Patterns and mechanisms of early Pliocene warmth.

About five to four million years ago, in the early Pliocene epoch, Earth had a warm, temperate climate. The gradual cooling that followed led to the establishment of modern temperature patterns, possibly in response to a decrease in atmospheric CO2 concentration, of the order of 100 parts per million, towards preindustrial values. Here we synthesize the available geochemical proxy records of sea surface temperature and show that, compared with that of today, the early Pliocene climate had substantially lower meridional and zonal temperature gradients but similar maximum ocean temperatures. Using an Earth system model, we show that none of the mechanisms currently proposed to explain Pliocene warmth can simultaneously reproduce all three crucial features. We suggest that a combination of several dynamical feedbacks underestimated in the models at present, such as those related to ocean mixing and cloud albedo, may have been responsible for these climate conditions.

Continuing optic nerve atrophy following optic neuritis: a serial MRI study.

To investigate optic neuritis as a model for atrophy in multiple sclerosis (MS) lesions we performed serial magnetic resonance imaging (MRI) on 10 patients with a history of optic neuritis using a fat saturated short-echo fast fluid-attenuated inversion recovery (sTE fFLAIR) sequence. The first study was performed a median of 19.5 months after the onset of optic neuritis and the second 1 year later. Using a computer-assisted contouring technique, a blinded observer calculated the mean area of the intro-orbital optic nerves. The mean area of affected optic nerves decreased over 1 year by 0.9 mm2 from 11.1 to 10.2 mm2 (p = 0.01). Poor visual acuity and decreased visual-evoked potential (VEP) amplitude were associated with atrophy. These findings suggest that atrophy is a feature of focal demyelinating lesions, it may evolve over several years, and may have functional significance. Optic neuritis provides a model to study the effect of inflammatory demyelination through the ability to accurately measure visual function and to visualize and measure the optic nerves using magnetic resonance imaging.

Remyelination of demyelinated CNS axons by transplanted human schwann cells: the deleterious effect of contaminating fibroblasts.

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.

Infratentorial hypointense lesion volume on T1-weighted magnetic resonance imaging correlates with disability in patients with chronic cerebellar ataxia due to multiple sclerosis.

In multiple sclerosis (MS), hypointense lesions on T1-weighted magnetic resonance imaging are thought to represent areas of tissue disruption and axonal loss. In previous studies of MS patients, infratentorial T1 hypointense lesions were found to be rare. In MS patients selected to have chronic cerebellar ataxia, we have determined the extent of infratentorial T1 hypointense lesions and their relationship with disability. We recruited nine patients with chronic cerebellar ataxia due to MS. An expanded disability status scale (EDSS) assessment was performed on each. The patients' brains were then imaged with axial-oblique dual-echo fast spin-echo and contrast-enhanced T1-weighted conventional spin-echo sequences. The number and total volume of infratentorial high-signal lesions on T2-weighted images and infratentorial hypointense lesions on T1-weighted images were calculated by a blinded observer using a computer-assisted contouring technique. A total of 96 infratentorial high-signal lesions were present, of which 62 (64.6%) appeared isointense and 34 (35.4%) hypointense with respect to the surrounding brain substance on the T1-weighted images. There was a median of 3 (range 0-10) and median volume of 0.43 ml (range 0-0.85 ml) infratentorial T1 hypointense lesions per patient. The EDSS score correlated with both the number (r=0.68, p=0.043) and the volume per patient (r=0.89, p=0.001) of infratentorial T1 hypointense but not T2 high-signal lesions. Infratentorial T1 hypointense lesions are often seen in patients with MS and chronic cerebellar ataxia. They may play a significant role in the disability suffered by these patients.

Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat-saturated short-echo fast FLAIR sequence.

We describe an MRI technique for quantifying optic nerve atrophy resulting from a single episode of unilateral optic neuritis. We imaged 17 patients, with a median time since onset of optic neuritis of 21 months (range 3-81 months), using a coronal-oblique fat-saturated short-echo fast fluid-attenuated inversion-recovery (sTE fFLAIR) sequence. The mean cross-sectional area of the intraorbital portion of the optic nerves was calculated by a blinded observer from five consecutive 3 mm slices from the orbital apex forwards using a semiautomated contouring technique and compared with data from 16 controls. The mean optic nerve area was 11.2 mm2 in the affected eye of the patients, 12.9 mm2 in the contralateral eye (P = 0.006 compared to the affected eye) and 12.8 mm2 in controls (P = 0.03 compared to the affected eyes). There was a significant negative correlation between disease duration and the size of the affected optic nerve (r = -0.59, P = 0.012). The measurement coefficient of variation was 4.8%. The sTE fFLAIR sequence enables measurement of optic nerve area with sufficient reproducibility to show optic nerve atrophy following a single episode of unilateral optic neuritis. The correlation of increasing optic nerve atrophy with disease duration would be consistent with ongoing axonal loss in a persistently demyelinated lesion, or Wallerian degeneration following axonal damage during the acute inflammatory phase.

Remyelination of Demyelinated CNS Axons by Transplanted Human Schwann Cells: The Deleterious Effect of Contaminating Fibroblasts.

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.