Science 1 August 2008: Vol. 321. no. 5889, pp. 626 - 627
SCIENCE AT THE OLYMPICS: Can Neuroscience Provide a Mental Edge?
A collaboration between sports psychologists and cognitive neuroscientists is trying to figure out what gives successful athletes their mental edge.

Science 1 August 2008: Vol. 321. no. 5889, pp. 702 - 705
The Cell and Molecular Basis of Mechanical, Cold, and Inflammatory Pain
Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel Na v1.8. Mice showed normal motor activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that Na v1.8-expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.

Science 1 August 2008: Vol. 321. no. 5889, p. 640
Comment on "Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in the Live Human Brain"
Manganas et al. (Reports, 9 November 2007, p. 980) used nuclear magnetic resonance spectroscopy to identify a biomarker of neural progenitor cells. However, their analysis relies on spectral processing methods that are known to be problematic. Absent detection using alternate methods of spectrum analysis or controls to quantify the false discovery rate, their conclusions may be premature.

Science 1 August 2008:
Vol. 321. no. 5889, p. 640
Comment on "Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in
the Live Human Brain"
Manganas et al. (Reports, 9 November 2007, p. 980) used a metabolic biomarker identified in vitro to characterize the existence of neural progenitor cells in vivo. Although their detailed experiments and general approach are laudable, aspects of their magnetic resonance spectroscopy data and analyses raise questions about their results.

Science 1 August 2008: Vol. 321. no. 5889, p. 640
Comment on "Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells
in the Live Human Brain"
Manganas et al. (Reports, 9 November 2007, p. 980) reported the discovery of a biomarker specific for neural progenitor cells detectable using magnetic resonance spectroscopy. A new algorithm was developed to extract the biomarker from noisy in vivo data. We question how this algorithm was validated, because the biomarker overlaps with peaks from nonspecific lipid signals.

Science 1 August 2008: Vol. 321. no. 5889, p. 640
Response to Comments on "Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in the Live Human Brain"
We reported on a neural progenitor cell biomarker, a lipid-based metabolite enriched in these cells, which we detected using spectroscopy both in vitro and in vivo, and singular value decomposition–based signal processing. The study provided an outline of our computational methodology. Herein, we report more extensively on the method of spectrum analysis used, demonstrating the specificity of our findings.

Nature 454, 589-590 (31 July 2008)
Behavioural neuroscience: The circuit of fear
Do you find it difficult to overcome an irrational fear? Blame it on the specific neural circuits hardwired in the brain that control fear recognition, and fear renewal even when fear has seemingly been overcome.
Learning to predict danger allows animals to defend themselves against harm and is crucial for survival. The neural mechanisms that subserve these functions are evolutionarily old, and their dysfunction is thought to underlie a host of anxiety disorders in humans, including post-traumatic stress and panic disorder.

Nature 454, 600-606 (24 July 2008)
Switching on and off fear by distinct neuronal circuits
Switching between exploratory and defensive behaviour is fundamental to survival of many animals, but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in mice, we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting memory or expression of behaviour. Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear behaviour.

Nature 454, 642-645 (24 July 2008)
Amygdala intercalated neurons are required for expression of fear extinction
Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders. In mammals, repeated presentations of a conditioned stimulus that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala, the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute probable mediators of extinction because they receive information about the conditioned stimulus from the basolateral amygdala (BLA), and contribute inhibitory projections to the central nucleus (CEA), the main output station of the amygdala for conditioned fear responses. Thus, after extinction training, ITC cells could reduce the impact of conditioned-stimulus-related BLA inputs to the CEA by means of feed-forward inhibition. Here we test the hypothesis that ITC neurons mediate extinction by lesioning them with a toxin that selectively targets cells expressing -opioid receptors (ORs). Electron microscopic observations revealed that the incidence of OR-immunoreactive synapses is much higher in ITC cell clusters than in the BLA or CEA and that ORs typically have a post-synaptic location in ITC cells. In keeping with this, bilateral infusions of the OR agonist dermorphin conjugated to the toxin saporin in the vicinity of ITC neurons caused a 34% reduction in the number of ITC cells but no significant cell loss in surrounding nuclei. Moreover, ITC lesions caused a marked deficit in the expression of extinction that correlated negatively with the number of surviving ITC neurons but not CEA cells. Because ITC cells exhibit an unusual pattern of receptor expression, these findings open new avenues for the treatment of anxiety disorders.

