Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase.

A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.

Pyrazinoindolone inhibitors of MAPKAP-K2.

Optimization of pyrazinoindolone inhibitors of MAPKAP-K2 (MK2) provides a reasonable balance of cellular potency and physicochemical properties. Mechanistic studies support the inhibition of MK2 which is responsible for the sub-micromolar cellular efficacy.

Personalization of NonEEG-based seizure detection systems.

Seizures affect each patient differently, so personalization is a vital part of developing a reliable nonEEG based seizure detection system. This personalization must be done while the patient is undergoing video EEG monitoring in an epilepsy monitoring unit (EMU) because seizure detection by EEG is considered to be the ground truth. We propose the use of confidence interval analysis for determining how many seizures must be captured from a patient before we can reliably personalize such a seizure detection system for him/her. Our analysis indicates that 6 to 8 seizures are required. In addition, we create seizure likelihood tables for future use by said system by comparing the number of times a prespecified biosignal activity level is induced by seizure to the total number of occurrences of that level of activity. We focus on complex partial seizures in this paper because they are more difficult to detect than are generalized seizures.

Deterministic generation of a cluster state of entangled photons.

Photonic cluster states are a resource for quantum computation based solely on single-photon measurements. We use semiconductor quantum dots to deterministically generate long strings of polarization-entangled photons in a cluster state by periodic timed excitation of a precessing matter qubit. In each period, an entangled photon is added to the cluster state formed by the matter qubit and the previously emitted photons. In our prototype device, the qubit is the confined dark exciton, and it produces strings of hundreds of photons in which the entanglement persists over five sequential photons. The measured process map characterizing the device has a fidelity of 0.81 with that of an ideal device. Further feasible improvements of this device may reduce the resources needed for optical quantum information processing.

Epileptic seizure detection using wristworn biosensors.

Single signal seizure detection algorithms suffer from high false positive rates. We have found a set of signals which can be easily monitored by a wristworn device and which produce a distinctive pattern during seizure for patients in an epilepsy monitoring unit (EMU). This pattern is much less likely to be reproduced by nonseizure events in the patient's daily life than are changes in heart rate alone. We collected 108 hours of data from three EMU patients who suffered a combined total of seven seizures, then developed a time series analysis/pattern recognition based algorithm which distinguishes the seizures from nonseizure events with 100% accuracy.

Experimental allergic encephalomyelitis. Passive transfer by the intraocular injection of sensitized cells.

Experimental allergic encephalomyelitis is a disease of cell-mediated immunity and can be transferred passively to virgin recipients by lymphoid cells from sensitized donors. The rabbit eye contains myelinated medullary rays that can be visualized ophthalmoscopically. Intraocular injection of autologous lymph node cells from myelin basic protein (BP)-immunized rabbits into the vitreous leads to readily visualized optic neuritis while injection of cells from adjuvant immunized control rabbits does not. Microscopical study confirmed the presence of myelin destruction in recipients of cells from BP-sensitized donors. This eye chamber technique provides a simple model for the study of demyelination in vivo under direct observation.

Blink-saccade synkinesis.

We studied two patients who could make saccades of normal velocity and amplitude only in association with a simultaneous blink. In one patient, the initiation of saccades was also facilitated by blinks. Both patients had signs of cerebellar or brainstem dysfunction, suggesting a posterior fossa localization for blink facilitation of saccadic velocity and amplitude.

Clinical spectrum of Niemann-Pick disease type C.

Analysis of the neurologic symptomatology in 22 patients with Niemann-Pick disease type C revealed 3 phenotypes: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; (3) a late-onset slowly progressive form distinguished from the 2nd pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. The existence of the 1st and 2nd phenotypes within the same sibship suggests that they are variant expressions of the same clinicopathologic disorder. Niemann-Pick disease type C should be considered not only in infants and children who present with organomegaly and a progressive neurodegenerative course, but also in adolescents and adults who have insidiously progressive neurologic dysfunction and only slight organomegaly. Associated with the disease is a marked deficiency in the ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Assay of this deficiency is particularly useful for confirming the diagnosis in patients with atypical presentation.

