This work describes a methodology for quantifying levels of total choline-containing compounds (tCho) in the breast using in vivo 1 H MR spectroscopy (MRS) at high field (4 Tesla). Water is used as an internal reference compound to account for the partial volume of adipose tissue. Peak amplitudes are estimated by fitting one peak at a time over a narrow frequency band to allow measurement of small metabolite resonances in spectra with large lipid peaks. This quantitative method significantly improves previously reported analysis methods by accounting for the variable sensitivity of breast 1 H MRS measurements. Using this technique, we detected and quantified a tCho peak in 214 of 500 in vivo spectra. tCho levels were found to be significantly higher in malignancies than in benign abnormalities and normal breast tissues, which suggests that this technique could be used to diagnose suspicious lesions and monitor response to cancer treatments. Breast cancer is a very common disease, affecting 11% of American women and causing more than 40000 deaths each year (1). While breast cancer mortality is decreasing, the incidence continues to rise (2). Thus, there is a great need for noninvasive diagnostic tools for both screening and treatment monitoring. The conventional diagnostics-X-ray mammography, sonography, and physical examination-are limited in their sensitivity for detecting disease and their specificity for distinguishing between benign and malignant lesions. Magnetic resonance imaging (MRI) of the breast is being used increasingly because of its high sensitivity, but its reported specificity is widely variable (3).Researchers have recently begun to augment breast MRI studies with MR spectroscopy (MRS) to increase specificity. In vivo MRS can detect a resonance at 3.25 ppm that has contributions from several different compounds, including choline, phosphocholine, glycerophosphocholine, and taurine. High-resolution in vitro and ex vivo studies indicate that the levels of choline compounds increase with malignancy (4 -6). At the lower field strengths used for in vivo work (1.5-4 T), these multiple resonances cannot be spectrally resolved and thus appear as a single peak, termed total choline-containing compounds (tCho).Several studies conducted at 1.5 T have shown that in vivo MRS can be used to distinguish between benign and malignant tissues (7-11). These studies used the hypothesis that tCho is only detectable in malignancies. A pooled analysis of these five studies showed that this tCho detectability criterion can identify malignancies with an 83% sensitivity and 85% specificity (12). This qualitative approach is promising, but it is only applicable if the MRS measurement sensitivity is invariant. In similar studies performed at 4 T, the increased sensitivity allows detection of tCho in benign lesions and normal subjects. A more general approach is to quantify the tCho peak with the expectation that tCho levels are higher in malignancies than in benign lesions or normal tissues. Two groups have reported quanti...

These results suggest that the change in tCho concentration between baseline and 24 hours after the first dose of PST can serve as an indicator for predicting clinical response to doxorubicin-based chemotherapy in locally advanced breast cancer.

Recent data indicate that T-type

Following critical evaluation of the available literature to date, The International Society of Sports Nutrition (ISSN) position regarding caffeine intake is as follows: Supplementation with caffeine has been shown to acutely enhance various aspects of exercise performance in many but not all studies. Small to moderate benefits of caffeine use include, but are not limited to: muscular endurance, movement velocity and muscular strength, sprinting, jumping, and throwing performance, as well as a wide range of aerobic and anaerobic sport-specific actions. Aerobic endurance appears to be the form of exercise with the most consistent moderate-to-large benefits from caffeine use, although the magnitude of its effects differs between individuals. Caffeine has consistently been shown to improve exercise performance when consumed in doses of 3–6 mg/kg body mass. Minimal effective doses of caffeine currently remain unclear but they may be as low as 2 mg/kg body mass. Very high doses of caffeine (e.g. 9 mg/kg) are associated with a high incidence of side-effects and do not seem to be required to elicit an ergogenic effect. The most commonly used timing of caffeine supplementation is 60 min pre-exercise. Optimal timing of caffeine ingestion likely depends on the source of caffeine. For example, as compared to caffeine capsules, caffeine chewing gums may require a shorter waiting time from consumption to the start of the exercise session. Caffeine appears to improve physical performance in both trained and untrained individuals. Inter-individual differences in sport and exercise performance as well as adverse effects on sleep or feelings of anxiety following caffeine ingestion may be attributed to genetic variation associated with caffeine metabolism, and physical and psychological response. Other factors such as habitual caffeine intake also may play a role in between-individual response variation. Caffeine has been shown to be ergogenic for cognitive function, including attention and vigilance, in most individuals. Caffeine may improve cognitive and physical performance in some individuals under conditions of sleep deprivation. The use of caffeine in conjunction with endurance exercise in the heat and at altitude is well supported when dosages range from 3 to 6 mg/kg and 4–6 mg/kg, respectively. Alternative sources of caffeine such as caffeinated chewing gum, mouth rinses, energy gels and chews have been shown to improve performance, primarily in aerobic exercise. Energy drinks and pre-workout supplements containing caffeine have been demonstrated to enhance both anaerobic and aerobic performance.

