Visual methods to assess cold fingers and experimental verification.

Cold fingers is complaint of many people. To independently assess actual finger temperature, this paper uses prototype sensors to capture blood vessel width and blood flow rates. We verify their feasibility for future home healthcare use along with far infrared camera outputs. We elucidate the impact of three remedies, massage, hot cocoa, and shoulder exercises, on 7 subjects.

Long-term complete remission of multiple extranodal natural killer/T-cell-type posttransplant lymphoproliferative disorder after surgical resection: a case report.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of organ transplantation that results from immunosuppression therapy. Most cases of PTLD derive from the B-cell lineage. T-cell PTLD, particularly natural killer (NK)/T-cell PTLD, is quite rare; only a few cases have been described. CASE REPORT: A 42-year-old woman received a living-related renal allograft from her father. Sixteen years after transplantation, the patient presented with a 1-week history of low-grade fever and epigastralgia. Computed tomography revealed intestinal masses and a right upper lung lobe mass. Gallium scintigraphy showed uptake in the abdominal mass. Epstein-Barr virus-related antibody was not detected in the patient's serum sample. We performed extirpation of the jejunum and ileum tumors. The pathologic findings showed that these 2 tumors were NK/T-cell lymphoma. After the operation, the lung mass rapidly enlarged, and right upper lobectomy was performed. The right upper lung lobe tumor showed the same histopathologic findings as the small bowel tumor. The final histologic diagnosis was established as multiple extranodal NK/T cell type PTLD of the small bowel and right upper lung lobe. CONCLUSIONS: After reduction of the immunosuppressive agent, no recurrence of PTLD has been observed for the past 9 years.

First Report of Tomato chlorosis virus in Potato in Brazil.

Potato plants (Solanum tuberosum cv. Ágata) exhibiting symptoms of leaf roll and interveinal chlorosis, especially on older leaves, were found in a commercial crop in the County of Cristalina, State of Goiás, Brazil in June 2011. The crop was severely infested by whitefly Bemisia tabaci biotype B. Four potato tubers from symptomatic plants were indexed for the presence of the following viruses: Tomato chlorosis virus (ToCV), Potato leaf roll virus (PLRV), Tomato severe rugose virus (ToSRV), and Potato virus Y (PVY). Total RNA was extracted separately from each tuber and used for reverse transcription (RT)-PCR using the HS-11/HS-12 primer pair, which amplifies a fragment of 587 bp from the highly conserved region of the heat shock protein (HSP-70) homolog gene reported for ToCV. The RT-PCR product was subsequently tested by nested-PCR for detection of ToCV with specific primers ToC-5/ToC-6 (2). Amplicons of 463 bp, amplified from total RNA separately extracted from three tubers, were purified and directly sequenced. Comparisons among the three consensus sequences of 448 bp (GenBank Accession Nos. JQ288896, JQ288897, and JQ288898) revealed respectively, 98, 100, and 100% identity with the reported sequence of a tomato isolate of ToCV from Brazil (GenBank Accession No. EU868927) (1). For ToSRV detection, total DNA was extracted from two tubers and a fragment of approximately 820 bp was amplified by PCR with specific primers (3). PLRV and PVY were indexed in two and three tubers, respectively, by double-antibody sandwich-ELISA (SASA, Edinburg, Scotland). Virus-free B. tabaci biotype B were separately transferred to potato and tomato leaves infected with ToCV for an acquisition access period of 24 h. Groups of 30 viruliferous whitefly were transferred to four, young, sprout-grown potato plants cv. Ágata (two plants per virus isolate) for 24-h inoculation access period. After 37 days of inoculation, one plant inoculated with the potato and tomato isolates of ToCV, respectively exhibited symptoms of leaf roll and interveinal chlorosis on order leaves, which were similar to that induced by PLRV. Experimental infection of potato plants with ToCV, which induced leaf roll symptoms resembling PLRV infection, was reported in the United States by Wisler et al. (4). The potato isolate of ToCV was also transmitted by B. tabaci to one of two inoculated tomato plants. The presence of ToCV in all inoculated plants was detected by nested-RT-PCR as described above. To our knowledge, this is the first report on detection of ToCV in field potato plants in the world. Considering that ToCV occurs in innumerous countries around the world, it is transmitted by a cosmopolitan insect, and it induces symptoms similar to PLRV, this finding triggers an alert to field dependent seed-potato multiplication, virus inspector, and certification system. References: (1) J. C. Barbosa et al. Plant Dis. 92:1709, 2008. (2) C. I. Dovas et al. Plant Dis. 86:1345, 2002. (3) F. R. Fernandes et al. Trop. Plant Pathol. 35:43, 2010. (4) G. C. Wisler et al. Plant Dis. 82:270, 1998.