Experimental myelin intrusion in the nerve head.

On the assumption that myelin intrusion into the papilla and peripapillary region might occur with traumatic lesions of the optic nerve, a study was made of the clinical and histopathologic changes that might be expected. Nine monkey eyes were subjected to hemostat compression of the nerve close to the globe and studied over variable periods up to 28 days. Myelin was demonstrable ophthalmoscopically, followed by variable and increasing amounts of hemorrhage. The myelin was demonstrable histopathologically only during the first 2 weeks after the manipulation and was then masked by the associated hemorrhage and gliosis. The optic nerve showed expected myelinolytic reactions.

Apolipoprotein A-I and B distribution in the human cornea.

PURPOSE: To determine the presence and localization of apolipoprotein A-I, a marker for high density lipoprotein, and apolipoprotein B, a marker for low density lipoprotein, in human cornea; to examine the relationship of these lipoprotein markers with areas of lipid accumulation in the cornea. METHODS: A-I and B apolipoproteins were localized in frozen sections of human corneas with specific monoclonal antibodies using avidin-biotin immunoperoxidase labelling. Corneal lipid was colocalized with apolipoproteins by oil red 0 staining of immunostained sections. RESULTS: Staining data showed that apolipoprotein B and lipid accumulated in the extracellular spaces of peripheral corneal stroma. However, their distributions were not coincident. The posterior region of peripheral corneal stroma (including Descemet's membrane) often contained lipid without immunodetectable apolipoprotein B. Unexpectedly, apolipoprotein A-I was associated with many keratocytes throughout the cornea in addition to an extracellular distribution heaviest in peripheral cornea. CONCLUSIONS: Lipid deposits lacking apolipoprotein B in peripheral cornea suggest that if accumulated corneal arcus lipid is derived from extracellular deposition of plasma low density lipoprotein, the low density lipoprotein is altered such that it looses its immunoreactive apolipoprotein B. The unexpected association of apolipoprotein A-I with keratocytes suggests that these cells are either taking up or synthesizing a protein sharing an immunoreactive epitope with apolipoprotein A-I.

Ocular involvement in disseminated intravascular coagulopathy.

Seven cases illustrate the ocular pathology of disseminated intravascular coagulopathy in its several stages, and correlate these changes with the clinical manifestations. The prime abnormalities consisted of detachments of the retina, vacuolar disruption of the pigment epithelium, choroidal hemorrhage, and, most importantly, thrombotic occlusion of the choriocapillaris and of the juxtaposed vessels in the submacular and peripapillary regions. The changes were characteristically symmetrical in the two eyes.

Colorimetry by a new principle.

A simple and informative method is described for determining the type and extent of color defects. The subjects' responses are registered automatically on a chromaticity diagram that is based on the newtonian model. Color defects are readily identifiable by a skewing of the normal central gray area toward the defectively perceived color. The examination permits independent variation of hue and saturation for each color and requires less than five minutes for the entire procedure. Unlike conventional color tests, the present method indicates exactly what colors are or are not seen at any level of saturation.

Accessory cells in vessels of the paranatal human retina.

Retinas of the paranatal period contain two types of cell clusters that are generally believed to play a role in the developing vasculature. The more posterior cluster consists of angioblastic cells, which undergo lumenization to form the definitive vessels. Anterior to this cluster and separated from it by a distinct boundary are clusters of spindle cells extending a variable distance toward the periphery. These clusters of spindle cells maintain a fixed position relative to the angioblastic masses, without any admixture of the two. The precise function of the spindle cells in the vascularizing process has been a subject of controversy. We found evidence to identify them as glia and to suggest that their role is to provide an energy source for the developing retina as the hyaloid vessels recede and until the retinal vessels take over this function. It further appears that congenital failure of the vessels to develop may result in a persistence of these spindle cells, in the form of hyperplastic glia in the inner layers of the retina. Our study included normal eyes from full-term and premature infants and eyes from patients with retinopathy of prematurity (oxygen-related retinopathy), anencephaly, and other congenital anomalies.

