Long-term adverse effects of paracetamol - a review.

Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long-term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.

New multi-scale perspectives on the stromatolites of Shark Bay, Western Australia.

A recent field-intensive program in Shark Bay, Western Australia provides new multi-scale perspectives on the world's most extensive modern stromatolite system. Mapping revealed a unique geographic distribution of morphologically distinct stromatolite structures, many of them previously undocumented. These distinctive structures combined with characteristic shelf physiography define eight 'Stromatolite Provinces'. Morphological and molecular studies of microbial mat composition resulted in a revised growth model where coccoid cyanobacteria predominate in mat communities forming lithified discrete stromatolite buildups. This contradicts traditional views that stromatolites with the best lamination in Hamelin Pool are formed by filamentous cyanobacterial mats. Finally, analysis of internal fabrics of stromatolites revealed pervasive precipitation of microcrystalline carbonate (i.e. micrite) in microbial mats forming framework and cement that may be analogous to the micritic microstructures typical of Precambrian stromatolites. These discoveries represent fundamental advances in our knowledge of the Shark Bay microbial system, laying a foundation for detailed studies of stromatolite morphogenesis that will advance our understanding of benthic ecosystems on the early Earth.

The Monros - three medical dynasties with a common origin.

From origins in their heartlands in Easter Ross, clan Munro produced no fewer than three distinct medical dynasties, all descended from Hugh Munro, 9th Baron Foulis (c1352-1425), 12th chief of the clan. This paper describes what we believe to be a unique family of related medical dynasties which were influential in Edinburgh, London and the Scottish Highlands. It sets out in detail the family genealogy, provides some biographical information, and explores the reasons for the development of such medical dynasties, which appear to be different for each of the three dynasties within this family. The 'Edinburgh Monros' included the three Alexanders Monro, primus, secundus and tertius, who between them occupied the university chair of Anatomy at the University of Edinburgh for 126 years from 1720. Dr David Monro, son of Alexander Monro tertius, emigrated to New Zealand where his descendants included several doctors, the last of whom died in 2013. The 'Bedlam Monros' achieved fame, and some notoriety, in managing mental illness in London for the 154 years from 1728-1882. In contrast, the 'Bonesetter Munros' practised their skills in the local community in Ross-shire and one of them attracted patients from all over Britain. They practised their trade for over 100 years from the start of the 19th to the early 20th century.

The ancestors of Norman Bethune (1890-1939) traced back to the Bethunes of Skye, leading members of the MacBeth/Beaton medical dynasty.

Norman Bethune became famous through his work in the Spanish Civil War, his advocacy of socialised medicine in North America and his association with Mao Zedong's revolutionary movement in China. It has been suggested that he may have been descended from the Bethune or Beaton medical dynasty, who for generations served as physicians to kings of Scotland, the Lords of the Isles and to some of the larger Scottish clans. This paper traces his lineage back to the Isle of Skye. In the absence of old parish records as aids to tracing genealogy, other available evidence has confirmed that Bethune was indeed in the direct line of descent from the Bethunes or Beatons of Husabost, in Skye, one of the largest branches of this medical kindred, who were physicians to the MacLeods of Dunvegan.

A sceptic and an empiric in medicine: George Young (1692-1757) and the beginnings of the Scottish medical Enlightenment.

The Edinburgh surgeon-apothecary and physician George Young was an empiric who emphasised observation, practical experience and a sceptical approach to evidence in medicine. He was an early member of the Rankenian Club, a group of young intellectuals whose ideas were to be at the heart of Scottish Enlightenment thinking. Young certainly influenced his pupil Robert Whytt, who went on to make important contributions to the understanding of nerve and muscle function. James Hill, Young's apprentice, to whom he emphasised the importance of experience and observation, would later advance thinking and practice in the management of head injury. Young was an important, but to date relatively neglected, figure in the early years of the Edinburgh Medical School and the Scottish Enlightenment. This paper describes what is known of his life and work, aims to assess his legacy and suggests that he deserves greater recognition and appreciation.

Scientific surgeon of the Enlightenment or 'plagiarist in everything': a reappraisal of Benjamin Bell (1749-1806).

