British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Does temporal artery biopsy influence the management of temporal arteritis?

BACKGROUND: Temporal arteritis (TA) is the commonest form of primary vasculitis. Symptoms are variable, and therefore the diagnosis (or exclusion) of TA is often difficult. Surgeons are frequently asked to perform a temporal artery biopsy (TAB), but whether the histological result actually influences clinical management is unclear. AIM: To assess whether, in routine clinical practice, a TAB affects clinical decision-making in patients with suspected TA. DESIGN: Retrospective audit. METHODS: All patients who underwent a TAB in a single hospital over a 2-year period were identified. This included patients referred from different specialist departments. Individual patient records were examined to document the TAB result, and in particular, the timings of commencement and discontinuation of corticosteroid therapy. RESULTS: A total of 44 patients were included. TAB was positive in seven patients and negative in 37. In 31, there was no change in their clinical management despite a negative biopsy result: 18 continued with corticosteroids for >6 months with a clinical diagnosis of TA, and in 13 patients a decision to stop steroids, or an alternative diagnosis, was made before the biopsy result was known. DISCUSSION: In this retrospective study, only a small number of TABs provided positive histological confirmation of TA, and in most patients undergoing TAB, there was little evidence that clinical decision-making with respect to corticosteroid therapy was influenced by the TAB result.

Contrasting effects of varicose vein surgery on endothelial-dependent and -independent cutaneous vasodilation in the perimalleolar region.

OBJECTIVES: To evaluate the effects of varicose vein surgery on cutaneous microvascular perfusion and vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) in the gaiter area of patients with great saphenous vein insufficiency. METHODS: Twenty-nine patients with isolated great saphenous vein incompetence attended three study mornings (before surgery, and 6-8 weeks and 6 months after sapheno-femoral ligation+partial stripping) during which cutaneous microvascular responses were measured in the supine and standing positions using laser Doppler fluximetry (LDF) combined with incremental-dose iontophoretic administration of endothelial-dependent (Ach) and -independent (SNP) vasodilators. RESULTS: Varicose vein surgery had no significant effect on baseline cutaneous perfusion or the microvascular response to Ach: e.g. peak vasodilator responses to the 1000 microC stimulus were mean 58 SEM 7, 64 SEM 6 and 65 SEM 7PU on the pre-operative, 6-8 weeks and 6 months assessments. In contrast, the corresponding responses to SNP were significantly increased following surgery: e.g. at 2000 microC, mean 63 SEM 9, 142 SEM 4 and 157 SEM 9PU (p<0.0001) in the upright position. CONCLUSIONS: Sapheno-femoral ligation and partial stripping in patients with great saphenous vein insufficiency improves endothelial-independent cutaneous vasodilator function at the gaiter area, which may at least partly explain the benefits of surgery in reducing the risk of venous ulceration.

Pharmacotherapy of anxiety.

The pharmacological treatment of anxiety has a long and chequered history, and recent years have seen a rich development in the options available to prescribers. Most of the currently used anxiolytic agents act via monoaminergic (chiefly serotonin) or amino acid (GABA or glutamate) neurotransmitters, and this chapter describes the pharmacology of the major drug groups. Clinical applications are discussed with respect to the five major anxiety disorders, as well as simple phobia and depression with concomitant anxiety. Prospective future developments in the field are considered.

The management of retroperitoneal liposarcoma with synchronous intra-duodenal sarcoma.

Intra-abdominal (as opposed to extremity or limb and limb-girdle) soft tissue sarcomas (STS) are rare and account for less than 1% of all diagnosed neoplasms. These tumours are usually associated with a poor prognosis and are often locally invasive and metastatic at the time of presentation. Retroperitoneal sarcomas with synchronous or metachronous different histological types are rare and intra-duodenal sarcomas extremely unusual. A case of a giant retroperitoneal STS weighing approximately 15 kg consisting of two histologically different types is presented. Intra-duodenal involvement with sarcoma was found intra-operatively. We discuss the management of this condition in the context of an illustrative case in our recent experience.

Effects of posture and venous insufficiency on endothelial-dependent and -independent cutaneous vasodilation in the perimalleolar region.

