plasma and thus results in the decreased efficiency of factor XIIa-mediated activation of prekallikrein. Decreased levels of kallikrein thus formed may be responsible for the inhibition of HK-dependent clotting activity and the decrease in rate and extent of HK cleavage in normal plasma on contact activation with dextran sulfate. MoAb 115-21 may thus prove very useful, especially with its high affinity for HK, in further delineation of the role of HK and prekallikrein in contact activation and kinin-related human pathology.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

Sudden infant death syndrome and diphtheria-tetanus-pertussis-poliomyelitis vaccination status

Summary— Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case-control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the study.     

Laparoscopic Right Hemicolectomy for Ileocolic Intussusception Secondary to Caecal Neoplasm

Intussusception in adults is a rare cause of abdominal pain. Unlike its paediatric counterpart, intussusception in adults is associated with obvious pathology. We describe a case of ileocolic intussusception extending to the splenic flexure. We were able to reduce the intussusception partially and pedicle was stapled carefully. The specimen was delivered through a small incision and right hemicolectomy was performed adhering to oncological principles. We recommend laparoscopic-assisted surgery is considered for adult intussusceptions.     

Use of the Internet by Patients Undergoing Elective Hernia Repair or Cholecystectomy

INTRODUCTION

Patient-directed information available on the internet is not always regulated; it may be confusing and sometimes just overwhelming. We aimed to establish the proportion of patients undergoing two common surgical procedures, who searched the internet for information about their operations and to assess the usefulness of the information they received.

PATIENTS AND METHODS

A total of 105 consecutive patients undergoing elective abdominal wall hernia repair (n = 54) or laparoscopic cholecystectomy (n = 51) in a single surgical firm were included in the study. Patients were counselled about their operation in pre-operative assessment clinics and standard trust information leaflets were provided without any mention of this study. Patients were then asked to complete a questionnaire on the morning of their operation.

RESULTS

All patients completed the questionnaire. Of the patients, 59% stated that they had access to the internet and 77% of these accessed the internet over 2 h a week. Of the patients with internet access, 31% used it to acquire additional information about their operations and 58% used internet search engines. Of the patients who searched the internet regarding their operations, 26% were confused and/or worried by the information they received.

CONCLUSIONS

A significant proportion of patients undergoing common surgical procedures used the internet and about one-third of them specifically sought information about their operation on the internet. Such information can cause worry and confusion in patients. Our study highlights the need for regulated, comprehensible, patient information on hospital websites to which patients should be directed.     

Acoustic monitoring (RFM) of total hip arthroplasty results of a cadaver study

Introduction

At present there are no reliable non-traumatic and non-invasive methods to analyse the healing process and loosening status after total hip replacement. Therefore early as well as late loosening of prosthesis and interface component problems are difficult to be found or diagnosed at any time.

Methods

In a cadaver study the potential application of Resonance Frequency Monitoring (RFM) will be evaluated as a non-invasive and non-traumatic method to monitor loosening and interface problems in hip replacement. In a 65 year old female cadaver different stability scenarios for a total hip replacement (shaft, head/modular head and cup, ESKA, Luebeck, Germany) are simulated in cemented and cement less prosthesis and then analysed with RFM. The types of stability vary from secure/press-fit to interface-shaft disruption.

Results

The RFM shows in cemented as well as cement less prosthesis significant intra-individual differences in the spectral measurements with a high dynamic (20 dB difference corresponding to the factor 100 (10000%)), regarding the simulated status of stability in the prosthesis system.

Conclusion

The results of the study demonstrate RFM as a highly sensitive non-invasive and non-traumatic method to support the application of RFM as a hip prosthesis monitoring procedure. The data obtained shows the possibility to use RFM for osteointegration surveillance and early detection of interface problems, but will require further evaluation in clinical and experimental studies.     

I-123] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects

OBJECTIVE: Serotonergic dysfunction is considered to be involved in the pathophysiology of borderline personality disorder (BPD). The aim of this study was to investigate serotonin transporter availability in patients with BPD as a marker of the central serotonergic system. METHODS: Eight unmedicated patients with BPD and 9 healthy control subjects received single photon emission computed tomography (SPECT) 4 hours after injection of 185 MBq [I-123] ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)). As a measure of brain serotonin transporter (SERT) availability, ratios of specific-to-nonspecific [I-123] ADAM binding for the brainstem and hypothalamus were calculated with an occipital reference. Levels of impulsiveness and depressive symptoms were assessed with the Barratt Impulsiveness Scale and the Beck Depression Inventory. RESULTS: Mean specific-to-nonspecific ratios showed a 43% higher brainstem and a 12% higher hypothalamus ADAM binding in patients, compared with control subjects. We found significant correlations of ADAM binding with both age and impulsiveness but not depression. Associations of BIS scores with ADAM binding remained significant after controlling for age and depression (r = 0.69, p < 0.01). CONCLUSION: The study provides evidence of a serotonergic dysfunction in patients with BPD and suggests a serotonergic component in the pathophysiology of the disorder. SERT binding reflected the level of impulsiveness as a common feature in BPD.