Structure of the muscles of the upper eyelid.

The human and monkey orbicularis muscle has fibers that are more uniform in size and structure than those of rectus muscles. They have distinct myofibrils, a moderate number of mitochondria, and a well-developed transverse T-tube system. The levator muscle also has relatively uniform fibers, but the myofibrils are less distinct than those of the orbicularis. Especially noteworthy is the unusual arrangement whereby Muller muscle arises directly from the undersurface of the levator muscle, causing an intimate intermingling of smooth and striated fibers. Muller muscle then inserts on the tarsus, whereas the levator muscle extends by an aponeurosis into the septa of the orbicularis muscle. In surgical specimens from patients with ptosis, the levator fibers show varying degrees of abnormality, whereas Muller fibers are normal.

Rapid eye movements in myasthenia gravis. I. Clinical observations.

Rapid eye movements, having high velocity and low amplitude, are described in 11 patients with myasthenia gravis. These movements occur with various degrees of ophthalmoplegia. To distinguish them from the somewhat similar lid-twitch phenomenon, they are called quiver movements. We believed that their presence is pathognomonic of myasthenia and results from a differential involvement of the two myoneural mechanisms that are peculiar to the extraocular muscles.

Ocular signs in thiamine-deficient monkeys and in Wernicke's disease in humans.

Thiamine deficiency in the monkey is the animal counterpart of Wernicke's disease in humans. In the present study, thiamine deficiency was induced in 11 monkeys while three monkeys were given paired feedings supplemented by thiamine hydrochloride and three monkeys were maintained on regular chow. The typical clinical symptoms were apathy, inattention to peripheral stimuli, ataxia, ptosis, mydriasis progressing to pupillary areflexia, nystagmus, and ophthalmoparesis progressing to total ophthalmoplegia. With thiamine treatment, recovery was prompt and complete in mild to moderate cases but delayed and incomplete in severe cases. The animals were killed six or more months after discontinuance of the experiments to determine the chronic effects of treated thiamine deficiency. The significant abnormalities in the brain stem were symmetric gliosis and neuronal loss in the inferior colliculi, the regions of the third and sixth nerve nuclei, and the medial vestibular nuclei. White matter was characteristically spared. With the exception of the inferior colliculi, the target sites for neuropathologic changes were the centers for ocular motor control.

Fundal abnormalities of Gaucher's disease.

The evidence for cherry-red maculas in Gaucher's disease is questionable, but in occasional patients, scattered white spots in and on the retina appear to be characteristic. These white spots consist of clusters of swollen histiocytes (Gaucher cells).

Ocular motor signs in some metabolic diseases.

Ocular motor disturbances are described with a miscellany of metabolic disturbances. Horizontal gaze abnormalities, often simulating congenital ocular motor apraxia, characterized Gaucher's disease. Vertical gaze abnormalities, especially downgaze paralysis, characterized what is generally considered a variant of Niemann-Pick disease, or sea-blue histiocytosis, but which we prefer to call the "DAF" syndrome. A form of internuclear ophthalmoplegia but with nystagmus of the adducting eye characterized abetalipoproteinemia. epileptiform eyelid and eye movements occurred in a case of methylmalonohomocystinuria. Ocular motor abnormalities are also described with variation of olivopontocerebellar degeneration and with ataxia telangiectasia.

Ocular signs of cerebellar disease.

Ocular signs of cerebellar disease have been increasingly appreciated with the advent of means for quantitative recording of eye movements. The graphs in this article illustrate ocular flutter, dysmetria, abnormal (nonsmooth) pursuit, instability of fixation, faulty vestibular suppression, impaired optokinetic response, end-position nystagmus, and rebound nystagmus. The signs may be categorized as follows: (1) proprioceptive abnormalities manifest by flutter, dysmetria, and instability of gaze and (2) defects of vision-dependent functions manifest by abnormalities of pursuit, vestibular suppression, optokinetic response, and nystagmus.