OBJECTIVES: To assess the effects of posture, endothelial function and venous insufficiency on cutaneous microvascular vasodilator function in the gaiter area, in particular defining factors which may affect microangiopathy and ulcer formation. METHODS: Endothelial-dependent and -independent vasodilator responses to incremental-doses of acetylcholine (Ach) and sodium nitroprusside (SNP) were evaluated in the perimalleolar region in the supine and standing positions in middle-aged patients with isolated superficial venous insufficiency (ISVI) (n = 25) and healthy controls (n = 28) using laser Doppler fluximetry (LDF) and iontophoresis of vasodilators. RESULTS: The venoarteriolar reflex (vasoconstriction on standing) was equally present in both groups, and reduced the vasodilator responses to SNP in the upright position (e.g., for patients with ISVI, peak SNP response was 82 +/- 11 PU [standing] vs 123 +/- 15 PU [supine]). The presence of ISVI had no effect on endothelial vasodilator function in the supine position, but on standing cutaneous reactivity to Ach was significantly reduced (e.g., peak Ach response 69 +/- 8 PU [ISVI] vs 109 +/- 11 PU [controls], p < 0.003). CONCLUSIONS: Upright posture impairs cutaneous endothelial-dependent vasodilation in the gaiter area of patients with ISVI. This may be of clinical and prognostic utility in identifying which patients with uncomplicated ISVI are at highest risk of tissue breakdown and ulcer formation in the gaiter area.

Does the angiotensin-converting enzyme (ACE) gene polymorphism affect rate of abdominal aortic aneurysm expansion?

OBJECTIVES: the tissue renin-angiotensin system (RAS), which plays an important role in vascular structure and function, is regulated in part by an insertion-deletion polymorphism of the angiotensin converting enzyme (ACE) gene. We hypothesised that ACE genotype might affect rate of AAA expansion via modulating long-term structural changes associated with RAS activation. METHODS: fifty-eight patients (50 M, mean age 70 years, mean initial aneurysm size 4.3 cm) with current or previous AAA and serial (>3) annual ultrasound measurements of antero-posterior AAA size provided a sample of leucocyte DNA for ACE genotyping. AAA expansion rate (cm per year) for individual subjects was calculated by linear regression. RESULTS: median AAA expansion rate was 0.28 cm/year (range 0-1.8 cm/year), and the genotype distribution included DD (n=14), DI (n=29) and II (n=15). Corresponding median AAA expansion rates for each of the three genetic subgroups were 0.22, 0.32 and 0.30 cm/year, respectively (p=0.6, nonparametric). CONCLUSIONS: the wide inter-individual variability in AAA expansion rate is likely to reflect complex genetic and environmental interactions, but the lack of any relationship with ACE genotype suggests that differences in vascular ACE activity in aortic tissue are not major determinants of the variability in rate of AAA dilatation.

Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression.

BACKGROUND: Sleep effects of antidepressants are important clinically and for elucidating mechanism of action: selective serotonin reuptake inhibitors disturb sleep and 5-HT(2) receptor-blocking compounds may enhance sleep quality. AIMS: To compare the objective and subjective effects on sleep of paroxetine and nefazodone in patients with moderate to severe depression. METHOD: Forty patients with depression were randomised to take paroxetine 20-40 mg/day or nefazodone 400-600 mg/day for 8 weeks. Objective and subjective quality of sleep and depression measures were assessed throughout. RESULTS: Nefazodone significantly increased objective sleep efficiency and total sleep time, and improved subjective sleep on days 3 and 10. Paroxetine decreased sleep efficiency early in treatment and some sleep disruption remained at week 8. Paroxetine but not nefazodone produced marked suppression of rapid eye movement (REM) sleep. CONCLUSIONS: Nefazodone improves sleep in early treatment compared with paroxetine in patients with moderate to severe depression. These effects are seen within the first 2 weeks of treatment and diminish thereafter.

Sestamibi scan-directed unilateral neck exploration for primary hyperparathyroidism due to a solitary adenoma.

AIM: To evaluate the accuracy of Tc-99m sestamibi scintography in pre-operative localization of a single parathyroid adenoma and to determine if neck exploration can be limited to the side of the adenoma. METHODS: Over a period of 4 years, 30 patients with primary hyperparathyroid disease underwent surgical treatment in the form of unilateral neck exploration after localization by Tc-99m sestamibi scintigraphy. The scan findings were interpreted by one radiologist with a special interest in parathyroid imaging and the operative findings were correlated with scan findings. RESULTS: Tc-99 sestamibi scan localized a single parathyroid adenoma in 29 patients. There was doubtful uptake of isotope in one patient. Unilateral cervical exploration confirmed isotope scan findings in 29 patients with a positive scan, and these were subsequently proven by histology. In the patient with doubtful sestamibi scan, bilateral neck exploration was undertaken and three enlarged glands were excised. All the three glands were reported to be abnormal, consistent with either adenomas or hyperplasia. All the patients were normocalcaemic after 6 months follow-up. CONCLUSIONS: Our results demonstrate that Tc-99m sestamibi scintigraphy is highly accurate in pre-operative localization of a single parathyroid adenoma when performed by an experienced radiologist. Unilateral cervical exploration, as directed by a positive Tc-99m sestamibi scintigram, seems to be a logical approach for the patients with primary hyperparathyroid disease due to solitary adenoma.

