Science 25 July 2008: Vol. 321. no. 5888, p. 486
BEHAVIOR GENETICS ASSOCIATION: Voting: In Your Genes?
At the Behavior Genetics Association meeting, a political scientist presented evidence that DNA has a hand in the intensity of people's partisan political attachments and even in whether they bother to vote.

Science 25 July 2008:
Vol. 321. no. 5888, p. 487
BEHAVIOR GENETICS ASSOCIATION: Do Good Sperm Predict a Good Brain?
In work presented at the Behavior Genetics Association meeting, researchers found a low but significant correlation between IQ and sperm quality.

Science 25 July 2008:
Vol. 321. no. 5888, pp. 494 - 495
DIVERSITY: Gender Similarities Characterize Math Performance
Standardized tests in the U.S. indicate that girls now score just as well as boys in math.

Nature 454, 373 (2008)
Spinal cord revealed in free gene map Allen Institute for Brain Science releases first data set.
The Allen Institute for Brain Science has released the first data from its ambitious project to map the spinal cord. When completed early next year, the freely accessible atlas will chart the expression patterns of at least 18,500 genes throughout the spinal cord of juvenile and adult mice.

Nature 454, 416-417 (24 July 2008)
Physiology: Myoglobin's new clothes
Nitric oxide generated from the nitrite ion limits the tissue damage caused by restricted blood flow. Gene knockout experiments in mice now reveal that myoglobin is the mediator of this effect.
All students of biology encounter the richly pigmented protein myoglobin early in their education, where it provides the first and most famous example of a revealed protein structure combined with a straightforward physiological role. Its restricted distribution to endurance muscle and heart cells throughout the vertebrates, and its notable expression in diving mammals, are a reflection of its widely accepted function in cellular oxygen transport and oxygen buffering.

Nature 454, 418-420 (24 July 2008)
Alzheimer's disease: Moving towards a vaccine
An agent that clears disease-associated amyloid aggregates from the brains of patients with Alzheimer's disease does not alleviate disease progression. Yet this disappointing news should not rule out such potential therapies.
Alzheimer's disease is the most common cause of dementia. But although there are some drugs that can slightly alleviate its symptoms, there is currently no treatment that can prevent this neurodegenerative disorder, delay its onset or slow its progress.

Nature 454, 486-491 (24 July 2008)
Structure of a 1-adrenergic G-protein-coupled receptor
G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of a β1-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane α-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the β1-adrenergic receptor and binding of carazolol to the β2-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the β2-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.

Nature 454, 528-532 (24 July 2008)
Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells
Adult skeletal muscle robustly regenerates throughout an organism's life, but as the muscle ages, its ability to repair diminishes and eventually fails. Previous work suggests that the regenerative potential of muscle stem cells (satellite cells) is not triggered in the old muscle because of a decline in Notch activation, and that it can be rejuvenated by forced local activation of Notch. Here we report that, in addition to the loss of Notch activation, old muscle produces excessive transforming growth factor (TGF)-β (but not myostatin), which induces unusually high levels of TGF- β pSmad3 in resident satellite cells and interferes with their regenerative capacity. Importantly, endogenous Notch and pSmad3 antagonize each other in the control of satellite-cell proliferation, such that activation of Notch blocks the TGF- β -dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15, p16, p21 and p27, whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determines the binding of pSmad3 to the promoters of these negative regulators of cell-cycle progression. Attenuation of TGF- β /pSmad3 in old, injured muscle restores regeneration to satellite cells in vivo. Thus a balance between endogenous pSmad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration.

Nature 454, 533-537 (24 July 2008)
Switch of rhodopsin expression in terminally differentiated Drosophila sensory neurons
Specificity of sensory neurons requires restricted expression of one sensory receptor gene and the exclusion of all others within a given cell. In the Drosophila retina, functional identity of photoreceptors depends on light-sensitive Rhodopsins (Rhs). The much simpler larval eye (Bolwig organ) is composed of about 12 photoreceptors, eight of which are green-sensitive (Rh6) and four blue-sensitive (Rh5). The larval eye becomes the adult extraretinal 'eyelet' composed of four green-sensitive (Rh6) photoreceptors . Here we show that, during metamorphosis, all Rh6 photoreceptors die, whereas the Rh5 photoreceptors switch fate by turning off Rh5 and then turning on Rh6 expression. This switch occurs without apparent changes in the programme of transcription factors that specify larval photoreceptor subtypes. We also show that the transcription factor Senseless (Sens) mediates the very different cellular behaviours of Rh5 and Rh6 photoreceptors. Sens is restricted to Rh5 photoreceptors and must be excluded from Rh6 photoreceptors to allow them to die at metamorphosis. Finally, we show that Ecdysone receptor (EcR) functions autonomously both for the death of larval Rh6 photoreceptors and for the sensory switch of Rh5 photoreceptors to express Rh6. This fate switch of functioning, terminally differentiated neurons provides a novel, unexpected example of hard-wired sensory plasticity.