Primitive neuroectodermal tumor involving the frontal skull base in an infant.

We report here a case of a primitive neuroectodermal tumor involving the frontal skull base in a 5-month-old male infant. He presented with rapidly progressing exophthalmos on the left side. Preoperative magnetic resonance imaging revealed a well-demarcated, enhanced mass of 6 cm in diameter in the intradural extra-axial frontal region. The tumor was totally removed by surgery. Pathological findings were consistent with a primitive neuroectodermal tumor (PNET). Intradural extra-axial PNET is very rare, and its prognosis is poor.

[Mechanism-based pharmacotherapy for cancer pain].

Cancer pain is usually treated by 1) pharmacotherapy, 2) nerve block, 3) radiation therapy, 4) cognitive therapy and 5) alternative medicine. Among these methods, pharmacotherapy is the simplest way to relieve cancer pain without special equipment or special settings. WHO cancer treatment guideline shows morphine is effective to most cancer pain. However, 10-20% of the patients' pain is refractory to morphine. A majority of such refractory pain is due to nerve injury caused by cancer itself or by treatment. Recently, many biological processes involved in the mechanism of neuropathic pain have been elucidated. Pharmacological treatment aimed at blocking such processes should produce specific effects on the pain. Such mechanism-based pharmacotherapy is the most effective way to treat difficult pain.

Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and [Dmt1] DALDA.

DALDA (H-Tyr-D-Arg-Phe-Lys-NH(2)) and [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)) (Dmt = 2',6'-dimethyltyrosine) are potent and highly selective mu-opioid agonists (K(i)(delta)/K(i)(mu) > 10,000 and K(i)(kappa)/K(i)(mu) > 100). Both peptides carry a 3+ charge at physiological pH. Their antinociceptive and respiratory effects were compared with morphine (MOR) after intrathecal administration in rats. Both DALDA and [Dmt1]DALDA produced dose-dependent and naloxone-reversible antinociceptive effects with relative potencies of 14 and 3000x that of MOR. The antinociceptive potency of [Dmt1]DALDA far exceeded its affinity and potency at the mu-opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synaptosomes. The antinociceptive response to [Dmt1]DALDA was significantly attenuated by the alpha(2)-adrenergic antagonist yohimbine. Thus, [Dmt1]DALDA may be regarded as a drug with dual actions, and its antinociceptive potency is better described by both its affinity and potency at mu-opioid receptors, and its potency at inhibiting NE uptake. The analgesic duration of an equipotent dose of MOR, DALDA, and [Dmt1]DALDA was 3, 7, and 13 h, respectively, and the long duration may be due to the hydrophilic nature of these peptide analogs. Respiratory effects were determined using whole body plethysmography at 3 and 30x the antinociceptive ED(50). A significant depression in minute ventilation was observed with the higher dose of morphine and both doses of DALDA, but not with either dose of [Dmt1]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensity to induce respiratory depression, [Dmt1]DALDA is of interest as a drug candidate for intrathecal analgesia.

[A case of granulomatous angiitis of the central nervous system presented with subacute mental deterioration resembling diffuse white matter disease].