Pathology in the new medical curriculum: what has replaced the subject courses?

In line with the UK General Medical Council recommendations, the traditional, taught curriculum at Liverpool was replaced from 1996 by a new one using problem-based learning (PBL) as its principal method of information transfer. There is integration of clinical and preclinical studies, coupled with a reduction in the factual knowledge content and the disappearance of identifiable separate subject courses. Learning is now student-centred. This requires a new approach to the acquisition of pathology knowledge. 1. Pathology is included in all relevant PBL case scenarios by pathology representation on module planning and review committees. 2. Special study modules (SSMs) allow students to observe the practice of pathology including surgical and autopsy work, carry out a detailed study and write a dissertation. Career selectives are provided for individual students in the final year. 3. Clinicopathological (CPC) teaching meetings are held, with the discussion of case examples, clinicians and students contributing. 4. Assessments include the input of appropriate pathology content, integrated with other subjects. 5. A pathology teaching website is provided, containing images, notes, self-assessment questions, handouts, timetables and information. Although the 1996 intake have not yet completed their studies, the results of in-course assessments have been encouraging. The response to the pathology SSMs has been very positive, and the level of presentations and dissertations reached is of a high standard. With the disappearance of a separate subject course in pathology, the subject is being learned by other routes, and the students will complete their undergraduate course with a sound basis for proceeding with their further studies.

An audit of emergency abdominal aortic aneurysm repair to establish the necessity for an emergency vascular surgical rota.

Mortality for emergency abdominal aortic aneurysm (AAA) repair remains high but results of specialist vascular surgeons are superior to those of general surgeons. A retrospective audit was performed on all patients undergoing emergency AAA repair over 53 months at one hospital to determine the necessity for a vascular specialist on-call rota. Patients were stratified into two groups, those treated by specialist vascular surgeons and those treated by general surgeons. There were 37 patients in the vascular surgeon group and 36 in the general surgeon group. There was no significant difference between the two groups when age, sex distribution, APACHE II score on admission, pre-operative delay and type of rupture were considered. The average operating time was 114.7 min in the vascular surgeon group and 111.9 min in the general surgeon group. Total blood transfusion requirements, and postoperative duration of ventilation, inotrope therapy and intensive treatment unit stay were similar in the two groups. Intra-operative, 30-day and cumulative hospital mortalities were 10.8% versus 8.3%, 32.4% versus 38.9% and 40.5% versus 38.9% in the vascular surgeon and general surgeon groups, respectively. The mortality figures compare favourably with other published series. As the results of the two groups were similar, there is currently no need for vascular surgeons to be routinely available for acute AAA surgery at our hospital.

Management of sexually transmitted disease by surgeons.

The management of 63 patients diagnosed by surgeons as having sexually transmitted disease (STD) was audited. A diagnosis of STD was made in 51 (81%) of patients without taking a sexual history. Only 2 (3%) patients were referred to genitourinary medicine (GUM). Appropriate microbiological specimens were obtained from only two of 52 (4%) patients diagnosed with either pelvic inflammatory disease (PID) or epididymo-orchitis. Reliance was placed on inappropriate specimens in 22 (42%). There was widespread use of inappropriate antibiotics. The management of sexually transmitted disease by surgeons was very poor. These patients should all be referred to genito-urinary medicine.

P-COMM-B induction chemotherapy in intermediate and high grade non-Hodgkin's lymphoma.

57 patients with newly diagnosed intermediate or high grade non-Hodgkin's lymphoma with stage II to IV disease were treated with P-COMM-B (prednisolone, cyclophosphamide, vincristine, mitozantrone, methotrexate and bleomycin). 46% patients achieved a complete remission and 26% achieved a partial remission. Projected disease-free survival in complete remission at 5 years is 56% and projected overall survival at 5 years is 37%. Neutropenia and proximal myopathy were the commonest severe toxicities encountered and two deaths were clearly related to treatment (3.5%). P-COMM-B is effective first-line chemotherapy in intermediate and high grade non-Hodgkin's lymphoma. The efficacy and toxicity of P-COMM-B appear to be comparable to those of the best contemporary regimen, CHOP.

Comparison of the molecular genetics of c-erb-B2 and p53 expression in stomach cancer in Britain and Japan.

