p53 protein accumulation and mutations in normal and benign breast tissue

Mutations in the p53 gene are amongst the most common molecular changes detected in breast cancer, and there are several reports suggesting that changes in p53 may contribute to the pathogenesis of this disease. In a previous case-control study, we demonstrated that p53 protein accumulation detected by immunohistochemistry in normal or benign breast tissue was associated with a 2.5-fold increase in the risk of subsequent breast cancer. In this study, we investigated whether p53 gene mutations were present in the 29 p53 immunopositive normal or benign breast tissue samples and in 15 p53 immunonegative normal or benign breast tissue samples selected randomly from the original study. DNA was extracted from paraffin sections and underwent PCR-SSCP analysis for exons 4 to 10. PCR products that showed abnormal mobility were excised and sequenced. Sixteen (59.2%) of the 27 immunopositive breast tissue samples and 4 (26.7%) of the 15 immunonegative samples had p53 sequence changes. There was no obvious association between the occurrence of these alterations and any specific histopathologic features. Ten cases showed p53 mutations, and they were all missense base substitutions of the transition type. Thirteen other gene changes occurred in 11 breast tissue samples and consisted of 8 silent (no amino acid change), 4 intronic alterations, and 1 indeterminate alteration. One individual had both a mutation and a silent change. In summary, p53 gene alterations can occur in normal or benign breast tissue, but resolution of their role in the pathogenesis of breast cancer will require long-term follow-up studies involving comparisons of breast cancer occurrence in patients with and without p53 mutations as well as functional assays to determine their significance.     

d-Fenfluramine in panic disorder: a dual role for 5-hydroxytryptamine

Rationale: 5-Hydroxytryptamine (5-HT) appears to modulate different forms of anxiety in different ways, but the importance of this in human anxiety disorders is unknown. Objectives: To investigate whether the 5-HT releasing agent d-fenfluramine (dFEN) has different effects on resting and panic anxiety in panic disorder. Methods: Thirteen drug-free patients with DSM-IIIR panic disorder were tested in a double-blind placebo-controlled crossover design. Carbon dioxide 7% (CO₂) was given as a panic challenge 270 min after administration of dFEN or placebo. Results: Compared to placebo, dFEN increased anxiety and arousal, maximal at 120 min, but tended to reduce CO₂-induced anxiety and panic attacks with a significant reduction in Panic Visual Analogue Scale ratings (P=0.040). Anxiety following CO₂, but not dFEN, administration resembled panic attacks (compared to Acute Panic Inventory symptom profile during patients’ usual attacks). Patients with more severe disorders exhibited enhanced behavioural responses and blunted prolactin responses to dFEN. Conclusions: dFEN caused anxiety similar to generalised anxiety in panic disorder patients but reduced anxiety following 7% CO₂ challenge, a laboratory analogue of naturally occurring panic attacks. These findings are consistent with a dual role for 5-HT in pathological anxiety. Patients with more severe symptoms differed in 5-HT function compared to more mildly affected individuals. Received: 4 August 1999 / Final version: 14 November 1999     

Systemic absorption of gentamicin in the management of active mucosal chronic otitis media.

A prospective study was performed on patients with active mucosal chronic otitis media who were being treated with the gentamicin-containing preparation Gentisone HC. In 27 patients plasma gentamicin levels were measured. Detectable levels were found in 7/27 (26%). Pre- and post-treatment audiometry was performed on 16 patients. There was no statistically significant difference in the change of the mean bone conduction thresholds as a result of treatment, between the treatment and control ears (P = 0.07, Wilcoxon signed Ranks Test at 95% C.I.). We conclude that there is evidence of systemic absorption of gentamicin that would ultimately be absorbed into the perilymph. Gentamicin is known to be ototoxic affecting the vestibular system in lower doses and the cochlea in high doses, hence audiometric assessment is not an appropriate screen for ototoxicity when using topical gentamicin-containing drops. Alternative topical preparations should be further investigated.     

Dome-shaped macula—Review of literature

Dome-shaped macula is a convex retinochoroidal elevation within the region of a posterior staphyloma seen commonly in high myopia on optical coherence tomography. With growing awareness of the condition facilitated by inclusion of optical coherence tomography in routine retinal practice, coupled with evolution of enhanced depth optical coherence tomography imaging, multiple studies have attempted to shed light on pathogenesis of this complex pathology, its clinical implications, and treatment of associated complications such as serous macular detachment and choroidal neovascularization with variable success. Our review aims to assimilate, scrutinize, and discuss the available literature for a comprehensive insight into dome-shaped macula.     

Maintaining Equity and Access: Successful Implementation of a Virtual Kidney Transplantation Evaluation

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Elastic stable intramedullary nailing for displaced proximal humeral fractures in older children

Purpose To demonstrate the effectiveness of intramedullary fixation of severely displaced proximal humeral physeal fractures in skeletally immature children using the elastic stable intramedullary nail (ESIN). Methods Retrospective recruitment of 14 patients aged 10–15-years old with severely displaced proximal humeral physeal fractures between 1999 and 2004 in a single regional specialist paediatric orthopaedic hospital. The fractures were graded using the Neer classification; severe displacement constituted Neer II–IV or displacement >1 cm and angulation >45°. Patients were followed up and assessed using the Disabilities of the Arm, Shoulder and Hand score (DASH) and the Neer Shoulder score. Radiographs were assessed for deformity. Subjective satisfaction was assessed. Results Fourteen patients with mean follow-up of 30 months (12–66 m) from surgery. All fractures were radiologically united at a median time of eight weeks (7–10 weeks). At follow-up, Neer Shoulder mean score was 96.79 (range 83–100) and DASH mean score 2.26 (0–7.5). Subjectively 71% were very satisfied and 29% were satisfied. Conclusions We commend stabilisation using ESIN in the management of the displaced proximal humeral physeal fracture in older children, once reduction of the fracture has been achieved by either closed or open means. ESIN is safe and allows early return to pre-injury function.     

Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.