Visual disturbances and migraine

There is a close relationship between headache and the visual system. Visual symptoms are prominent features of clinical syndromes such as migraine, cluster headache, and the trigeminal autonomic cephalgias. There are also strong links between headache and the visual system on the basis of genetics, molecular biology, neurophysiology, and neuroimaging. Studies of these links are leading to the development of novel therapies for a variety of headache syndromes. This review is designed to summarize the most recent literature on headache and the visual system. A particular emphasis is placed on publications of interest to clinicians.     

Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice

In this study, human T cells were provided with a reactivity against the Lewis-Y (Le(Y)) carbohydrate antigen, which is overexpressed on 70% of epithelial-derived tumors, but not normally recognized by T cells. Antitumor reactivity was achieved by transduction of T cells with a gene encoding a cell-surface chimeric receptor composed of single-chain anti-Le(Y) antibody linked to an enhanced cytoplasmic signaling domain made up of CD28 and CD3-zeta. Importantly, the single-chain antibody was humanized to try to reduce potential problems of human anti-mouse antibody responses in patients receiving chimeric receptor-modified T cells in future clinical trials. T cells expressing the chimeric receptor were demonstrated to secrete cytokines and proliferate in response to receptor ligation and lysed Le(Y+) tumors in vitro. Another aspect of this study was the finding that no activity was observed against normal tissue, as represented by autologous neutrophils that express low levels of Le(Y). Significantly, systemic delivery of anti-Le(Y) T cells dramatically inhibited established s.c. human ovarian OVCAR-3 tumors (a recognized difficult model to treat) in mice. Finally, we demonstrated that anti-Le(Y) T cells preferentially expanded or accumulated in the tumor compared with control empty vector T cells, thereby providing mechanistic insight into the specific antitumor response. This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies.     

H215O PET study of impairment of nonverbal recognition with normal aging

Little research has been conducted regarding age-related changes in nonverbal memory. Using positron emission tomography (PET), the authors studied 17 elderly volunteers and 20 young volunteers, during nonverbal recognition task performance, to examine differences in brain blood flow. The subjects were asked to recognize a study list size (SLS) of shapes that was adjusted so that each subject performed at approximately 75% accuracy. Positron emission tomography results showed that, relative to younger individuals, elderly subjects engaged different regions, including the insula, during recognition. Elderly subjects did not show the relationship between parahippocampal flow and SLS, which was observed in younger subjects. These differences suggest that age-related functional brain changes partly explain performance deficits.     

B(1) destructive interferences and spatial phase patterns at 7 T with a head transceiver array coil.

RF behavior in the human head becomes complex at ultrahigh magnetic fields. A bright center and a weak periphery are observed in images obtained with volume coils, while surface coils provide strong signal in the periphery. Intensity patterns reported with volume coils are often loosely referred to as "dielectric resonances," while modeling studies ascribe them to superposition of traveling waves greatly dampened in lossy brain tissues, raising questions regarding the usage of this term. Here we address this question experimentally, taking full advantage of a transceiver coil array that was used in volume transmit mode, multiple receiver mode, or single transmit surface coil mode. We demonstrate with an appropriately conductive sphere phantom that destructive interferences are responsible for a weak B(1) in the periphery, without a significant standing wave pattern. The relative spatial phase of receive and transmit B(1) proved remarkably similar for the different coil elements, although with opposite rotational direction. Additional simulation data closely matched our phantom results. In the human brain the phase patterns were more complex but still exhibited similarities between coil elements. Our results suggest that measuring spatial B(1) phase could help, within an MR session, to perform RF shimming in order to obtain more homogeneous B(1) in user-defined areas of the brain.     

Limitations on upper bound dose to adults due to intake of 129I in drinking water and a total diet-implications relative to the proposed Yucca Mountain high level radioactive waste repository

The purpose of this report is to comment on the potential annual doses due to the intake by adults of I, an important radionuclide in the proposed high-level radioactive waste repository at Yucca Mountain. An often overlooked, but significant, factor is that, in this case, the ground water, which would be the primary transport vehicle for any releases, contains relatively high concentrations of stable iodine (127I); in fact, the median concentration in the ground water in the vicinity of the proposed repository is 5.0 microg L-1. In comparison, the maximum concentration of 129I in the ground water, due to potential releases of 129I during the first 10,000 y following closure of the repository, is estimated to be approximately 3.7 x 10(-7) Bq L-1 (approximately 10(-5) pCi L-1). This would result in a 127I to 129I ratio in the water of almost 90 million to one. Assuming no other sources of these two isotopes were being consumed, this would place an upper bound on the annual committed thyroid dose of 1.2 x 10(-1) mSv (1.2 x 10(-1) mrem), less than one thousandth of the Ground Water Protection Standard of 4 mrem y-1. When the additional intake of stable and radioactive iodine in other components of the diet is considered, the overall ratio of 127I to 129I would be more than 2 billion to one. The would place an upper bound on the annual committed effective dose of approximately 2.5 x 10(-8) mSv (approximately 2.5 x 10(-6) mrem), less than one millionth of the Individual Protection Standard of 0.15 mSv (15 mrem).     

Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects

AIM: The primary objective of this interaction study was to confirm preclinical data suggesting that moxifloxacin is not metabolized by CYP 450 isozymes. Itraconazole, a strong CYP 3A4 inhibitor, was used as comedication. METHODS: Twelve healthy male subjects were enrolled in this randomized study using 400 mg of oral moxifloxacin (MXF) administered alone and on the 7th day of a 9-day treatment regimen with itraconazole (ITR) 200 mg p.o., o.d. In addition to the assessment of safety and tolerability, non-compartmental pharmacokinetics of moxifloxacin, itraconazole and their respective metabolites were analyzed using plasma concentrations obtained using HPLC. RESULTS: All treatment regimens were safe and well-tolerated. No interaction with itraconazole was observed for moxifloxacin (relative bioavailability: 111.6% (90% CI 106.5 to 117.0%), C(max) ratio: 103.7% (84.8-126.9%) and its sulfometabolite (Ml) (AUC ratio: 107.7% (95.6, 121.4%), C(max) ratio: 105.8% (89.9-124.5%)). There was a 30% decrease in AUC with M2 moxifloxacin metabolite (glucuronide) accompanied by an approximately 54% increase in renal excretion, which may be due to changes in phase 2 metabolism and/or transport mechanisms altered by itraconazole. Exposure (AUC) to itraconazole and its hydroxymetabolite were marginally altered by moxifloxacin (AUC +5% for itraconazole and -5% for hydroxy-itraconazole (OH-ITR)) indicating the absence of a clinically relevant influence of moxifloxacin on itraconazole. Mean peak concentrations in plasma (C(max)) were reduced for ITR and OH-ITR by approximately 14% and 18%, respectively, when administered concomitantly with moxifloxacin. This was attributed to the sensitivity of itraconazole absorption to changes in gastric physiology (pH, gastric transit, administration after fasting) and was deemed as clinically irrelevant. CONCLUSION: Results of this study indicate that moxifloxacin is not a substrate for CYP 450 3A4 isozymes confirming previous preclinical in vitro data. Moxifloxacin can therefore be safely coadministered with CYP 3A4 inhibitors without the need for dose adjustment. No clinically relevant changes in the pharmacokinetics of itraconazole were observed during the study.     

Combination therapy in Alzheimer's disease: a review of current evidence

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.     

Behavioral impulsivity paradigms: a comparison in hospitalized adolescents with disruptive behavior disorders

BACKGROUND: Behavioral impulsivity paradigms vary widely and studies using these measures have typically relied on a single measure used in isolation. As a result, comparisons between measures are difficult, with little consensus regarding which method may be most sensitive to individual impulsivity differences of different populations. METHOD: A single testing session of each of four different impulsivity tasks was completed by two groups of adolescents aged 13-17: hospitalized inpatients with disruptive behavior disorders (DBD; n = 22) and controls (n = 22). Tasks included two rapid-decision (IMT/DMT and GoStop) and two reward-directed (TC and SKIP) impulsivity paradigms. Behavioral testing took place within 3 days of hospitalization for the adolescents with DBD. RESULTS: Compared to controls, the DBD group exhibited higher commission error rates, lower inhibited response rates after a stop-signal, and twice as many reward-directed responses even after IQ differences between the groups were taken into account. When the four paradigms were compared, effect-size calculations indicated that the two rapid-decision paradigms were more sensitive to group differences than the reward-directed tasks. CONCLUSIONS: Despite the initiation of pharmacotherapy within the first 3 days of hospitalization, in contrast to the control group, the adolescents with DBD performed consistently with what has been operationally defined as impulsivity. Based on these results, these tasks appear to measure similar, but unique components of the impulsivity construct. With further study, laboratory behavioral paradigms may prove to be useful additions to current clinical diagnostic and treatment procedures in a variety of psychiatric populations.