Recent studies have demonstrated a previously unrecognized contribution of T-type Ca 2ϩ channels in peripheral sensory neurons to pain sensation (nociception). However, the cellular mechanisms underlying the functions of these channels in nociception are not known. Here, in both acutely dissociated and intact rat dorsal root ganglion neurons, we characterize a novel subpopulation of capsaicin-and isolectin B 4 -positive nociceptors that also expresses a high density of T-type Ca 2ϩ currents. Using these "T-rich" cells as a model, we demonstrate that the endogenous reducing agent L-cysteine lowers the threshold for nociceptor excitability and induces burst firing by increasing the amplitude of T-type currents and shifting the gating parameters of T-type channels. These findings, which provide the first direct evidence of T-type Ca 2ϩ channel involvement in the control of nociceptor excitability, suggest that endogenous T-type channel agonists may sensitize a unique subpopulation of peripheral nociceptors, consequently influencing pain processing under normal or pathological conditions.

Recent studies have demonstrated an important role for T-type Ca2ϩ channels (T-channels) in controlling the excitability of peripheral pain-sensing neurons (nociceptors). However, the molecular mechanisms underlying the functions of T-channels in nociceptors are poorly understood. Here, we demonstrate that reducing agents as well as endogenous metal chelators sensitize C-type dorsal root ganglion nociceptors by chelating Zn 2ϩ ions off specific extracellular histidine residues on Ca v 3.2 T-channels, thus relieving tonic channel inhibition, enhancing Ca v 3.2 currents, and lowering the threshold for nociceptor excitability in vitro and in vivo. Collectively, these findings describe a novel mechanism of nociceptor sensitization and firmly establish reducing agents, as well as Zn 2ϩ , Zn 2ϩ -chelating amino acids, and Zn 2ϩ -chelating proteins as endogenous modulators of Ca v 3.2 and nociceptor excitability.

Earlier, we showed that streptozocin (STZ)-induced type 1 diabetes in rats leads to the development of painful peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia and mechanical allodynia accompanied by significant enhancement of T-type calcium currents (T-currents) and cellular excitability in medium-sized dorsal root ganglion (DRG) neurons. Here, we studied the in-vivo and in-vitro effects of gene-silencing therapy specific for the Cav3.2 isoform of T-channels, on thermal and mechanical hypersensitivity, and T-current expression in small and medium-size DRG neurons of STZ-treated rats. We found that silencing of the T-channel Cav3.2 isoform using antisense oligonucleotides, had a profound and selective anti-hyperalgesic effect in diabetic rats and is accompanied by significant down-regulation of T-currents in DRG neurons. Anti-hyperalgesic effects of CaV3.2 antisense oligonucleotides in diabetic rats were similar in models of rapid and slow onset of hyperglycemia following intravenous and intraperitoneal injections of STZ, respectively. Furthermore, treatments of diabetic rats with daily insulin injections reversed T-current alterations in DRG neurons in parallel with reversal of thermal and mechanical hypersensitivity in-vivo. This confirms that CaV3.2 T-channels, important signal amplifiers in peripheral sensory neurons, may contribute to the cellular hyperexcitability that ultimately leads to the development of painful PDN.

Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. To address this issue, we studied the expression of T-type Ca2+ currents in small nociceptive dorsal root ganglion (DRG) cells from L4-5 spinal ganglia of adult rats with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve. In control rats, whole cell recordings revealed that T-type currents, measured in 10 mM Ba2+ as a charge carrier, were present in moderate density (20 +/- 2 pA/pF). In rats with CCI, T-type current density (30 +/- 3 pA/pF) was significantly increased, but voltage- and time-dependent activation and inactivation kinetics were not significantly different from those in controls. CCI-induced neuropathy did not significantly change the pharmacological sensitivity of T-type current in these cells to nickel. Collectively, our results indicate that CCI-induced neuropathy significantly increases T-type current expression in small DRG neurons. Our finding that T-type currents are upregulated in a CCI model of peripheral neuropathy and earlier pharmacological and molecular studies suggest that T-type channels may be potentially useful therapeutic targets for the treatment of neuropathic pain associated with partial mechanical injury to the sciatic nerve.