Clinical and Statistical Considerations when Assessing Oxygen Levels in Tumors: Illustrative Results from Clinical EPR Oximetry Studies.

The success of treatment for malignancies, especially those undergoing radiation therapy or chemotherapy, has long been recognized to depend on the degree of hypoxia in the tumor. In addition to the prognostic value of knowing the tumor's initial level of hypoxia, assessing the tumor oxygenation during standard therapy or oxygen-related treatments (such as breathing oxygen-enriched gas mixtures or taking drugs that can increase oxygen supply to tissues) can provide valuable data to improve the efficacy of treatments. A series of early clinical studies of tumors in humans are ongoing at Dartmouth and Emory using electron paramagnetic resonance (EPR) oximetry to assess tumor oxygenation, initially and over time during either natural disease progression or treatment. This approach has the potential for reaching the long-sought goal of enhancing the effectiveness of cancer therapy. In order to effectively reach this goal, we consider the validity of the practical and statistical assumptions when interpreting the measurements made in vivo for patients undergoing treatment for cancer.

Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach.

OBJECTIVE: Idiopathic peripheral neuropathy is common and likely due to genetic factors that are not detectable using standard linkage analysis. We initiated a candidate gene approach to study the genetic influence of the small heat shock protein (sHSP) gene family on an axonal motor and motor/sensory neuropathy patient population. METHODS: The promoter region and all exonic and intronic sequences of the 10 sHSP genes (HSPB1-HSPB10) were screened in a cohort of presumed nonacquired, axonal motor and motor/sensory neuropathy patients seen at the Ohio State University Neuromuscular Clinic. RESULTS: A missense mutation in the gene encoding small heat shock protein B3 (HSPB3, also called HSP27, protein 3) was discovered in 2 siblings with an asymmetric axonal motor neuropathy. Electrophysiologic studies revealed an axonal, predominantly motor, length-dependent neuropathy. The mutation, HSPB3(R7S), is located in the N-terminal domain and involves the loss of a conserved arginine. CONCLUSIONS: The discovery of an HSPB3 mutation associated with an axonal motor neuropathy using a candidate gene approach supports the notion that the small heat shock protein gene family coordinately plays an important role in motor neuron viability.

Late-onset hereditary axonal neuropathies.

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

The role of the septohippocampal pathway in the regulation of hippocampal field activity and behavior: analysis by the intraseptal microinfusion of carbachol, atropine, and procaine.

The role of the septohippocampal pathway in the regulation of hippocampal field activity and behavior was assessed using the technique of intraseptal microinfusion of carbachol, atropine, and procaine. The effects of these manipulations were assessed by comparing them with the effects of intraseptal saline control infusions on spontaneously occurring motor behaviors and their correlated hippocampal field activities. In control conditions hippocampal theta field activity, with up to 40% of the total power concentrated in a 1-Hz band around the peak frequency, was recorded only during type 1 voluntary motor behaviors. Hippocampal large-amplitude irregular activity was recorded during type 2 automatic motor behaviors and during immobility. Microinfusion of carbachol into the MS/vDBB (medial septum/vertical limb of the diagonal band of Broca) resulted in continuous theta field activity regardless of what type of motor behavior the animal performed or whether it was immobile. However, under these conditions the performance of a voluntary movement consistently resulted in an upward shift of theta frequency, demonstrating that the frequency of carbachol-elicited type 2 theta can be modulated by the behavioral activation of type 1 theta. The subsequent infusion of atropine abolished the carbachol-elicited theta, while that occurring during type 1 voluntary movement was preserved. In contrast to the selective blockade of carbachol-elicited theta by atropine, procaine suppression of the MS/vDBB abolished both spontaneous movement-related (type 1) theta and carbachol-elicited (type 2) theta. During the postprocaine period theta frequency recovered rapidly in contrast to theta amplitude (power). This result applied to the recovery of both the coactivated type 1 and type 2 theta occurring during spontaneous movement and the carbachol-elicited type 2 theta alone. The behavioral results were discussed within the context of Bland's (Prog. Neurobiol. 26, 1-54, 1986) sensorimotor model which posits that hippocampal theta activity recorded during voluntary movement represents the coactivation of a cholinergically mediated sensory processing component and a feedback (possibly serotonergic) motor component.

Hippocampal theta field activity and theta-on/theta-off cell discharges are controlled by an ascending hypothalamo-septal pathway.

The nature of the control of hippocampal formation field activity [theta (theta) and large-amplitude irregular activity (LIA)] and theta-on/theta-off cell discharges by an ascending hypothalamo-septal pathway was investigated in urethane-anesthetized rats. Electrical stimulation of the dorsomedial-posterior hypothalamus in the range of 0.1-1.0 mA in 0.1-mA steps produced theta in the hippocampal formation, with a linear positive relation between stimulus intensity, theta frequency, and theta amplitude. Reversible blockade of the medial septal (MS)/vertical limb of the diagonal band of Broca (vDBB) region by microinjection of procaine hydrochloride abolished spontaneous and hypothalamically elicited theta, resulting in a field activity at 1-min post-procaine that had a lower power than pre-procaine LIA levels. The efficacy and recovery of the MS/vDBB suppression was tested at 1, 10, 20, 30, 40, 50, and 60 min post-procaine using 0.5, 0.8, and 1.0 mA of hypothalamic stimulation. All three of the dependent measures of hippocampal field activity (frequency, amplitude, and power) showed a progressive recovery during the 60-min post-procaine period. Frequency exhibited a rapid recovery with a shallow slope between 20 and 60 min post-procaine. In contrast, the amplitude and power of theta exhibited a gradual recovery with a steeper slope between 20 and 60 min post-procaine. During the time of maximal MS/vDBB suppression, theta-on cell discharges were reduced to 0 in most cases. The initial recovery of theta-on cells in the post-procaine condition was correlated with the first appearance of theta and was characterized by low discharge rates.(ABSTRACT TRUNCATED AT 250 WORDS)