Importance of reinfection in the pathogenesis of trachoma

The authors' epidemiologic studies of trachoma on Taiwan and experimental monkey eye infections with and without Chlamydia trachomatis immunization are reviewed for the data they provide on the pathogenesis of trachoma. These studies indicate that trachoma is an immunopathologic disease in which the more severe progressive trachoma infections with pannus and scar formation occur only after reinfection. This hypothesis is supported by a 10-year study of 32 family households that were followed with repeated clinical and laboratory observations. Although most cases of active trachoma healed spontaneously, there were 26 persons in nine families who developed clinical and laboratory evidence of 29 episodes of new trachoma eye infection. On the basis of the clinical disease, its persistence, and the laboratory findings, these 29 new infections could be divided into 10 primary, nine secondary, and 10 tertiary infections. Details of the different stages of infection leading to chronic trachoma are presented.     

Outcome at 7 years of children diagnosed with autism at age 2: predictive validity of assessments conducted at 2 and 3 years of age and pattern of symptom change over time

OBJECTIVE: To examine the predictive validity of symptom severity, cognitive and language measures taken at ages 2 and 3 years to outcome at age 7 in a sample of children diagnosed with autism at age 2. METHOD: Twenty-six children diagnosed with autism at age 2 were re-assessed at ages 3 and 7 years. At each age symptom severity, cognitive and language assessments were completed. RESULTS: The pattern of autistic symptom severity varied over time by domain. Across time, children moved across diagnostic boundaries both in terms of clinical diagnosis and in terms of instrument diagnosis on the Autism Diagnostic Interview-Revised (ADI-R). On all measures group variability in scores increased with age. Although non-verbal IQ (NVIQ) for the group as a whole was stable across the 3 assessments, this masked considerable individual instability. Standard assessments at age 2 did not predict outcome at age 7 even within the same domain of functioning. In contrast, standard assessments at age 3 did predict outcome. However, a measure of rate of non-verbal communicative acts taken from an interactive play-based assessment at age 2 was significantly associated with language, communication and social outcomes at age 7. CONCLUSIONS: The trajectory of autism symptoms over time differed in different domains, suggesting that they may be, at least in part, separable. Variability in language, NVIQ and symptom severity increased over time. Caution is required when interpreting the findings from assessments of children with autism at age 2 years. At this age measures of rate of non-verbal communication might be more informative than scores on standard psychometric tests. Predictive validity of assessments at age 3 years was greater.     

Amygdala damage impairs emotional memory for gist but not details of complex stimuli

Neurobiological studies demonstrate the amygdala's role in emotional memory, and psychological studies suggest a particular pattern: enhanced memory for the gist but not the details of complex stimuli. We hypothesized that these two findings are related. Whereas normal (n = 52) and brain-damaged (n = 22) controls showed the expected enhancement of gist memory when the encoding context was emotional, persons with unilateral damage to the medial temporal lobe including the amygdala (n = 16) did not show this pattern. Furthermore, amygdala volume showed a significant positive correlation with gist memory but not with overall memory. A further study in four subjects with selective medial temporal damage sparing the amygdala, and one with selective damage confined to the amygdala, confirmed the specificity of this effect to the amygdala. The data support a model whereby the amygdala focuses processing resources on gist, possibly accounting for features of traumatic memories and eyewitness testimony in real life.     

Hydraulic Strengthening Affects the Stiffness and Strength of Cortical Bone

A nonlinear, interstitial fluid flow constitutive model for cortical bone was developed to study the strain-rate dependency of cortical bone apparent modulus (E_a). Nine representative volume element (RVE) structural models of cortical bone spanning an effective pore volume fraction P range of 1–40% were examined. Dynamic loading conditions were used to study the fluid flow contribution or hydraulic strengthening (HS) effect on E_a for each RVE model. The model indicated that there is an upper and lower asymptotic bound of strain-rate (10^{± 3} sec^–1) above or below which there are no further HS effects on E_a. At certain strain-rates (10^–1 to 10⁰ sec^–1) variations in cortical bone porosity had little or no influence on E_a. At lower and higher frequencies, the loss tangent, hence the magnitude of viscoelastic effects is greater. For strain-rates less than 10^–1 sec^–1, lower porosity RVE models were always stiffer than higher porosity RVE models. A generalized power law model is proposed to account for the fact that HS in cortical bone exhibits an upper and lower asymptotic bound and is bi-modal in terms of strain-rate.     

Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1

Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold). We have previously shown that YC-1 markedly enhances long-term potentiation in hippocampal and amygdala slices via NO-cGMP-PKG-dependent pathway. We here further investigated whether YC-1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC-1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC-1 30 min after foot-shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC-1 inhibited the scopolamine-induced learning deficit. The enhancement of learning behaviour by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor L-NAME and PKG inhibitors of KT5823 and Rp-8-Br-PET-cGMPS, indicating that NO-cGMP-PKG pathway is also involved in the learning enhancement action of YC-1. YC-1 is thus a good drug candidate for the improvement of learning and memory.     

Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia

Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.     

Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities

We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-beta1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-beta1 mice compared to non-transgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions. A highly significant inverse correlation was found between the density of thioflavin-S-positive blood vessels and blood flow in the hippocampus and the cortex. An inverse correlation was likewise found between meningeal staining and blood flow in thalamic nuclei and regions of high blood flow. Thus, the vascular abnormalities were associated locally with reduced perfusion rate and more widely with limitation in the blood flow. These chronic changes may be related to fibrillar and soluble A beta peptides, the amount of which was almost doubled in the brains of TGF-beta1 mice. Comparison with previous results of cerebral glucose utilization in TGF-beta1 mice shows that reduced utilization preferentially occurred in regions with a high metabolic rate and a relatively low blood flow, suggesting that the metabolic needs are not met by blood supply in these regions.     

Clinical and magnetic resonance imaging manifestations of Holmes tremor

Holmes tremor is a rare symptomatic slow tremor in the proximal parts of the limbs. It may be present at rest or maintenance of a posture, or during the movement of the affected limb. We describe herein three patients of Holmes tremor with possible etiologies of brainstem infarction and head injury. The intervals between the causal events and the appearance of tremor range from 1 month to 12 months. Magnetic resonance imaging studies reveal hypertrophy of the inferior olivary nucleus in all of the three patients, although only one of them has palatal myoclonus. The surface electromyographic recordings reveal characteristic slow oscillation with frequencies of 3.5 to 4.2 Hz. These features suggest that perturbation of the dentato-rubral-olivary circuitry may play a pivotal role for the generation of Holmes tremor. However, no tight correlation is observed between the presence of inferior olivary nuclear hypertrophy and the appearance of symptomatic palatal myoclonus in the current report.     

Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial

Animal studies and a preliminary clinical observation suggest that nutritional supplementation with long chain omega-3 fatty acids (omega-3 FAs) may be useful in the nonpharmacological treatment of patients with epilepsy. Omega-3 FAs increase seizure thresholds, and lower inflammatory mediators, which are increased in patients with epilepsy. In this first randomized, placebo-controlled parallel group trial of omega-3 FA supplementation with 1 g eicosapentaenoic acid (EPA) and 0.7 g docosahexaenoic acid (DHA) daily, 57 patients completed a 12-week double-blind phase. Seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained. The supplementation produced a significant increase in EPA and DHA concentrations and a reciprocal fall in arachidonic and linoleic acid concentrations. No change in serum AED concentrations was detected. Further studies are required to examine different omega-3 FA preparations, different doses, longer treatment duration, and larger sample sizes.     

An optimal state estimation model of sensory integration in human postural balance

We propose a model for human postural balance, combining state feedback control with optimal state estimation. State estimation uses an internal model of body and sensor dynamics to process sensor information and determine body orientation. Three sensory modalities are modeled: joint proprioception, vestibular organs in the inner ear, and vision. These are mated with a two degree-of-freedom model of body dynamics in the sagittal plane. Linear quadratic optimal control is used to design state feedback and estimation gains. Nine free parameters define the control objective and the signal-to-noise ratios of the sensors. The model predicts statistical properties of human sway in terms of covariance of ankle and hip motion. These predictions are compared with normal human responses to alterations in sensory conditions. With a single parameter set, the model successfully reproduces the general nature of postural motion as a function of sensory environment. Parameter variations reveal that the model is highly robust under normal sensory conditions, but not when two or more sensors are inaccurate. This behavior is similar to that of normal human subjects. We propose that age-related sensory changes may be modeled with decreased signal-to-noise ratios, and compare the model's behavior with degraded sensors against experimental measurements from older adults. We also examine removal of the model's vestibular sense, which leads to instability similar to that observed in bilateral vestibular loss subjects. The model may be useful for predicting which sensors are most critical for balance, and how much they can deteriorate before posture becomes unstable.