We reported a 60-year-old man with granulomatous angiitis of the central nervous system (GACNS) manifesting as subacute mental deterioration. His first symptoms were nausea and vomiting which brought him to a hospital, where no abnormality was found except for gastritis. One month later, he began to feel dizziness and brain tumor was suspected by a neurosurgeon with the MRI findings such as abnormal T2 signal and swelling in his brainstem. While he was followed up, he gradually presented mental change, disorientation and dysmnesia with the abnormal T2 signal spreading over the cerebral white matter bilaterally. Corticosteroid therapy was started based on the suspicion of a lymphoproliferative disease, and his symptoms and the abnormal MRI findings improved. Then he was referred to our department for further evaluation. Because we could not find any evidence of systemic diseases and he had been almost fully recovered, we discontinued the therapy. Soon after that, his mental deterioration as well as the abnormal T2 signal lesions on MRI relapsed. By open brain biopsy, the diagnosis of GACNS was established, and steroid pulse therapy was started. His symptoms and the abnormal T2 signal lesions improved gradually and the steroid was tapered to the maintenance dose without remission. Since the laboratory and imaging findings are not specific for the diagnosis of the angiitis confined to the central nervous system, brain biopsy is recommended for these disorders.

Experimental pain augments experimental dyspnea, but not vice versa in human volunteers.

BACKGROUND: Pain and dyspnea frequently coexist in many clinical situations. However, whether the two different symptoms interact with each other has not been elucidated. To elucidate the interaction between pain and dyspneic sensations, the authors investigated separately the effects of pain on dyspnea and the effects of dyspnea on pain in 15 healthy subjects. METHODS: Subjects were asked to rate their sensation of pain or dyspnea using a visual analog scale (VAS) during pain stimulation produced by tourniquet inflation (inflation cuff pressure: 350 mmHg) around the calf, and/or the respiratory loading consisted of a combination of resistive load (77 cm H2O x l(-1) x s(-1)) and hypercapnia induced by extra mechanical dead space (255 ml). In addition to changes in VAS scores, changes in ventilatory airflow and airway pressure were continuously measured. RESULTS: Pain stimulation and loaded breathing increased VAS scores, ventilation, and occlusion pressure (P0.1). The addition of a pain stimulus during loaded breathing increased the dyspneic VAS score (median 56 [interquartile range 50-62] vs. 64 [55-77]: before vs. after addition of pain stimulus, P < 0.05) with concomitant increases in minute ventilation (10.8 [10.1-13.3] vs. 12.4 [11.0-14.8] l/min, P < 0.05) and P0.1 (5.5 [4.9-7.2] vs. 6.8 [5.8-9.0] cm H2O, P < 0.05). The addition of respiratory loading during pain stimulation did not cause a significant change in pain VAS score (40 [33-55] vs. 31 [30-44]: before vs. after addition of respiratory loading), although both additional burdens increased further minute ventilation (10.0 [8.8-10.9] vs. 12.0 [10.6-13.2] l/min, P < 0.05) and P0.1 (2.5 [2.0-3.0] vs. 6.2 [4.9-7.0] cm H2O, P < 0.05). CONCLUSION: The authors' findings suggest that pain intensifies the dyspneic sensation, presumably by increasing the respiratory drive, whereas dyspnea may not intensify the pain sensation.

Oral ketamine is antinociceptive in the rat formalin test: role of the metabolite, norketamine.

The present study was designed to evaluate the oral efficacy and bioavailability of ketamine. Antinociceptive efficacy was determined with the rat formalin test and oral bioavailability by the measurement of plasma and brain concentrations of ketamine and its major metabolite, norketamine. Oral ketamine in a dose range from 30 to 180 mg/kg or saline was given prior to intraplantar formalin and the flinching behavior was measured. Oral ketamine dose-dependently reduced the flinching during phase 2, while flinching during phase 1 was reduced only with the highest dose given. Following oral ketamine at 100 mg/kg, blood and brain samples were obtained and plasma and brain ketamine and norketamine levels were measured using high-performance liquid chromatography (HPLC). The average concentration ratio of norketamine/ketamine, as expressed by the area under the curve (AUC) value, was 6.4 for plasma and 2.9 for brain. These results demonstrate that a significant amount of norketamine is formed by first pass biotransformation of ketamine and is distributed to the brain. Competition binding assays for the [3H]MK-801-labeled non-competitive site of the N-methyl-D-aspartate receptor (NMDA) receptor revealed that both norketamine and ketamine displaced [3H]MK-801 at low micromolar concentrations with Ki values of 2.5 and 0.3 mM in the forebrain, and 4.2 and 1.0 mM in the spinal cord, respectively. Spinal norketamine was approximately equipotent to ketamine in producing antinociceptive effects during phase 2 of the formalin test. Thus, norketamine appears to contribute to the antinociceptive effects of oral ketamine through its NMDA receptor antagonist activity.

d-Methadone is antinociceptive in the rat formalin test.

