Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Transfer Entropy in Artificial and Cardiovascular Environment in Stress.

The paper examines the influence of acute and chronic stress on the relationship between systolic blood pressure (SBP) and pulse interval (PI) recorded from laboratory rats with different genetic predispositions for the development of the hypertensive disease. Transfer entropy (TE) was used to examine the direction of information flow between SBP and PI, spontaneous baroreflex sensitivity (BRS) was used to evaluate the ability of adaptation of PI time series to changes in SBP, and the cross-approximate entropy (XApEn) to quantify the SBP-PI synchronization. The effects of the time series length on TE estimation was also investigated in an artificial environment for the time series without a strong causal relation. The consistency of the TE estimation was achieved only for extremely long time series. The results showed that chronic stress influence on the increase in information transmission between SBP and PI (TE) while changes of (BRS) and XApEn were not noticed.

Heart rate dynamics in doxorubicin-induced cardiomyopathy.

The clinical use of doxorubicin, an effective chemotherapeutic is hampered by the development of irreversible cardiotoxicity. Here we test time-frequency analysis of heart rate (HR) variability (HRV) for early detection of doxorubicin-induced cardiotoxicity. Experiments were conducted in adult male Wistar rats treated for 15 days with doxorubicin (DOXO, total dose 15 mg kg(-1), i.p.) or saline (CONT). DOXO rats exhibited cardiotoxicity confirmed by histological examination without developing heart failure as estimated by echocardiography. However, HR variability increase reflected subtle microscopic changes of cardiac toxicity in DOXO rats. The results recommend time-frequency analysis of HRV for early detection of doxorubicin-induced cardiomyopathy.

Periaqueductal gray neuroplasticity following chronic morphine varies with age: role of oxidative stress.

The development of tolerance to the antinociceptive effects of morphine has been associated with networks within ventrolateral periaqueductal gray (vlPAG) and separately, nitric oxide signaling. Furthermore, it is known that the mechanisms that underlie tolerance differ with age. In this study, we used a rat model of antinociceptive tolerance to morphine at two ages, postnatal day (PD) 7 and adult, to determine if changes in the vlPAG related to nitric oxide signaling produced by chronic morphine exposure were age-dependent. Three pharmacological groups were analyzed: control, acute morphine, and chronic morphine group. Either morphine (10mg/kg) or equal volume of normal saline was given subcutaneously twice daily for 6½ days. Animals were analyzed for morphine dose-response using Hot Plate test. The expression of several genes associated with nitric oxide metabolism was evaluated using rtPCR. In addition, the effect of morphine exposure on immunohistochemistry for Fos, and nNOS as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) reaction at the vlPAG were measured. In both age groups acute morphine activated Fos in the vlPAG, and this effect was attenuated by chronic morphine, specifically in the vlPAG at the level of the laterodorsal tegmental nucleus (LDTg). In adults, but not PD7 rats, chronic morphine administration was associated with activation of nitric oxide function. In contrast, changes in the gene expression of PD7 rats suggested superoxide and peroxide metabolisms may be engaged. These data indicate that there is supraspinal neuroplasticity following morphine administration as early as PD7. Furthermore, oxidative stress pathways associated with chronic morphine exposure appear age-specific.

Ultrastructural analysis of rat ventrolateral periaqueductal gray projections to the A5 cell group.

Stimulation of neurons in the ventrolateral periaqueductal gray (PAG) produces antinociception as well as cardiovascular depressor responses that are mediated in part by pontine noradrenergic neurons. A previous report using light microscopy has described a pathway from neurons in the ventrolateral PAG to noradrenergic neurons in the A5 cell group that may mediate these effects. The present study used anterograde tracing and electron microscopic analysis to provide more definitive evidence that neurons in the ventrolateral PAG form synapses with noradrenergic and non-catecholaminergic A5 neurons in Sasco Sprague-Dawley rats. Deposits of anterograde tracer, biotinylated dextran amine, into the rat ventrolateral PAG labeled a significant number of axons in the region of the rostral subdivision of the A5 cell group, and a relatively lower number in the caudal A5 cell group. Electron microscopic analysis of anterogradely-labeled terminals in both rostral (n=127) and caudal (n=70) regions of the A5 cell group indicated that approximately 10% of these form synapses with noradrenergic dendrites. In rostral sections, about 31% of these were symmetric synapses, 19% were asymmetric synapses, and 50% were membrane appositions without clear synaptic specializations. In caudal sections, about 22% were symmetric synapses, and the remaining 78% were appositions. In both rostral and caudal subdivisions of the A5, nearly 40% of the anterogradely-labeled terminals formed synapses with non-catecholaminergic dendrites, and about 45% formed axoaxonic synapses. These results provide direct evidence for a monosynaptic pathway from neurons in the ventrolateral PAG to noradrenergic and non-catecholaminergic neurons in the A5 cell group. Further studies should evaluate if this established monosynaptic pathway may contribute to the cardiovascular depressor effects or the analgesia produced by the activation of neurons in the ventrolateral PAG.

