Experimental pain perception remains equally active over all sleep stages

The literature on sensory perception during sleep suggests that light sleep (Stage 2) is more responsive to external sensory stimulation (e.g. sound, electrical shock) than deep sleep (Stages 3 and 4) and REM sleep. The main objective of this study was to characterize the specificity of nociceptive stimulation to trigger sleep arousal–awakening over all sleep stages. Thirteen healthy adults (e.g. without pain or sleep problems; six female and seven male of a mean age of 24.2±1.3 years) were included in the study. The responses to noxious intramuscular 5% hypertonic infusion were compared to innocuous vibrotactile and to respective control stimulations: isotonic infusion and auditory stimulations. These stimulations were applied during wakefulness and were repeated during sleep. Polygraphic signals (e.g. brain activity, heart rate) signals were recorded to score sleep arousal over all sleep stages. A subjective assessment of sleep quality was made on next morning. No overnight sensitization or habituation occurred with any of the experimental stimulations. The vibratory–auditory stimulations and the noxious hypertonic infusions triggered significantly (P<0.05) more awakenings in sleep Stage 2 and in REM than their respective control stimulations. In sleep Stage 2, both vibratory+auditory stimulations and the noxious hypertonic infusions has the same awakening response frequency (≈30%), however, with the noxious infusions the response frequency were similar in sleep Stages 3 and 4 (P<0.05) and in REM (trend). Compared to the baseline night, sleep quality was lower following the night with noxious stimulation (90.1±2.7 and 73.3±7.4 mm, respectively; P<0.03). These data suggest that pain during sleep could trigger a sleep awaking response over all sleep stages and not only in light sleep.     

Influence of an elemental diet on 5-fluorouracil-induced morphological changes in the mouse salivary gland and colon

Purpose

The elemental diet (ED) Elental® reportedly reduces adverse reactions to chemotherapy in digestive system cancer patients; however, the mechanism is unclear. Therefore, we verified the protective effect of ED against gastrointestinal disorders induced by the antineoplastic drug 5-fluorouracil (5-FU).

Methods

After 5 days of tail vein injections of 40 mg/kg/day 5-FU in female BALB/c mice, the mice were given oral ED (ED group) or dextrin with the same number of calories (control group). We measured the weight of salivary glands and the PAS-positive area of colonic mucosa and verified the antitumor effect in tumor-bearing mice given 5-FU and ED.

Results

Although body weight decreased after 5-FU treatment, ED group mice weighed more than control group mice. Additionally, although control mice developed diarrhea after 5-FU treatment, the ED group showed only loose stools. The control group saliva volume was approximately one sixth of the vehicle group volume after 5-FU treatment; this was improved to approximately half in the ED group. The area ratio of PAS-positive cells in the colonic mucosa was reduced by 5-FU treatment, with the ratio being higher in the ED group than that in the control group. Similar tumor growth suppression was observed in the 5-FU and ED groups.

Conclusions

ED alleviated adverse reactions to 5-FU without affecting antitumor activity. Protection against 5-FU-induced weight loss was potentially due to both improved nutritional support with combined ingredients and prevention of diarrhea that is associated with reduced colonic goblet cells and decreased saliva production from reduced salivary gland contraction.

     

Panton–Valentine leukocidin-positive novel sequence type 5959 community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction in a 1-month-old infant

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a pathogen of major importance in pediatric patients. CA-MRSA can cause skin and soft tissue infection in children and young active adults with no predisposing factors, and life-threatening infections such as meningitis or necrotizing pneumonia have been reported. We report here a case of CA-MRSA meningitis complicated by acute left middle cerebral artery (MCA) infarction and necrotizing pneumonia in a previously healthy 1-month-old Vietnamese boy. He was firstly treated with vancomycin, but changed to linezolid because of persistent fever and low vancomycin trough level.He recovered successfully with residual right-sided hemiparesis. The mode of transmission of CA-MRSA and the mechanism of cerebral infarction (thrombotic or embolic) were unknown. The isolate was genotyped as staphylococcal cassette chromosome (SCC) mec type V with a novel sequence type (ST) 5959 harboring the Panton–Valentine leukocidin (PVL) gene. ST 5959 is a double locus variant of ST 59, which is a major PVL-positive CA-MRSA strain isolated in invasive disease in Asian countries. This case report may serve as a warning about the dissemination of PVL-positive CA-MRSA in and around Japan, with the possibility of causing serious life-threatening disease. The potential of linezolid for the treatment of MRSA meningitis as one of the alternative MRSA therapeutic drugs is also discussed.     

