Determination of pollution and recovery time of karst springs, an example from a carbonate aquifer in Israel.

This work combines the monitoring of two incidents of spring water pollution in the Western Galilee region of Israel, together with artificial tracer tests that provided valuable information regarding karst system connections and direct estimation of groundwater velocities. Almost simultaneous contamination of seven springs endangered the water supply for the region. The variations over time in contaminant concentration in the different springs were not similar, indicating more than one contamination source.

Colloid transport in porous media: impact of hyper-saline solutions.

The transport of colloids suspended in natural saline solutions with a wide range of ionic strengths, up to that of Dead Sea brines (10(0.9) M) was explored. Migration of microspheres through saturated sand columns of different sizes was studied in laboratory experiments and simulated with mathematical models.

Line-source multi-tracer test for assessing high groundwater velocity.

Segmented line-source multi-tracer injection is suggested as an effective method for assessing groundwater velocities and flow directions in subsurfaces characterized by high water flux. Modifying the common techniques of injecting a tracer into a well became necessary after point-source natural and forced gradient tracer tests ended with no reliable information on the local groundwater flow. The tracer's line-source increases the likelihood of success of the test and could provide additional information regarding the lateral heterogeneity of the aquifer.

Design and synthesis of 6-oxo-1,6-dihydropyridines as CDK5 inhibitors.

Cyclin-dependent kinase 5 (CDK5) is a serine-threonine protein kinase that plays a significant role in neuronal development. In association with p25, CDK5 abnormally phosphorylates a number of cellular targets involved in neurodegenerative disorders. Using active site homology and previous structure-activity relationships, a new series of potent CDK5 inhibitors was designed.

Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 beta inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury.

We compared the neuroprotective efficacy of a potent and CNS-penetrant cyclin dependent kinase (CDK) and glycogen synthase kinase 3 beta (GSK3beta) inhibitor (Compound 1) in juvenile (postnatal day 21; P21) and adult C57Bl/6 mice (postnatal day 60; P60) using a model of hypoxic-ischemic brain injury (HI). Neuronal cell counts and density measures from brain sections stained with Cresyl Violet revealed that exposure of P21 mice to 60 min of HI resulted in extensive damage to the ipsilateral cornu ammonis 1 (CA1) region of the hippocampus (40% cell loss) and striatum (30% cell loss) 7 days later. Exposure of P60 mice to 40 min of HI produced a similar pattern of cell loss.

Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats.

Antagonists of the vanilloid receptor TRPV1 (transient receptor potential vanilloid type 1) have been reported to produce antihyperalgesic effects in animal models of pain. These antagonists, however, also caused concomitant hyperthermia in rodents, dogs, monkeys, and humans. Antagonist-induced hyperthermia was not observed in TRPV1 knockout mice, suggesting that the hyperthermic effect is exclusively mediated through TRPV1.

Inflammatory pain in the rabbit: a new, efficient method for measuring mechanical hyperalgesia in the hind paw.

The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits.

Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.

Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors.

Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade.

Capsaicin, the active ingredient in some pain-relieving creams, is an agonist of a nonselective cation channel known as the transient receptor potential vanilloid type 1 (TRPV1). The pain-relieving mechanism of capsaicin includes desensitization of the channel, suggesting that TRPV1 antagonism may be a viable pain therapy approach. In agreement with the above notion, several TRPV1 antagonists have been reported to act as antihyperalgesics.

The use of stem cells' hematopoietic stimulating factors therapy following spinal cord injury.

Spinal cord injury (SCI) remains one of the most devastating conditions in medicine, particularly due to the loss of productive life years and the high economic burden it places on our society. There are limited therapeutic options available to reduce the morbidity and mortality related to SCI. However, recent work with stem cells in repairing SCI appears to be promising, making this one of the most exciting frontiers in medicine.

The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.

The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics.

Neuroprotective effect of darbepoetin alfa, a novel recombinant erythropoietic protein, in focal cerebral ischemia in rats.

Background And Purpose: Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for treating anemia. In animal models, exogenous recombinant human erythropoietin has been reported to be beneficial in treating experimental cerebral ischemia. In this study, we determined whether darbepoetin alfa would protect in a rat model of transient focal cerebral ischemia.

Spiral ganglion neurons are protected from degeneration by GDNF gene therapy.

Perceptual benefits from the cochlear prosthesis are related to the quantity and quality of the patient's auditory nerve population. Multiple neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have been shown to have important roles in the survival of inner ear auditory neurons, including protection of deafferented spiral ganglion cells (SGCs). In this study, GDNF gene therapy was tested for its ability to enhance survival of SGCs after aminoglycoside/diuretic-induced insult that eliminated the inner hair cells.

Distribution of immunophilin FKBP-12 protein and mRNA within the mammalian cochlea and cochlear nucleus.