JAMA. 2008;300(4):379-380.
FDA: Antipsychotics Risky for Elderly
The US Food and Drug Administration (FDA) is warning physicians that using conventional antipsychotic drugs to treat elderly patients with dementia may increase the risk of death in these patients. In 2005, the agency warned of similar risks associated with newer atypical antipsychotic drugs. 
Antipsychotic medications pose particular health risks to elderly patients with dementia. Under new authority granted to the agency by the Food and Drug Administration Amendments Act of 2007, the agency is requiring manufacturers of conventional antipsychotics (which include prochlorperazine, haloperidol, loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, trifluoperazine, chlorpromazine, and perphenazine) to add a boxed warning to the labels of these drugs notifying physicians that using conventional antipsychotics to treat behavioral problems in elderly patients with dementia is associated with an increased risk of death. Previously, the agency could only request and negotiate for such a change.

BMJ 2008;337:a796
Letters Antipsychotics for dementia
Antipsychotics for dementia is metaphor for elderly care
The blunt treatment of so called behavioural and psychological symptoms of dementia with antipsychotics is a metaphor for medical care of the older patient.1 Individualised care plans with a true patient focus in a supportive environment will filter many prescriptions. The problem very often isn’t the patient but the provider and the care setting. Our residential prevalence of prescribing antipsychotics has fallen from 36% to 20% in 18 months, thanks to a concerted team approach to challenging behaviours.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 177
This unremembered state
Dementia is perhaps the cruellest manifestation of ageing, inexorably melting away all that which makes us individual and human. Increased life expectancy in the developed world has raised the incidence of dementia, commonly caused by Alzheimer's disease, and the burden of dementia is serious in developing countries too. Not all old people have or will have dementia, but today more than 1% of the UK's total population does, and the number of people with dementia is forecast to double in the next 30 years.

The Lancet
Vol: 372 Issue: 9634, July 19 - 25 2008   pp: 179-180
Dimebon in Alzheimer's disease: old drug for new indication
Alzheimer's disease, the commonest cause of dementia, is a chronic neuropsychiatric disorder that affects 25 million people worldwide and costs £17 billion each year in the UK alone. Current management is directed at improving, or at least controlling, symptoms (such as memory loss, agitation, and depression), maintaining independence, and supporting patients and their families. Available drugs, which are moderately effective overall but can sometimes provide substantial improvement, include the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the glutamatergic agent memantine. The cost-effectiveness of these drugs has been examined by the UK's National Institute for Health and Clinical Excellence (NICE), leading to their use only for people with moderate Alzheimer's disease in the National Health Service (NHS) in England and Wales.

The Lancet
Vol: 372 Issue: 9634, July 19 - 25 2008   pp: 180-182
Will anti-amyloid therapies work for Alzheimer's disease?
In today's Lancet, Clive Holmes and co-workers report a 6-year prospective follow-up of 80 patients entered into the first phase I clinical trial of active immunisation against amyloid-β42 (Aβ) as a treatment for Alzheimer's disease. Their report contains both expected and unexpected results. As had been widely predicted from the initial animal studies, cortical Aβ loads were lower in patients who were immunised than in the control group. Equally predictably, patients with the biggest antibody response had more extensive Aβ removal. Unexpectedly, however, there was no statistically significant evidence for improvement in cognitive function or survival, even in patients with high antibody titres. Indeed, several of those who had near complete plaque removal at autopsy had clinically deteriorated to severe dementia.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 182-183
Dementia: psychosocial interventions for family caregivers
Caring for a family member with dementia increases the caregiver's risk for depression, chronic illness, and even death. In addition to the physical and emotional tolls, families incur significant monetary costs, which increase with the progression of functional and cognitive impairment and contribute to the strain experienced by caregivers.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 183-185
Giving consent in dementia research
Dementia is in the news again. The upswing of interest in dementia among politicians, health-care providers, clinicians, and advocacy groups has something of a hollow ring if dementia care is not underpinned by a comprehensive and relevant evidence-base. Such a base is lacking. In the UK, only £11 is spent on research for each individual with dementia compared with around £300 for each cancer patient. There are many reasons for the paucity of research in dementia—ethical concerns, particularly around capacity to consent, might be one.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 185-186
Apolipoprotein B/A1 and risk of cardiovascular disease
In recent years, whether measurements of apolipoproteins are better than lipoproteins for risk prediction of cardiovascular disorders, and whether the apolipoprotein B/A1 ratio should be the preferred lipid measurement in the future has been debated. In today's Lancet, new fuel to this discussion has been added by the INTERHEART study, a large international case–control study about risk factors for myocardial infarction with more than 9000 patients. The investigators found that the apolipoprotein B/A1 ratio was better than any other conventional lipid measure, including other ratios, with a population attributable risk of 54% for the apolipoprotein B/A1 ratio compared with 37% for the best conventional lipid measure (LDL-cholesterol/HDL-cholesterol, p<0·0001).