BACKGROUND: Differences in the epidemiology and treatment outcome of stomach cancer have led to the suggestion that in Japan, this disease may be biologically less aggressive than that found in the West. The authors compared p53b and c-erb-B2 expression, trying to identify genetic differences in Japanese compared with Western stomach cancers. METHODS: Paraffin embedded formalin fixed tissues from 89 British and 89 matched Japanese patients were examined by immunohistochemistry after microwave treatment. Cases were matched for T-stage, year of surgery, and histopathologic grade. RESULTS: Tumors from 48 British and 46 Japanese patients expressed p53, whereas those of 27 British and 28 Japanese patients expressed c-erb-B2. No significant difference in the density or distribution of protein expression was found between the two populations. The distribution of expression between diffuse and intestinal types and the proportion of cases expressing both antigens were similar in the two groups. CONCLUSIONS: p53 and c-erb-B2 are expressed in the same way in stomach carcinomas from Japanese and British patients. This study found no evidence of genetic differences in the cancers from the two countries.

Human papillomavirus in squamous cell carcinoma of the oesophagus associated with tylosis.

Human papillomavirus (HPV) may have a pathogenic role in squamous cell carcinoma of the oesophagus. Tylosis, an inherited thickening of the skin of the palms and soles, was associated with a high risk of developing squamous cell carcinoma of the oesophagus among members of a large family in Liverpool. The resected carcinomas of the oesophagus was examined from four such patients with DNA probes to HPV types 6,11,16,18,31,33 and 35 using in situ hybridisation under conditions of high stringency. No reaction was detected. The oesophageal biopsy specimens from 10 tylotic subjects without carcinoma were also examined. No HPV DNA was detected. It is concluded that there is no evidence that HPV infection has a role in the development of squamous cell carcinoma of the oesophagus in tylosis.

Expression of tumour necrosis factor-alpha in cryptogenic fibrosing alveolitis.

We have studied 15 cases of cryptogenic fibrosing alveolitis stained with a monoclonal antibody reactive with human tumour necrosis factor-alpha (TNF alpha), a cytokine that has been implicated in inflammation and fibrosis. Seven were examples of lone cryptogenic fibrosing alveolitis and eight were examples of cryptogenic fibrosing alveolitis in patients with systemic sclerosis. There was widespread staining of epithelial cells, particularly hyperplastic type II pneumocytes. Macrophages stained only weakly. In a control group of 10 patients dying of unrelated conditions, staining for TNF alpha was weak and, in the alveolar epithelium, was confined to a very occasional type II pneumocyte. The strong expression of TNF alpha in hyperplastic type II pneumocytes suggests that TNF alpha produced during alveolar epithelial regeneration may play a part in the fibrosis seen in this disease.

The transanal resectoscope: an under-used instrument?

The use of the urological resectoscope in the treatment of rectal tumours has been described in detail. We report the use of the purpose built transanal resectoscope in the treatment of 34 patients. Fourteen patients had villous adenomas and all but one were relieved of symptoms. Of 20 patients with rectal carcinoma, three presented with acute intestinal obstruction and three had rectal stump recurrences. Palliation was excellent in patients with general symptoms, but the results were disappointing for rectal stump recurrences. Transanal resection (TAR) is a novel form of treatment for patients with rectal obstruction. Two patients in this study had their obstruction successfully relieved by transanal resection alone. This allowed formal bowel preparation and full pre-operative assessment. We feel that this technique is under-used and that the results of treatment justify more widespread acceptance of the procedure.

Recombinant basic fibroblast growth factor in red blood cell ghosts accelerates incisional wound healing.

The pharmacological manipulation of wound healing with locally applied growth factors is now a practical possibility. The effect of topical applications of recombinant basic fibroblast growth factor (bFGF) on the strength and cellularity of healing incisional rat skin wounds was investigated. Applications of bFGF in a simple vector (either a collagen suspension or saline) were not associated with any positive effects on wound breaking load at 7 days after injury in comparison with vector-treated control wounds; at the highest dose of 50 micrograms per wound, breaking loads were significantly decreased from a mean(s.e.m.) of 287(22) g/cm2 in controls to 201(23) g/cm2 (P < 0.005). Increasing doses of applied peptide were paralleled by increasing wound cellularity. Delay of bFGF release at the site of application was achieved by encapsulation into red blood cell ghosts. Wounds treated with bFGF in such ghosts were 50 per cent stronger than paired control wounds (388(27) versus 256(28) g/cm2, P < 0.002) 7 days after injury. Treated wounds were significantly more cellular at 4 days than paired control wounds. Topical applications of bFGF applied at the time of injury exert a positive effect on incisional wound strength only when a vector that delays release is used.