The Edinburgh surgeon Benjamin Bell has been regarded as a scientific thinker in the Enlightenment tradition, despite being accused during his lifetime of both plagiarism and a failure to be innovative. Yet subsequent historical accounts regard him much more favourably. A review of his life and work discusses possible explanations for this apparent lack of concordance.

Surgical site infection after groin hernia repair.

BACKGROUND: Post-discharge surveillance for 30 days is needed to determine the true incidence of surgical site infection (SSI). This study was undertaken to determine the incidence of, and risk factors for, SSI after hernia repair. METHODS: A total of 3150 patients who had undergone groin hernia repair in 32 Scottish hospitals were telephoned 10, 20 and 30 days after operation to screen for SSI. Patients who believed the wound to be infected were seen by a healthcare worker to confirm the diagnosis. Details of operations and risk factors were obtained by case-note review. RESULTS: One hundred and four patients (3.3 per cent) declined to give a contact telephone number, leaving 3046 patients who agreed to take part in the study. Some 108 patients (3.4 per cent) could not be contacted at any point, giving a response rate of 93.3 per cent. Complete data were available for 2665 patients (87.5 per cent); 140 (5.3 per cent) developed SSI and 57 (2.1 per cent) thought the wound infected but this was not confirmed by the healthcare worker. Patients given a prophylactic antibiotic had a lower incidence of SSI (P = 0.002), but neither increase in the American Society of Anesthesiologists grade of fitness for operation nor prolonged duration of operation was a significant risk factor for infection. CONCLUSION: SSI after hernia repair is common and large clinical trials are required to determine whether the use of prophylactic antibiotics reduces the incidence of infection.

Effect of nitric oxide donor nitroglycerin on bone mineral density in a rat model of estrogen deficiency-induced osteopenia.

Nitric oxide (NO) may modulate estrogen's anabolic effects on bone homeostasis by restraining osteoclast-mediated bone resorption and stimulation of osteoblast activity. Accordingly, NO donated by organic nitrates, including nitroglycerin, is thought to protect against bone loss associated with estrogen deficiency. In this study, we have explored this phenomenon. Thirty-two 12-week-old female Wistar rats were divided into four groups prior to bilateral ovariectomy or a sham operation. The ovariectomised rats received (1). vehicle control (OVX control), (2). 17-beta-estradiol (OVX+E2), or (3). transdermal nitroglycerin (OVX+NG) for 4 weeks. Femoral and tibial bone mineral density (BMD), serum alkaline phosphatase and urine deoxypyridinoline and NO metabolites were analysed at the end of the study period together with failure torque and torsional rigidity of the tibiae and cellular localisation of the NO-synthase (NOS) isoforms. In OVX+E2 group, proximal and distal femoral and proximal tibial BMD exceeded that of the Sham controls. Nitroglycerin prevented BMD loss at these three sites at levels comparable to that of the Sham controls. Deoxypyridinoline excretion did not change except in the OVX-E2 group that showed an expected reduction when compared to the Sham and OVX controls. There were no treatment-related differences in total alkaline phosphatase or urinary NO metabolites. Tibial failure torque was comparable between the groups but both OVX+E2 and OVX+NG groups showed decreased torsional rigidity compared with the OVX controls. Endothelial and inducible NOS were found in osteoblast-like cells associated with calcifying cartilage spicules in the distal femoral metaphysis. These data confirm previous findings and show that nitroglycerin counteracts the estrogen deficiency-induced osteopenia in the ovariectomised rat model. Organic nitrates may thus be beneficial in conditions where bone turnover is compromised such as in osteoporosis.

Chronic pain after laparoscopic and open mesh repair of groin hernia.