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 198-199
How smart are smart drugs?
Cognitive decline, and in particular memory loss, are key features of the early stages of Alzheimer's disease, so it is scarcely surprising that the focus of research aimed at treatment has been on identifying drugs to alleviate or reverse this decline. But once such drugs are available, might they not also be more broadly useful? If mild cognitive decline is a fact of life for many of us over the age of about 50 years, as some maintain, perhaps we should all be taking the pills, much as many now take statins and aspirin? And how about students revising for exams, or businessmen wishing to gain a competitive edge? This, essentially, is the case for cognitive enhancers or nootropics, known more colloquially as smart drugs.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 201-202
Are all antipsychotics equal?
In the EUFEST study (March 29, p 1085), 1 René Kahn and colleagues found that haloperidol, compared with several second-generation antipsychotics, was associated with higher rates of overall treatment discontinuation and discontinuation because of lack of efficacy and because of side-effects, and worse outcome on the clinical global impression scale and the global assessment of functioning scale in patients with first-episode schizophrenia and schizophreniform disorder. Surprisingly, Kahn and colleagues' last sentence reads: “it cannot be concluded that [second-generation antipsychotics] are more efficacious than is haloperidol…” Clearly, they are being too conservative in the interpretation of their important findings.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008   pp: 202
Are all antipsychotics equal? – Authors' reply
Jan Volavka suggests that we downplayed the superior effectiveness of the second-generation antipsychotics tested in our study compared with haloperidol. Our primary hypothesis (ie, all-cause discontinuation of a low dose of haloperidol is similar to that of the second-generation antipsychotics) was indeed rejected, and the difference between the second-generation antipsychotics and haloperidol was large and clinically meaningful.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 207-215
Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study
Background
Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease.

Methods
We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10–24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov , number NCT00377715 .

Findings
155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference −4·0 [95% CI −5·73 to −2·28]; p<0·0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference −1·9 [−2·92 to −0·85]; p=0·0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ.

Interpretation
Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 216-223
Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial
Background
Immunisation of patients with Alzheimer's disease with full-length amyloid-β peptide (Aβ42) can clear amyloid plaques from the brain. Our aim was to assess the relation between Aβ42 immune response, degree of plaque removal, and long-term clinical outcomes.

Methods
In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Aβ42 (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Aβ immunostaining (Aβ load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.

Findings
20 participants—15 in the AN1792 group, five in the placebo group—died before follow-up started. A further 22 patients—19 in the AN1792 group, three in the placebo group—died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Aβ load was lower than in an unimmunised control group that was matched for age at death (2·1% [SE 0·7] in treated participants vs 5·1% [0·9] in controls; mean difference 3·0%, 95% CI 0·6–5·4; p=0·02). Although there was considerable variation in Aβ load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0·02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0·93, 95% CI 0·43–3·11; p=0·86) or of an improvement in the time to severe dementia (1·18, 0·45–3·11; p=0·73) in the AN1792 group versus the placebo group.

Interpretation
Although immunisation with Aβ42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 234-245
Polymyalgia rheumatica and giant-cell arteritis
Summary
Polymyalgia rheumatica and giant-cell arteritis are closely related disorders that affect people of middle age and older. They frequently occur together. Both are syndromes of unknown cause, but genetic and environmental factors might have a role in their pathogenesis. The symptoms of polymyalgia rheumatica seem to be related to synovitis of proximal joints and extra-articular synovial structures. Giant-cell arteritis primarily affects the aorta and its extracranial branches. The clinical findings in giant-cell arteritis are broad, but commonly include visual loss, headache, scalp tenderness, jaw claudication, cerebrovascular accidents, aortic arch syndrome, thoracic aorta aneurysm, and dissection. Glucocorticosteroids are the cornerstone of treatment of both polymyalgia rheumatica and giant-cell arteritis. Some patients have a chronic course and might need glucocorticosteroids for several years. Adverse events of glucocorticosteroids affect more than 50% of patients. Trials of steroid-sparing drugs have yielded conflicting results. A greater understanding of the molecular mechanisms involved in the pathogenesis should provide new targets for therapy.

The Lancet Vol: 372 Issue: 9634, July 19 - 25 2008    pp: 262
Exit, pursued by a bear
In August, 2004, a 71-year-old man was admitted to our hospital, with a hoarse voice and “noisy sleep”. His medical history was essentially uneventful: mild hypertension, for which he took valsartan; and a brief episode of laryngitis in the early 1980s. He had dysphonia, and persistent nocturnal inspiratory stridor, but no diurnal dyspnoea or stridor. Neurological examination revealed slight difficulty with tandem gait, which we considered normal, given the patient's age. Blood tests, CT of the chest, and MRI of the brain and cervical spine showed nothing of note. Laryngoscopy revealed bilateral vocal-fold motion impairment: we diagnosed idiopathic bilateral recurrent-laryngeal-nerve palsy. 1 The patient was discharged 8 days after admission.