The l-isomer of methadone possesses opioid activity, whereas the d-isomer is weak or inactive as an opioid. Both d- and l-methadone have been shown to bind to the N-methyl-D-aspartate (NMDA) receptor. To determine whether d-methadone has functional, in vivo NMDA receptor antagonist activity, the antinociceptive effects of d-methadone were evaluated in the rat tail-flick and formalin tests. Cumulative dose-response analysis in the tail-flick test revealed an ED50 value for intrathecal (spinal) l-methadone of 15.6 microg/rat. In contrast, spinal d-methadone produced no antinociception at a cumulative dose of 460 microg/rat. d-Methadone in a dose range from 32 to 320 microg/rat dose-dependently reduced formalin-induced flinching behavior during phase 2 but not during phase 1 of the formalin test. These antinociceptive effects of d-methadone were not blocked by a spinal dose of naloxone that effectively antagonized an antinociceptive (tail-flick test) dose of l-methadone. d-Methadone at an intrathecal dose of 250 microg shifted the ED50 value for NMDA-induced nociceptive behaviors more than 3-fold to the right, which indicates an antagonism of these NMDA receptor-mediated effects. These results indicate that d-methadone is antinociceptive as a result of its NMDA receptor antagonist activity.

Gabapentin enhances the antinociceptive effects of spinal morphine in the rat tail-flick test.

The antinociceptive effects of the combination of spinal morphine and gabapentin were evaluated in the tail-flick test in rats. The intrathecal coadministration of a subantinociceptive dose of morphine at 0.2 microgram and gabapentin at 300 micrograms produced significant antinociception. Pretreatment with spinal gabapentin at 300 micrograms shifted the dose-response curve of spinal morphine to the left with a decrease in morphine ED50 value from 1.06 micrograms to 0.34 microgram. The antinociceptive effects produced by the combination of a subantinociceptive dose of morphine and gabapentin were reversed by spinal naloxone at 30 micrograms but were not reversed by spinal bicuculline at 0.3 microgram. Furthermore, the concurrent administration of spinal naloxone at 30 micrograms with the combination of morphine and gabapentin blocked antinociception, while the concurrent administration of spinal bicuculline at 0.3 microgram failed to prevent antinociception. These results indicate that the combination of spinal gabapentin and morphine produces an enhancement of antinociception that appears to involve the spinal mu opioid receptors. Furthermore, repeated administration of gabapentin for 3 days did not affect the enhancing effect of gabapentin on the antinociceptive effect of morphine, indicating that tolerance did not develop to gabapentin's ability to enhance morphine antinociception.

Spinal gabapentin is antinociceptive in the rat formalin test.

Gabapentin is a novel anticonvulsant that may be of value for the relief of clinical pain. To determine whether gabapentin is antinociceptive after spinal administration, the drug was given via an intrathecal catheter in doses from 6 to 200 micrograms/rat 10 min prior to intraplantar formalin. Five percent formalin injected subcutaneously in the right hind paw produced a biphasic reaction consisting of flinching and licking behaviors (phase 1, 0-10 min; phase 2, 10-60 min). Gabapentin dose-dependently reduced the numbers of flinches and the duration of licking during phase 2 of the formalin test. The highest dose of gabapentin (200 micrograms/rat) did not affect the tail-flick response. These results demonstrate that spinal gabapentin is antinociceptive in the formalin test.

Oral ketamine produces a dose-dependent CNS depression in the rat.

The oral to parenteral potency of ketamine to produce central nervous system (CNS) depression was estimated in rats using a behavioral scale. As a function of dose, ketamine produces CNS depression that ranges from ataxia to anesthesia by either route of administration. The oral ED50 value for ketamine was 120 mg/kg (82.2-159.2, 95% CI) while the intravenous ED50 value was 3.7 mg/kg (2.4-5.1, 95% CI). Oral ketamine produces CNS effects comparable to intravenous ketamine, although the drug is approximately 32 fold less potent by the oral route.

Ketamine attenuates and reverses morphine tolerance in rodents.

BACKGROUND: The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. METHOD: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. RESULTS: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. CONCLUSIONS: Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.