Nature 454, 646-650 (24 July 2008)
Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors
Reprogramming of somatic cells is a valuable tool to understand the mechanisms of regaining pluripotency and further opens up the possibility of generating patient-specific pluripotent stem cells. Reprogramming of mouse and human somatic cells into pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, has been possible with the expression of the transcription factor quartet Oct4 (also known as Pou5f1), Sox2, c-Myc and Klf4. Considering that ectopic expression of c-Myc causes tumorigenicity in offspring2 and that retroviruses themselves can cause insertional mutagenesis, the generation of iPS cells with a minimal number of factors may hasten the clinical application of this approach. Here we show that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells, and that exogenous Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells. These two-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimaeras. We propose that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.

BMJ 2008;337:a895
Antipsychotics for dementia Antipsychotic prescribing in care homes
Antipsychotic prescription in care homes shows a lack of understanding of the needs of residents and inadequate systems for the healthcare support of people in care homes generally.
There are now some three care home beds for every "NHS" establishment bed (all specialties) in England; a high proportion of these provide refuge and care for people with mental impairment, usually related to dementia. Commonly, people are transferred to care homes after a crisis and acute hospital admission, and our experience is that some 40% of antipsychotic prescriptions to care home residents have been initiated in NHS hospitals. The transfer of medical care to receiving general practitioners (who typically are not the patient’s usual or previous doctor) is seldom supported by adequate information to encourage a programme of gradual drug withdrawal.

BMJ 2008;337:a955
Joint guidelines call for speedier assessment of patients with stroke
All patients suspected of having had a stroke should be admitted as quickly as possible to an acute stroke unit and, if appropriate, given thrombolytic treatment, say new guidelines for the United Kingdom.
Patients who have had transient ischaemic attacks ("mini-strokes") should no longer have to face the risk of having a full acute stroke while they wait, sometimes weeks, for assessment, the guidelines state.
Two sets of guidelines were launched on Wednesday 23 July, one from the Royal College of Physicians and the other from the National Institute for Health and Clinical Excellence (NICE). Both documents highlight the fact that one in 10 deaths in the UK are caused by a stroke and that every year an estimated 150 000 people have a stroke. Stroke is the third largest cause of disability, with 250 000 people living with severe disabilities resulting from the condition.

BMJ 2008;337:a671 Clinical Review Guillain-Barré syndrome
Summary points
Guillain-Barré syndrome is a rare but important disease that can lead to life threatening respiratory failure
Structural similarities between a triggering infectious organism and peripheral nerve tissue are important in its pathogenesis
Treatment consists of rapid administration of intravenous immunoglobulin or plasma exchange, which shortens the time to recovery
Around 10% of patients die from respiratory failure, pulmonary emboli, or infection
Around 20% of patients have residual disability, with weakness or persistent sensory disturbance

Guillain-Barré syndrome is a peripheral neuropathy that causes acute neuromuscular failure. Misdiagnosis is common and can be fatal because of the high frequency of respiratory failure, which contributes to the 10% mortality seen in prospective studies. Our understanding of the wide spectrum of the disease and its pathogenesis has increased enormously in recent years. Several high quality randomised controlled trials have established the effectiveness of early treatment.

