Bipolar, or manic-depressive, disorder is a frequent, severe, mostly recurrent mood disorder associated with great morbidity. The lifetime prevalence of bipolar disorder is 1.3 to 1.6%. The mortality rate of the disease is two to three times higher than that of the general population. About 10-20% of individuals with bipolar disorder take their own life, and nearly one third of patients admit to at least one suicide attempt. The clinical manifestations of the disease are exceptionally diverse. They range from mild hypomania or mild depression to severe forms of mania or depression accompanied by profound psychosis. Bipolar disorder is equally prevalent across sexes, with the exception of rapid cycling, a severe and difficult to treat variant of the disorder, which arises mostly in women. Because of the high risk of recurrence and suicide, long-term prophylactic pharmacological treatment is indicated. Lithium salts are the first choice long-term preventive treatment for bipolar disorder. They also possess well documented antisuicidal effects. Second choice prophylactic treatments are carbamazepine and valproate, although evidence of their effectiveness is weaker.

Primary sclerosing cholangitis is strongly linked to inflammatory bowel disease, but any model to explain the development of primary sclerosing cholangitis must take into account the fact that it usually runs a course independent from inflammation in the bowel, illustrated by the fact that this disease can develop many years after proctocolectomy. Thus, liver disease can develop in the absence of a diseased colon and cannot be explained solely by release of toxic factors from the inflamed gut. We propose the existence of an enterohepatic circulation of lymphocytes, whereby some mucosal lymphocytes generated in the gut during active inflammatory disease subsequently persist as longlived memory cells capable of recirculation through the liver. Under the right conditions, these dual-homing lymphocytes might become activated in the liver resulting in hepatic inflammation that is independent from inflammation in the gut. Recent reports that some lymphocyte homing-receptors are shared by the liver and gut provide a molecular basis for this hypothesis and explain the distribution of extraintestinal disease in inflammatory bowel disease.

Descriptive studies often represent the first scientific toe in the water in new areas of inquiry. A fundamental element of descriptive reporting is a clear, specific, and measurable definition of the disease or condition in question. Like newspapers, good descriptive reporting answers the five basic W questions: who, what, why, when, where. and a sixth: so what? Case reports, case-series reports, cross-sectional studies, and surveillance studies deal with individuals, whereas ecological correlational studies examine populations. The case report is the least-publishable unit in medical literature. Case-series reports aggregate individual cases in one publication. Clustering of unusual cases in a short period often heralds a new epidemic, as happened with AIDS. Cross-sectional (prevalence) studies describe the health of populations. Surveillance can be thought of as watchfulness over a community; feedback to those who need to know is an integral component of surveillance. Ecological correlational studies look for associations between exposures and outcomes in populations-eg, per capita cigarette sales and rates of coronary artery disease-rather than in individuals. Three important uses of descriptive studies include trend analysis, health-care planning, and hypothesis generation. A frequent error in reports of descriptive studies is overstepping the data: studies without a comparison group allow no inferences to be drawn about associations, causal or otherwise. Hypotheses about causation from descriptive studies are often tested in rigorous analytical studies.

Crohn's disease is a disorder mediated by T lymphocytes which arises in genetically susceptible individuals as a result of a breakdown in the regulatory constraints on mucosal immune responses to enteric bacteria. Regulation of immune reactivity to enteric antigens has improved understanding of the pathophysiological mechanisms of Crohn's disease, and has expanded therapeutic options for patients with this disorder. Disease heterogeneity is probable, with various underlying defects associated with a similar pathophysiological outcome. Although most conventional drug treatments are directed at modification of host response, therapeutic manipulation of the enteric flora is becoming a realistic option.

Many clinicians report that they cannot read the medical literature critically. To address this difficulty, we provide a primer of clinical research for clinicians and researchers alike. Clinical research falls into two general categories: experimental and observational, based on whether the investigator assigns the exposures or not. Experimental trials can also be subdivided into two: randomised and non-randomised. Observational studies can be either analytical or descriptive. Analytical studies feature a comparison (control) group, whereas descriptive studies do not. Within analytical studies, cohort studies track people forward in time from exposure to outcome. By contrast, case-control studies work in reverse, tracing back from outcome to exposure. Cross-sectional studies are like a snapshot, which measures both exposure and outcome at one time point. Descriptive studies, such as case-series reports, do not have a comparison group. Thus, in this type of study, investigators cannot examine associations, a fact often forgotten or ignored. Measures of association, such as relative risk or odds ratio, are the preferred way of expressing results of dichotomous outcomes-eg, sick versus healthy. Confidence intervals around these measures indicate the precision of these results. Measures of association with confidence intervals reveal the strength, direction, and a plausible range of an effect as well as the likelihood of chance occurrence. By contrast, p values address only chance. Testing null hypotheses at a p value of 0.05 has no basis in medicine and should be discouraged.