Asymmetric development of the hippocampal region is common: a fetal MR imaging study.

BACKGROUND AND PURPOSE: Hippocampal development is poorly understood. This study evaluated the normal development of the hippocampal region during the fetal period by using MR imaging. MATERIALS AND METHODS: MR images of 63 fetuses without intracranial pathology were reviewed independently by 2 radiologists with no knowledge of the fetal GA. Three MR images were performed postmortem and 60 in vivo. The progress of hippocampal inversion was analyzed in coronal sections, and the left and right sides of the hippocampal region were compared in every case. RESULTS: The fetuses in the postmortem examinations were at GWs 17-18 and in the in vivo examinations, at GWs 19-36. The hippocampal sulcus was open, bi- or unilaterally, in 39 fetuses. The oldest was at GW 32. The sulcus was closed at GW 21 at the earliest, unilaterally. In 26/63 fetuses (41%), the deepening or closure of the hippocampal sulcus or hippocampal inversion was asymmetric; in 23 fetuses, the right side developed faster. A shallow collateral sulcus was found earliest at GW 17. A deep collateral sulcus was visible earliest at GW 26 unilaterally, but in all fetuses from GW 31 onward, it was seen bilaterally. The orientation of the collateral sulcus was not related to the GA. CONCLUSIONS: There are wide individual temporal variations in the development and the inversion process of the hippocampal sulcus as well as in the formation of the collateral sulcus. Asymmetric development is common, and in most of the asymmetric cases, the right hippocampus develops faster.

Development of the hippocampal region demonstrated by fetal MRI. A preliminary report.

Coronal slices of three fetal MRIs performed post mortem and 37 performed in utero, all without intracranial pathology, was assessed. Progress of the hippocampal inversion was analyzed, the left and right sides were compared and occurrence of the collateral sulcus was revealed. The fetuses in the post mortem examinations were at gestation weeks (GW) 17-18 and in the in utero examinations at GW 19-35. The symmetric development of the hippocampal sulcus was revealed in 26 subjects and asymmetric in 14. The non-ovoid hippocampal formation could be evaluated at GW 24 at earliest and an ovoid hippocampus at GW 29. The collateral sulcus could be recognized at GW 17 in post mortem and at GW 22 in in utero examinations. From GW 29 onwards it was seen in all fetuses and it was symmetric in all but one case. Evaluation of the hippocampi is difficult on fetal MRI, especially in in utero examinations. The hippocampal development is not fulfilled at GW 21 as presumed. There is a wide temporal variation in the development of the hippocampal region, and the developmental process does not progress simultaneously in the right and left side of the same individual.

Acute noxious stimulation modifies morphine effect in serotonergic but not dopaminergic midbrain areas.

It is poorly understood if and how pain may modify the effect of opioids on neural systems that contribute to reward and addictive behavior. We hypothesized that the activation of ascending dopaminergic and serotonergic nuclei by morphine is modified by the presence of noxious stimulation. Immunohistochemical double-labeling technique with Fos was used to examine if an intraplantar formalin injection, an acute noxious input, changed the effect of morphine on dopaminergic neurons of the ventral tegmental area (VTA), and serotonergic neurons of the dorsal raphe nucleus (DR). Four groups of rats were analyzed: (1) control injected with normal saline s.c., (2) rats treated with formalin into the hind paw 30 min after normal saline injection, (3) rats injected with morphine sulfate s.c., and (4) rats treated with formalin into the hind paw 30 min after morphine injection (morphine/formalin). Following morphine injection, there was an increase in the number of dopaminergic neurons in the VTA with Fos immunolabeling. However, noxious stimulation did not detectably change morphine's effect on Fos expression in VTA dopamine neurons. In contrast, the number of serotonergic neurons containing Fos was increased in the morphine/formalin group compared to all other groups and this effect was topographically selective for the dorsal area of the DR at mid rostro-caudal levels. Therefore, morphine's activation of the VTA, which is associated with motivated behavior and reward seeking, appears similar in the context of pain. However, activation of the ascending serotonin system, which influences mood and has the capacity to modify reward pathways, appears different. In addition, these findings reveal interactions between nociceptive signaling and opioids that contrasts with the notion that opioids simply block access of nociceptive signaling to supraspinal structures.