Immunophilin FK binding protein-12 (FKBP-12), the soluble receptor for the immunosuppressant drug FK506, is involved in a number of neuronal activities including increased nerve regeneration in the peripheral nervous system and enhanced recovery in animal models of neurodegenerative diseases. In addition, FKBP-12 is tightly bound to the calcium release channel ryanodine receptor and physiologically interacts with the inositol 1,4,5-trisphosphate receptor. In nearly all cell types, release of intracellular Ca(2+) and subsequent second messenger signaling involves activation of these ion channels.

Rescue and regrowth of sensory nerves following deafferentation by neurotrophic factors.

Trauma and loss of cochlear inner hair cells causes a series of events that result first in the retraction of the peripheral processes of the auditory nerve, scar formation in the organ of Corti, and over the course of weeks to months (depending on the species) the loss of auditory nerve cell bodies (spiral ganglion cells). Neurotrophic factors play an important role in the mature nervous system as survival factors for maintenance and protection and also can play a role in regrowth. Studies in the cochlea now show that application of exogenous neurotrophic factors can enhance survival of spiral ganglion cells after deafness and induce regrowth of peripheral processes, perhaps by replacing lost endogenous factors.

Glial cell line-derived neurotrophic factor. Potential for otoprotection.

Sensorineural hearing loss results from the degeneration of hair cells and/or auditory neurons in the cochlea of the inner ear. BDNF and NT-3 were shown to support survival of auditory neurons both in vitro and in vivo. Cochlea from P3-P4 rats were cultured as floating explants and hair cells in the organ of Corti were identified by phalloidin-FITC immunostaining.

Glial cell line-derived neurotrophic factor has a dose dependent influence on noise-induced hearing loss in the guinea pig cochlea.

We examined the effectiveness of glial cell line-derived neurotrophic factor (GDNF) to attenuate cochlear damage from intense noise stress. Subjects were exposed to 115 dB SPL one octave band noise centered at 4 kHz for 5 h. They received artificial perilymph with or without GDNF into the left scala tympani at 0.

Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor.

Aminoglycosides are commonly used antimicrobial drugs that often have ototoxic side effects. The ototoxicity often involves permanent loss of cochlear hair cells (HCs). Neurotrophic factors have been shown to protect a variety of tissues, including HCs, from toxic trauma.

Guinea pig auditory neurons are protected by glial cell line-derived growth factor from degeneration after noise trauma.

For patients with profound hearing loss, cochlear implants have become the treatment of choice. These devices provide auditory information through direct electrical stimulation of the auditory nerve. Prosthesis function depends on survival and electrical excitability of the cochlear neurons.

GDNF protects the cochlea against noise damage.

Glial-derived neurotrophic factor (GDNF) was tested for its ability to prevent hearing and sensory cell loss in guinea pigs exposed to acoustic trauma. Hearing was measured prior to any treatment. Animals were exposed to damaging levels of noise either before or after local application of GDNF to one ear.

Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system.

The gene mutated in X-linked adrenoleukodystrophy (ALD), a progressive demyelinating disease, codes for a protein (ALDP) involved in very-long-chain fatty acid (VLCFA) transport. The expression of ALDP and of two peroxisomal enzymes involved in beta-oxidation of VLCFA, acyl-CoA oxidase, and catalase was studied in human and mouse brain. The pattern of expression was similar in both species.

B61, a ligand for the Eck receptor protein-tyrosine kinase, exhibits neurotrophic activity in cultures of rat spinal cord neurons.

Although the Eph subfamily represents the largest group of receptor protein-tyrosine kinases, the biological roles of the Eph-related receptors and their ligands are not well understood. B61 has been identified recently by receptor affinity chromatography as a ligand for the Eph-related receptor Eck (Bartley et al.: Nature 368:558-560, 1994).

Inhibition of p185c-erbB-2 proto-oncogene expression by antisense oligodeoxynucleotides down-regulates p185-associated tyrosine-kinase activity and strongly inhibits mammary tumor-cell proliferation.

The c-erbB-2 proto-oncogene codes for a 185-kd putative growth factor receptor that is highly homologous to but distinct from the epidermal growth factor (EGF) receptor. Amplification and overexpression of c-erbB-2 occurs in a number of human tumors, in some of which it is a negative prognostic factor. This study investigates the possibility of inhibiting tumor-cell proliferation by blocking c-erbB-2 expression in the human mammary carcinoma cell line SK-Br-3 using chemically modified antisense oligodeoxynucleotides.

Effects of ciliary neurotrophic factor on the survival and response to nerve growth factor of cultured rat sympathetic neurons.

The development and maturation of cells depends not only on their genetic history, but also on sequences and combinations of environmental signals appropriate to their developmental age. Early postnatal rat sympathetic neurons are dependent on nerve growth factor (NGF) for survival in vivo and in vitro, but earlier sympathetic neuroblasts may not require NGF. Ciliary neurotrophic factor (CNTF) provides short-term in vitro trophic support to embryonic and neonatal sympathetic neurons, but its role in vivo is not understood.