BACKGROUND: The aim of this study was to compare the incidence of chronic pain or discomfort after laparoscopic totally extraperitoneal (TEP) repair and open mesh repair of groin hernia, and to assess the impact of such pain on patients' physical activity. METHODS: A postal questionnaire was sent to patients who had TEP or open mesh repair of groin hernia between January 1998 and December 1999. The patients were asked about any persistent pain or discomfort in relation to the groin hernia repair and whether this pain or discomfort restricted their ability to undertake physical or sporting activity. RESULTS: Of the 560 available patients 454 (81.1 per cent) replied. Laparoscopic TEP repair was performed in 240 patients (52.9 per cent) and open mesh repair in 214 (47.1 per cent). Of the 454 patients, 136 (30.0 per cent) reported chronic groin pain or discomfort, which was significantly more common after open repair than after laparoscopic repair (38.3 versus 22.5 per cent; P < 0.01). Chronic groin pain or discomfort restricted daily physical or sporting activity in 18.1 per cent of the patients. The patients who had open repair complained of significantly more restriction of daily physical activity than patients who underwent laparoscopic repair (walking, P < 0.05; lifting a bag of groceries, P < 0.01). CONCLUSION: Chronic pain or discomfort was reported by 30.0 per cent of patients after groin hernia repair and was significantly more common after open mesh repair than after laparoscopic TEP repair. It restricted physical or sporting activities in 18.1 per cent of the patients and significantly more so after open mesh repair.

Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity.

Nitric oxide (NO) has been implicated in the local regulation of bone metabolism. However, the contribution made by specific NO synthase (NOS) enzymes is unclear. Here we show that endothelial NOS gene knockout mice (eNOS-/-) have marked abnormalities in bone formation. Histomorphometric analysis of eNOS-/- femurs showed bone volume and bone formation rate was reduced by up to 45% (P: < 0.01) and 52% (P: < 0.01), respectively. These abnormalities were prevalent in young (6 to 9 weeks old) adults but by 12 to 18 weeks bone phenotype was restored toward wild-type. Dual energy X-ray absorptiometry analysis confirmed the age-related bone abnormalities revealing significant reductions in femoral (P: < 0.05) and spinal bone mineral densities (P: < 0.01) at 8 weeks that were normalized at 12 weeks. Reduction in bone formation and volume was not related to increased osteoclast numbers or activity but rather to dysfunctional osteoblasts. Osteoblast numbers and mineralizing activity were reduced in eNOS-/- mice. In vitro, osteoblasts from calvarial explants showed retarded proliferation and differentiation (alkaline phosphatase activity and mineral deposition) that could be restored by exogenous administration of a NO donor. These cells were also unresponsive to 17ss-estradiol and had an attenuated chemotactic response to transforming growth factor-beta. In conclusion, eNOS is involved in the postnatal regulation of bone mass and lack of eNOS gene results in reduced bone formation and volume and this is related to impaired osteoblast function.

Modulation of the effects of osteoprotegerin (OPG) ligand in a human leukemic cell line by OPG and calcitonin.

The discovery of osteoprotegerin (OPG), osteoprotegerin ligand (OPGL), and RANK has elucidated the mechanism by which osteoblasts and stromal cells regulate osteoclastic differentiation and function and mediate the effects exerted by other hormones and cytokines. We have investigated the effects of these novel cytokines on the preosteoclastic cell line FLG 29.1. We show that OPGL alone and in combination with macrophage colony-stimulating factor (CSF-1) dramatically reduced replication and increased tartrate-resistant acid phosphatase activity. However, although FLG29.1 cells appear to adhere to the bone surface, they are not able to form resorption lacunae. OPG and calcitonin completely abolished the differentiation induced by OPGL. RANK was detectable in FLG 29.1 and the number of positive cells was increased by OPGL/CSF-1 treatment while reduced by calcitonin. We propose that calcitonin could interact with the OPG/OPGL, and its effects on RANK may explain in part the action of this hormone in suppressing bone resorption.

Groin hernia repair in Scotland.