Effects of orexin (hypocretin) on GIRK channels.

Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress G-protein-coupled inward rectifier (GIRK) channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and the nucleus tuberomammillaris (TM) were used, as well as HEK293A cells transfected with GIRK1 and 2, either human orexin receptor type 1 (OX1R) or type 2 (OX2R), mu opioid receptor and GFP cDNAs. In GTPgammaS-loaded cells, orexin A (OXA, 3 microM) inhibited GIRK currents that had previously been activated by somatostatin (in LC cells), nociceptin (TM cells), or the mu opioid agonist DAMGO (HEK cells). In guanosine triphosphate (GTP)-loaded HEK cells, in which GIRK currents were not preactivated, OXA induced a biphasic response through both types of orexin receptors: an initial current increase and a subsequent decrease to below resting levels. Current-voltage (I-V) relationships revealed that both the OXA-induced and suppressed currents are inwardly rectifying with reversal potentials around EK. The OXA-induced initial current was partially pertussis toxin (PTX) sensitive and partially PTX insensitive, whereas the OXA-suppressed current was PTX insensitive. These data suggest that orexin receptors couple with more than one type of G-protein, including PTX-sensitive (such as Gi/o) and PTX-insensitive (such as Gq/11) G-proteins. The modulation of GIRK channels by orexins may be one of the cellular mechanisms for the regulation of brain nuclei (e.g., LC and TM) that are crucial for arousal, sleep, and appetite.

Two different inward rectifier K+ channels are effectors for transmitter-induced slow excitation in brain neurons.

Substance P (SP) excites large neurons of the nucleus basalis (NB) by inhibiting an inward rectifier K(+) channel (Kir). The properties of the Kir in NB (KirNB) in comparison with the G protein-coupled Kir (GIRK) were investigated. Single-channel recordings with the cell-attached mode showed constitutively active KirNB channels, which were inhibited by SP. When the recording method was changed from the on-cell to the inside-out mode, the channel activity of KirNB remained intact with its constitutive activity unaltered. Application of Gbeta(1gamma2) to inside-out patches induced activity of a second type of Kir (GIRK). Application of Gbeta(1gamma2), however, did not change the KirNB activity. Sequestering Gbeta(1gamma2) with Galpha(i2) abolished the GIRK activity, whereas the KirNB activity was not affected. The mean open time of KirNB channels (1.1 ms) was almost the same as that of GIRKs. The unitary conductance of KirNB was 23 pS (155 mM [K(+)](o)), whereas that of the GIRK was larger (32-39 pS). The results indicate that KirNB is different from GIRKs and from any of the classical Kirs (IRKs). Whole-cell current recordings revealed that application of muscarine to NB neurons induced a GIRK current, and this GIRK current was also inhibited by SP. Thus, SP inhibits both KirNB and GIRKs. We conclude that the excitatory transmitter SP has two types of Kirs as its effectors: the constitutively active, Gbetagamma-independent KirNB channel and the Gbetagamma-dependent GIRK.

Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus.