The Lancet
Vol: 372 Issue: 9635, July, 26 - August, 1 2008    pp: 344
Case Report The writing on the wall
In August, 2007, a 59-year-old, widely travelled lecturer developed short-term memory loss. Over the next 4 weeks, he developed intermittent fever (highest temperature 39·0°C), low mood, anxiety, urinary retention, and reversal of his sleep-wake cycle. He had previously been well; his medical history was notable chiefly for pulmonary tuberculosis, for which he had been treated in 2006. He was admitted to hospital in Malaysia, where he lived. Doctors noted intermittent orofaciolingual dyskinesia, and occasional generalised myoclonic jerks. MRI revealed slight meningeal enhancement at the brainstem and cervical spine. Cerebrospinal fluid (CSF) contained 135 white blood cells per μL (95% lymphocytes); the concentrations of protein and glucose were 2·16 g/L and 2·3 mmol/L respectively (serum glucose 5·2 mmol/L). Although these results were consistent with tuberculous meningitis, the doctors suspected bacterial meningitis, because of the patient's travel history, and prescribed vibramycin and ceftriaxone. Exhaustive blood and CSF cultures were negative. 2 weeks later, the patient had not improved, so he was treated for presumed tuberculosis, with rifampicin, isoniazid, pyrazinamide, and prednisolone. However, his condition continued to deterioriate. 3 weeks after admission, he was transferred to our hospital.

NEJM Volume 359:492-507  July 31, 2008  Number 5
Malignant Gliomas in Adults
Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year.1,2,3 Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality. Despite optimal treatment, the median survival is only 12 to 15 months for patients with glioblastomas and 2 to 5 years for patients with anaplastic gliomas. Recently, there have been important advances in our understanding of the molecular pathogenesis of malignant gliomas and progress in treating them.

NEJM Volume 359:508  July 31, 2008  Number 5
Complex Regional Pain Syndrome Type 1
An otherwise healthy and functional 35-year-old man had an undisplaced fracture of the right fifth metacarpal neck after a fall. He presented 21 months later with pain, extensive swelling, and loss of function in his right hand up to the middle third of his upper arm. On physical examination, there was nonpitting edema, hair loss, allodynia, and vasomotor instability, with increased temperature, sweating, and erythema. These changes had developed since the initial fracture and had progressed slowly. Radiologic studies showed that the fracture had healed. 
 
NEJM Volume 359:e5  July 31, 2008  Number 5
Horizontal Pendular Nystagmus in a Patient with Ocular Albinism
A 32-year-old Hispanic woman with ocular albinism presented with a congenital horizontal pendular nystagmus (see video). Other than being fair-skinned, the patient had no cutaneous manifestations of albinism, and pigmentation of body hair was intact. The nystagmus was characterized by rapid saccades, but there was no null point, and it was worse on rightward gaze than on leftward gaze. The patient reported no oscillopsia (the sensation that viewed objects are moving back and forth). She had bilateral iris transillumination and foveal hypoplasia, and her bilateral visual acuity was 20/200.

NEJM Volume 359:509-515  July 31, 2008  Number 5
Case 24-2008 — A 35-Year-Old Woman with Postpartum Confusion, Agitation, and Delusions
Dr. Alexia E. Koukopoulos (Psychiatry): A 35-year-old woman was admitted to the inpatient psychiatry service of this hospital 5 days after the birth of her first child because of confusion, agitation, and delusions. The patient had been well until approximately 2 years earlier, when insomnia, auditory hallucinations, and disorientation, followed by severe depression and suicidal ideation, developed. After two inpatient psychiatric admissions, a diagnosis of bipolar disorder was made. The patient's symptoms were controlled with lithium, 900 mg at bedtime, and citalopram, 40 mg per day, for the next 9 months.

NEJM Volume 359:539-541  July 31, 2008  Number 5
Cytomegalovirus Immunity after Vaccination with Autologous Glioblastoma Lysate
To the Editor: Glioblastoma is a malignant brain tumor with overall survival rates of less than 3.3% at 5 years. Few effective treatments are available. The durability of a radiographically defined response to treatment is limited, and median survival is less than 2 years.
We are conducting a phase 1 trial of autologous dendritic-cell vaccination as adjunctive therapy in glioma,
a study that has been approved by the institutional review board at the University of California, Los Angeles.