BACKGROUND: The use of mesh for groin hernia repair has dramatically changed the way this common operation is performed. The aim of this study was to survey the methods of groin hernia repair in Scotland and to assess patient satisfaction with the operation. METHODS: Between 1 April 1998 and 31 March 1999 all patients who underwent groin hernia repair in the National Health Service in Scotland were identified. As well as looking at the type of hernia repair performed and postoperative morbidity, patients were sent a Short Form-36 about 3 months after the operation to assess satisfaction and return to normal activity. RESULTS: Information was obtained on 5506 (97 per cent) of patients who underwent groin hernia repair during the study period. Eighty-five per cent of patients had an open mesh repair and 4 per cent had a laparoscopic repair. Most operations (85 per cent) were performed using general anaesthesia on an inpatient basis (78 per cent), and 8 per cent were for repair of a recurrent hernia. Potentially serious intraoperative complications were rare (seven patients), although they were significantly (P < 0. 001) more likely to be associated with a laparoscopic approach or repair of a femoral hernia: relative risk compared with open inguinal hernia repair 33 (95 per cent confidence interval (c.i.) 6-197) and 22 (95 per cent c.i. 3-152) respectively. Wound complications were common and 10 per cent of patients required a district nurse to attend the wound. Patients expressed a high degree of satisfaction; 94 per cent would recommend the same operation to someone else if required. CONCLUSION: An open mesh repair using general anaesthesia has become the repair of choice for a groin hernia in Scotland. Despite a high incidence of wound complications, patients are satisfied with this operation.

Nitric oxide mediates 17beta-estradiol-stimulated human and rodent osteoblast proliferation and differentiation.

Oestradiol can stimulate osteoblast activity. Osteoblast function is thought to be regulated by nitric oxide (NO). We hypothesised that the effect of 17beta-oestradiol (17beta-E(2)) on osteoblast activity is mediated by NO. This hypothesis was tested using osteoblasts isolated from human trabecular bone, calvariae of rats, endothelial NO synthase (eNOS) gene-deficient mice, and their wild-type counterparts. Our results show that 17beta-E(2) dose-dependently stimulated proliferation and differentiation of primary human, rat and wild-typeosteoblasts. The presence of N(G)-monomethyl-l-arginine (10(-3) M), an inhibitor of NOS activity, blocked the 17beta-E(2)-(10(-7) M)-induced increases in thymidine incorporation (P < 0.01), alkaline phosphatase activity (P < 0.01) and bone nodule formation (P < 0.01) of wild-type, human and rat osteoblasts, respectively. Moreover, 17beta-E(2) did not induce a response in eNOS gene-deficient osteoblasts. 17beta-E(2) also increased total eNOS enzyme expression in rat osteoblasts. These findings indicate 17beta-E(2) modulates osteoblast function by NO-dependent mechanisms mediated via the eNOS isoform.

The role of microbes in accretion, lamination and early lithification of modern marine stromatolites.

For three billion years, before the Cambrian diversification of life, laminated carbonate build-ups called stromatolites were widespread in shallow marine seas. These ancient structures are generally thought to be microbial in origin and potentially preserve evidence of the Earth's earliest biosphere. Despite their evolutionary significance, little is known about stromatolite formation, especially the relative roles of microbial and environmental factors in stromatolite accretion. Here we show that growth of modern marine stromatolites represents a dynamic balance between sedimentation and intermittent lithification of cyanobacterial mats. Periods of rapid sediment accretion, during which stromatolite surfaces are dominated by pioneer communities of gliding filamentous cyanobacteria, alternate with hiatal intervals. These discontinuities in sedimentation are characterized by development of surface films of exopolymer and subsequent heterotrophic bacterial decomposition, forming thin crusts of microcrystalline carbonate. During prolonged hiatal periods, climax communities develop, which include endolithic coccoid cyanobacteria. These coccoids modify the sediment, forming thicker lithified laminae. Preservation of lithified layers at depth creates millimetre-scale lamination. This simple model of modern marine stromatolite growth may be applicable to ancient stromatolites.

The biphasic effects of nitric oxide in primary rat osteoblasts are cGMP dependent.

Nitric oxide is a gas radical regulating cell behaviour in the cardiovascular, immune, and central nervous systems. It has now been established as an important signalling molecule in bone. However, the effects of this gas radical on osteoblastic function are still unclear; in fact, while NO seems to be involved in anabolic processes mediated by mechanical strain, sex hormones and fracture healing, it also mediates catabolic processes in response to inflammation. We show here that a slow and moderate release of nitric oxide stimulates the replication of primary rat osteoblasts and alkaline phosphatase activity, while a rapid release and high concentrations of NO inhibit proliferation and induce apoptosis. We demonstrate that both the stimulatory and apoptosis-inducing effects of NO on primary osteoblasts are mediated by the second messenger cGMP, since both are abolished by the guanylate cyclase inhibitor ODQ.