Peripheral sympathetic nerves and brainstem noradrenergic neurons of the locus coeruleus (LC) respond in parallel to a variety of stress-related stimuli which results in norepinephrine release both peripherally and centrally. Elucidation of central pathways subserving modulation of LC neurons point to extranuclear noradrenergic dendrites of LC somata that extend into peri-coerulear areas as a major target of afferents that participate in behavioral and physiological responses to stress. Anterograde tract tracing combined with immunoelectron microscopic detection of the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) has demonstrated that the nucleus of the solitary tract (NTS) and the ventrolateral aspect of the periaqueductal gray (PAG), regions that participate in coordinating autonomic and motor behavior in response to stress, preferentially target the rostral ventromedial aspect of the peri-LC. In contrast, limbic forebrain afferents including the central nucleus of the amygdala (CNA) and the bed nucleus of the stria terminalis (BNST), regions that coordinate emotional responses to external stressors, provide direct synaptic input to noradrenergic dendrites that extend into rostral dorsolateral peri-coerulear areas. Neurochemical identification of transmitter systems impinging on LC indicate that the CNA provides corticotropin-releasing factor (CRF), a peptide essential for integrated physiological responses to stress, to the dorsolateral LC. Endogenous opioid peptides that originate from medullary sources, however, target primarily the "core" of the LC. Our physiological data suggest that stress engages CRF and opioid afferents to the LC, which have opposing influences on this noradrenergic system. The balance between opioid and CRF influences acting in the LC may, in part, maintain the balance of active and passive coping behaviors in response to stress. Understanding the afferent and neurochemical organization of the LC may help elucidate adaptations in neural circuits associated with stress which impact on central noradrenergic function.

Ultrastructural analysis of ventrolateral periaqueductal gray projections to the A7 catecholamine cell group.

Stimulation of neurons in the ventrolateral periaqueductal gray produces antinociception that is mediated in part by pontine noradrenergic neurons. Previous light microscopic analysis provided suggestive evidence for a direct projection from neurons in the ventrolateral periaqueductal gray to noradrenergic neurons in the A7 cell group that innervate the spinal cord dorsal horn. Therefore, the present ultrastructural study used anterograde tracing combined with tyrosine hydroxylase immunoreactivity to provide definitive evidence that neurons in the ventrolateral periaqueductal gray form synapses with the somata and dendrites of noradrenergic neurons of the A7 cell group. Injections of the anterograde tracers biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin into the ventrolateral periaqueductal gray of Sasco Sprague-Dawley rats yielded a dense innervation in the region of the lateral pons containing the A7 cell group. Electron microscopic analysis of anterogradely labeled terminals (n=401) in the region of the A7 cell group indicated that approximately 10% of these formed plasmalemmal appositions to tyrosine hydroxylase-immunoreactive dendrites with no intervening astrocytic processes. About 23% of these were asymmetric synapses, 10% were symmetric synapses, and 67% did not exhibit clearly differentiated synaptic specializations. The majority of anterogradely labeled terminals (60%) formed plasmalemmal appositions with dendrites and somata that lacked detectable tyrosine hydroxylase immunoreactivity. About 35% of these were symmetric synapses, 9% were asymmetric synapses and 56% did not form synaptic specializations. Approximately 30% of all anterogradely labeled terminals displayed features characteristic of axo-axonic synapses.The present results provide direct ultrastructural evidence to support the hypothesis that the analgesia produced by stimulation of neurons in the ventrolateral periaqueductal gray is mediated, in part, by activation of spinally projecting noradrenergic neurons in the A7 catecholamine cell group.

Periaqueductal gray neurons monosynaptically innervate extranuclear noradrenergic dendrites in the rat pericoerulear region.

Previous reports using light microscopy have provided anatomical evidence that neurons in the ventrolateral periaqueductal gray (PAG) innervate the medial pericoerulear dendrites of noradrenergic neurons in the nucleus locus coeruleus (LC). The present study used anterograde tracing and electron microscopic analysis to provide more definitive evidence that neurons in the ventrolateral PAG form synapses with the somata or dendrites of noradrenergic LC neurons. Deposits of either biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin into the rat ventrolateral PAG labeled a moderate to high number of axons in the region of the medial pericoerulear region and Barrington's nucleus, but a relatively low number were labeled in the nuclear core of the LC. Ultrastructural analysis of anterogradely labeled terminals at the levels of the rostral (n = 233) and caudal (n = 272) subdivisions of the LC indicated that approximately 20% of these form synapses with tyrosine hydroxylase-immunoreactive dendrites; most of these were located in the medial pericoerulear region. In rostral sections, about 12% of these were symmetric synapses, 9% were asymmetric synapses, and 79% were membrane appositions without clear synaptic specializations. In caudal sections, about 30% were symmetric synapses, 11% were asymmetric synapses, and 59% were appositions. In both rostral and caudal sections, 60% of the anterogradely labeled terminals formed synapses with noncatecholamine dendrites, and 20% formed axoaxonic synapses. These results provide direct evidence for monosynaptic projections from neurons in the ventrolateral PAG to the extranuclear dendrites of noradrenergic LC neurons. This monosynaptic pathway may mediate in part the analgesia, reduced responsiveness to external stimuli, and decreased excitability of somatic motoneurons produced by stimulation of neurons in the ventrolateral PAG.