There is no generally accepted explanation for the excess risk of adverse pregnancy outcome after short interpregnancy intervals. In this paper, we present a hypothesis that is both biologically plausible, empirically testable, and able to explain many observations. Maternal serum and erythrocyte concentrations of folate decrease from the fifth month of pregnancy onwards and remain low for a fairly long time after delivery. Women who become pregnant before folate restoration is complete have a raised risk of folate insufficiency at the time of conception and during pregnancy. As a consequence, their offspring have higher risks of neural tube defects, intrauterine growth retardation, and preterm birth. We make several predictions based on our hypothesis and suggest ways of testing them empirically. The proposed mechanism implies, among other things, that postpartum supplementation with folic acid might prevent excess risk of unfavourable pregnancy outcome in women with short interpregnancy intervals.

Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect.

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Many common gram-positive pathogens (eg, Staphylococcus aureus, Enterococcus spp, and Streptococcus pneumoniae) have become increasingly resistant to antimicrobial agents, and new drugs with activity against gram-positive bacteria are urgently needed. The oxazolidinones, a new chemical class of synthetic antimicrobial agent, have a unique mechanism of inhibiting bacterial protein synthesis. Linezolid, the first oxazolidinone to be approved for clinical use, displays in-vitro activity (generally bacteriostatic) against many important resistant pathogens, including meticillin-resistant Staph aureus, vancomycin-resistant enterococci, and penicillin-resistant Strep pneumoniae. Linezolid is a parenteral agent that also possesses near-complete oral bioavailability plus favourable pharmacokinetic and toxic effect profiles. Clinical trials confirm the activity of linezolid in the setting of pneumonia, skin and soft-tissue infections, and infections due to vancomycin-resistant enterococci. Linezolid shows promise as an alternative to glycopeptides and streptogramins to treat serious infections due to resistant gram-positive organisms. New agents with greater potency and new spectra of activity could arise from further modification of the oxazolidinone nucleus.

UK government proposals to reduce the risks posed by people with "dangerous" severe personality disorders (DSPD) include a new legal framework for indeterminate detention. We aimed to establish the degree to which those operating the framework will be able to predict which people will act violently in the future.

Drug development has accelerated exponentially since the 1950s. It is difficult to estimate the relative contributions or rates of success of industry sponsored as opposed to government supported research in any field. However, it is clear that much of the therapeutic innovation of recent decades has emerged from biotechnology and pharmaceutical industry sponsored efforts. This sponsorship is leading to new stresses in the relationship between academic institutions and industry.

The pyrrolidone (2-oxopyrrolidine) family of chemicals has been the subject of research for more than three decades. Experimental and clinical work first focused on their so-called nootropic effects; later came the possibilities for neuroprotection after stroke and use as antiepileptic agents. Piracetam, the first of the class, was developed by pioneering research by C Giurgea in the late 1960s, and it was he who coined the term "nootropic", to mean enhancement of learning and memory. The term is sometimes extended to include other actions such as neuroprotection. These properties, together with the lack of other generally adverse psychopharmacological actions (eg, sedation, analgesia, or motor or behavioural changes), distinguish the pyrrolidones from other psychoactive drug classes. The mechanisms of action of these drugs are still not fully established; indeed, different compounds in this class may have different modes of action. Interest in this drug class has recently been reawakened by the licensing of levetiracetam as a potentially major new antiepileptic drug and of piracetam for its antimyoclonic action and effects after stroke and in mild cognitive impairment. Other drugs in this class are currently at an advanced stage of development, and the renewal of interest in this therapeutic area is likely to mean not only that more pyrrolidones will enter clinical practice in the next few years but also that the clinical indications of drugs already licensed will widen.

Pulsatile gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH) and thus controls the hormonal and reproductive function of the gonads. Blockade of GnRH effects may be wanted for a variety of reasons-eg, to prevent untimely luteinisation during assisted reproduction or in the treatment of sex-hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. Only recently have GnRH-receptor antagonists, that immediately block GnRH's effects, been developed for clinical use with acceptable pharmacokinetic, safety, and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All current indications for GnRH-agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence so far has been in assisted reproduction and prostate cancer.

Deterrence is an established theme in criminal justice, but its role in prevention of assault has been treated with ambivalence and even hostility in medicine. The extent to which offenders can be persuaded, through knowledge of criminal and health risks, not to injure others is emerging from studies of the health effects of firearm and other crime legislation, and from macro-level studies and controlled experiments of police interventions. There is convincing evidence that motorists can be deterred from alcohol-impaired driving, and recognition that specific, targeted, and visible police work and increasing certainty of punishment are effective interventions. By contrast, duration of imprisonment and generic police initiatives such as blanket increases in police numbers seem to have little effect on deterrence, at least in the context of the decline in US homicide rates since 1991, to which demographic and economic factors seem to have contributed little. Together with established and cost-effective preschool education and early family support, targeted policing and increasing rates of conviction should be integrated into strategies for injury prevention.

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.