Infantile hemangioendothelioma. A case report.

The case of a 3-month-old boy with a hepatic infantile hemangioendothelioma is reported. There was no previous history of disease and no symptoms, only an incidentally found abdominal mass. The case is presented as an example of establishing the diagnosis, deciding upon the treatment, and performing the follow-up using only non-invasive imaging techniques.

Preclinical evaluation of benzoporphyrin derivative combined with a light-emitting diode array for photodynamic therapy of brain tumors.

OBJECTIVE: The aim of this study was to investigate the second-generation photosensitizer benzoporphyrin derivative (BPD) and a novel light source applicator based on light-emitting diode (LED) technology for photodynamic therapy (PDT) of brain tumors. METHODS: We used a canine model to investigate normal brain stem toxicity. Twenty-one canines underwent posterior fossa craniectomies followed by PDT with BPD. These animals were compared to light only and BPD control. In addition, we investigated the ability of BPD and LED to cause inhibition of cell growth in canine glioma and human glioma cell lines, in vitro. The biodistribution of BPD labeled with 111In-BPD in mice with subcutaneous and intracerebral gliomas and canines with brain tumors was studied. RESULTS: The in vivo canine study resulted in a maximal tolerated dose of 0.75 mg/kg of BPD and 100 J/cm(2) of LED light for normal brain tissue. The in vitro study demonstrated 50% growth inhibition for canine and human glioma cell lines of 10 and 4 ng/ml, respectively. The mucine study using 111In-BPD showed a tumor to normal tissue ratio of 12:1 for intracerebral tumors and 3.3:1 for subcutaneous tumors. Nuclear scans of canines with brain tumors showed uptake into tumors to be maximal from 3 to 5 h. CONCLUSION: Our study supports that BPD and LED light sources when used at appropriate drug and light doses limit normal brain tissue toxicity at doses that can cause significant glioma cell toxicity in vitro. In addition, there is higher BPD uptake in brain tumors as compared to normal brain in a mouse glioma model. These findings make BPD a potential new-generation photosensitizer for the treatment of childhood posterior fossa tumors as well as other malignant cerebral pathology.

Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception.

Stimulation of neurons in the periaqueductal gray (PAG) produces antinociception that is mediated in part by noradrenergic neurons that innervate the spinal cord dorsal horn. Because norepinephrine-containing neurons are not found in the PAG, noncatecholamine neurons in the PAG must project to, and activate, spinally projecting catecholamine neurons located in the pons or medulla. The present studies determined the projections of neurons in the ventrolateral PAG to the A5, A6 (locus coeruleus), and A7 catecholamine cell groups that are known to contain spinally projecting noradrenergic neurons. The anterograde tracer biotinylated dextran amine (BDA) was injected into the ventrolateral PAG, and labeled axon terminal profiles were identified near noradrenergic neurons that were visualized by processing tissue sections for tyrosine hydroxylase immunoreactivity. Highly varicose, anterogradely labeled terminal profiles were found apposed to the dendrites and somata of tyrosine-hydroxylase-immunoreactive neurons and non-tyrosine-hydroxylase-immunoreactive neurons in the dorsolateral and ventrolateral pontine tegmentum. These axon terminal profiles were more dense on the side ipsilateral to the BDA deposit, and both A7 and locus coeruleus neurons received a more dense innervation than did the A5 neurons. Although definitive evidence for a direct pathway from PAG neurons to spinally projecting A7 neurons requires ultrastructural studies, the results of the present studies provide presumptive evidence for direct projections from neurons in the PAG to noradrenergic A7 neurons that innervate the spinal cord dorsal horn and modulate pain perception. If neurons in the ventrolateral PAG do form synapses with noradrenergic A7 neurons, these spinally projecting catecholamine neurons may mediate part of the analgesic effect produced by systemic administration of morphine. In contrast, the projections of PAG neurons to the A5 cell group and the locus coeruleus may mediate the cardiovascular and motor effects produced by stimulation of sites in the ventrolateral PAG.

Use of cytochrome-P450 mono-oxygenase 2 E1 isozyme inhibitors to delay seizures caused by central nervous system oxygen toxicity.

BACKGROUND: The neuronal origins and mechanisms of central nervous system oxygen toxicity are only partly understood. Oxygen free radicals are felt to play a major role in the production of CNS oxygen toxicity because of the interactions of free radicals with plasma membranes producing lipid peroxidation. The cytochrome P-450 monooxygenase system IIE1 isozyme is important in the brain. This led to trials of P450 monooxygense inhibitors for prevention of oxygen toxicity. Diethyldithiocarbonate (DDC) proved to be the most promising agent in this class; 21-aminosteroid lazeroid compounds have been successful in experimentally limiting pulmonary oxygen toxicity. This led to our trying to prevent neuronal oxygen toxicity by the use of 21-aminosteroid and six other drugs during hyperoxia. METHODS: In our experiments, mice were placed in an oxygen-filled hyperbaric chamber in paired experiments. One pre-treated mouse and one control mouse were exposed simultaneously to assess the efficacy of drugs in preventing seizures caused by hyperbaric oxygen at 5.1 atmospheres absolute. Time to seizure was observed through a port hole in the hull of the hyperbaric chamber. RESULTS: DDC, 21-aminosteroid and propranolol produced significant delays in the onset of seizures (p < 0.001) with no observable side effects; 1-aminobenzotriazole and disulfiram produced much shorter delays in the onset of seizures caused by hyperbaric oxygen and also had unacceptable side effects.

Light-emitting diodes as a light source for intraoperative photodynamic therapy.

The development of more cost-effective light sources for photodynamic therapy of brain tumors would be of benefit for both research and clinical applications. In this study, the use of light-emitting diode arrays for photodynamic therapy of brain tumors with Photofrin porfimer sodium was investigated. An inflatable balloon device with a light-emitting diode (LED) tip was constructed. These LEDs are based on the new semiconductor aluminum gallium arsenide. They can emit broad-spectrum red light at high power levels with a peak wavelength of 677 nm and a bandwidth of 25 nm. The balloon was inflated with 0.1% intralipid, which served as a light-scattering medium. Measurements of light flux at several points showed a high degree of light dispersion. The spectral emission of this probe was then compared with the absorption spectrum of Photofrin. This analysis showed that the light absorbed by Photofrin with the use of the LED source was 27.5% of that absorbed with the use of the monochromatic 630-nm light. Thus, to achieve an energy light dose equivalent to that of a laser light source, the LED light output must be increased by a factor of 3.63. This need for additional energy is the difference between a 630- and 677-nm absorption of Photofrin. Using the LED probe and the laser balloon adapter, a comparison of brain stem toxicity in canines was conducted. LED and laser light showed the same signs of toxicity at equivalent light energy and Photofrin doses. The maximal tolerated dose of Photofrin was 1.6 mg/kg, using 100 J/cm2 of light energy administered by laser or LED. This study concludes that LEDs are a suitable light source for photodynamic therapy of brain tumors with Photofrin. In addition, LEDs have the potential to be highly efficient light sources for second-generation photosensitizers with absorption wavelengths closer to the LED peak emission.

Gallium nitrate delays the progression of microscopic disease in a human medulloblastoma murine model.

The goal of adjuvant chemotherapy is to treat postoperative microscopic disease in the hope of preventing tumor recurrence and/or metastasis. Since the introduction of chemotherapeutic agents, the disease-free survival of children with medulloblastoma has improved only modestly. Therefore, there is a need to develop and investigate new chemotherapeutic agents for this malignancy. Gallium nitrate has demonstrated significant antineoplastic activity toward human medulloblastoma in vitro and in vivo and may prove to be an optimal chemotherapeutic agent in treating medulloblastoma microscopic disease. The present study consisted of injecting medulloblastoma Daoy intradermally into both flanks of nude mice. A 15-day 50-mg/kg/day regimen was implemented the day after tumor inoculation. All treated and control mice received saline hyperhydration during the treatment period. The interval between tumor cell inoculation and first measurable tumor detection, tumor occurrence, growth rate, and size were recorded. Results indicated that gallium nitrate significantly prolonged the interval between tumor cell inoculation and measurable tumor detection.