Blood distribution of bortezomib and its kinetics in multiple myeloma patients

Objectives

Pharmacokinetic disposition of bortezomib in the blood has not been fully characterized in humans. This study aimed to evaluate the blood distribution of bortezomib and its kinetics in multiple myeloma patients.

Design and method

Eighteen multiple myeloma patients receiving bortezomib–dexamethasone combination therapy were enrolled. Blood specimens were drawn just before bortezomib administration on days 1 and 8 in the second and third cycles and after discontinuation. The relationships between bortezomib concentration and blood components were evaluated.

Results

Bortezomib concentration in the blood on day 1 was higher than that on day 8 in the second cycle. No difference was observed in bortezomib blood concentrations between day 8 in the second and third cycles. The bortezomib concentration in the blood and blood cells was 3- and 7-fold higher than that in plasma. Bortezomib concentration in the blood was correlated with the red blood cell count. The half-life of bortezomib in the blood was 23 days.

Conclusion

Bortezomib was taken up into red blood cells to only a limited extent and eliminated in parallel to the red blood cells' lifespan. The turnover of red blood cells can affect the pharmacokinetic disposition of bortezomib in multiple myeloma patients.     

First case of feline systemic Cryptococcus albidus infection.

This paper, as best as the authors can determine, is the first to describe a documented case of systemic infection caused by Cryptococcus albidus in a cat. The patient had a history of paralysis of the hind legs and had been treated with prednisone for 1 month. Microscopic examination of a fine needle biopsy specimen from a right popliteal lymph node showed granulomatous inflammation with many encapsulated yeast cells. Moreover, microscopic examination of Indian ink preparations of the cerebrospinal fluid revealed encapsulated ovoid yeast cells. Thus this case was diagnosed to be cryptococcosis. However, the cat died after treatment for three days with voriconazole. Isolates recovered from samples of the cerebrospinal fluid, liver and spleen were identified as C. albidus by molecular analysis, as well as through morphologic and biochemical studies. Therefore, this case indicates that C. albidus should be considered as a potential feline pathogen.     

Enhanced production of nitric oxide,reactive oxygen species,and pro-inflammatory cytokines in very long chain saturated fatty acid-accumulated macrophages

Background  

Deterioration of peroxisomal β-oxidation activity causes an accumulation of very long chain saturated fatty acids (VLCSFA) in various organs. We have recently reported that the levels of VLCSFA in the plasma and/or membranes of blood cells were significantly higher in patients with metabolic syndrome and in patients with coronary artery disease than the controls. The aim of the present study is to investigate the effect of VLCSFA accumulation on inflammatory and oxidative responses in VLCSFA-accumulated macrophages derived from X-linked adrenoleukodystrophy (X-ALD) protein (ALDP)-deficient mice.     

Anterior versus posterior surgery for osteoporotic vertebral collapse with neurological deficit in the thoracolumbar spine

Despite the increasing number of reports on surgical treatments for thoracolumbar osteoporotic vertebral collapse with neurological deficits, the choice of surgery remains controversial. In this retrospective study, we compared the outcomes of posterior and anterior surgeries for single-level osteoporotic vertebral collapse with neurological deficit in the thoracolumbar spine. Both posterior and anterior surgical approaches were performed with a consistent procedure for a single surgical indication at one institution. Twenty-four patients treated with posterior surgery and 28 patients treated with anterior surgery were followed-up over an average of 5 years after surgery. Radiographic results (kyphotic angle, bony fusion, and instrumentation failure), neurological improvement, and surgical complications were compared between the two groups. The average correction angle after surgery was larger in the posterior group than in the anterior group (P = 0.013), but not at final follow-up (P = 0.755). The average loss of correction was also higher in the posterior group than in the anterior group (P = 0.037). There was no significant difference in neurological outcomes between anterior and posterior approaches (P = 0.080). Two-way analysis of variance (ANOVA) showed that the neurological outcome was better in wedge type than in flat type vertebral collapse, regardless of the type of surgical approach (P = 0.0093). In wedge type vertebral collapse, neurological improvement tended to be greater after anterior than after posterior surgery. In four of six cases with instrumentation failure in the anterior group, a titanium cage subsided more than 5 mm but bony fusion was eventually achieved without causing neurological problems. In the posterior group, six cases experienced instrumentation failure during the postoperative course (two cases with screws loosened from pedicles and bodies, and one case with breakage of a screw neck). None of the patients developed instrumentation-related neurological problems. Two cases in each group developed pseudoarthrosis. In single-level osteoporotic vertebral collapse with neurological deficit, anterior surgery tended to improve neurological deficit in wedge type, but not in flat type collapse, compared with posterior surgery.     

Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population

Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and 50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis 50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.Naoko Iwasaki, Yukio Horikawa and Takafumi Tsuchiya contributed equally to this work.     

Precise quantification of pulsatility is a necessity for direct comparisons of six different pediatric heart-lung machines in a neonatal CPB model

Generation of pulsatile flow depends on an energy gradient. Surplus hemodynamic energy (SHE) is the extra hemodynamic energy generated by a pulsatile device when the adequate pulsatility is achieved. The objective of this study was to precisely quantify and compare pressure-flow waveforms in terms of surplus hemodynamic energy levels of six different pediatric heart-lung machines in a neonatal piglet model during cardiopulmonary bypass (CPB) procedures with deep hypothermic circulatory arrest (DHCA). Thirty-nine piglets (average weight, 3 kg) were subjected to CPB with a hydraulically driven physiologic pulsatile pump (PPP; n=7), Jostra-HL 20 pulsatile roller pump (Jostra-PR; n=6), Stockert Sill pulsatile roller pump (SIII-PR; n=6), Stockert Sill mast-mounted pulsatile roller pump with a miniature roller head (Mast-PR; n=7), Stockert Sill mast-mounted nonpulsatile roller pump (Mast-NP; n=7), or Stockert CAPS nonpulsatile roller pump (CAPS-NP, n=7). Once CPB was begun, each animal underwent 20 minutes of hypothermia, 60 minutes of DHCA, 10 minutes of cold reperfusion, and 40 minutes of rewarming. The pump flow rate was maintained at 150 ml x kg(-1) x min(-1) and the mean arterial pressure (MAP) at 45 mm Hg. In the pulsatile experiments, the pump rate was kept at 150 bpm and the stroke volume at 1 ml/kg. The SHE (ergs/cm3) = 1,332 ([(integral fpdt) / (integral fdt)] - MAP) was calculated at each experimental stage. During normothermic CPB (15 minutes on pump), the physiologic pulsatile pump generated the highest surplus hemodynamic energy (8563 +/- 1918 ergs/cm3, p < 0.001) compared with all other pumps. The Jostra HL-20 and Stockert Sill pulsatile roller pumps also produced adequate surplus hemodynamic energy. Nonpulsatile roller pumps and the Stockert Sill mast-mounted pulsatile roller pump did not generate any extra hemodynamic energy. During hypothermic CPB and after DHCA and rewarming, the results were extremely similar to those seen during normothermic CPB. The surplus hemodynamic energy formula is a novel method to precisely quantify different levels of pulsatility and nonpulsatility for direct and meaningful comparisons. The PPP produced the greatest surplus hemodynamic energy. Most of the pediatric pulsatile pumps (except Mast-PR) generated significant surplus hemodynamic energy. None of the nonpulsatile roller pumps generated adequate surplus hemodynamic energy.     

Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids

Glucocorticoids are extensively used in anti-inflammatory therapy and may contribute to the normal regulation of lymphopoiesis. This study utilized new information about the early stages of lymphopoiesis in mouse and man to determine precisely which cell types are hormone sensitive. Cycling B lineage precursors were depleted in dexamethasone-treated mice, while mature, non-dividing CD45R(Hi) CD19(Hi) lymphocytes, myeloid progenitors and stem cells with the potential for lymphocyte generation on transplantation were spared. Lineage marker-negative (Lin(-)) IL-7R(+) Flk-2(+) pro-lymphocytes also declined, but not as rapidly as the terminal deoxynucleotidyl transferase-positive cells within an early Lin(-) c-kit(Hi) Sca-1(Hi) fraction of bone marrow. Hormone-sensitive cells with additional properties of early lymphoid progenitors (ELP) were identified within the same Lin(-) c-kit(Hi) Sca-1(Hi) subset using human mu transgenic mice and recombination-activating gene 1 (RAG1)/green fluorescent protein knock-in animals. Furthermore, cells with a recent history of RAG1 expression were more glucocorticoid sensitive than mature lymphocytes in marrow and spleen. Lymphocyte progenitors in mice bearing a human bcl-2 transgene were protected from dexamethasone treatment. However, isolated progenitors from either wild-type or bcl-2 transgenic mice were directly sensitive to the hormone in stromal cell-free cultures, suggesting that additional factors must determine vulnerability to glucocorticoids. B lineage lymphocyte precursors were found to be abnormally elevated in the bone marrow of adrenalectomized or RU486-treated mice. This suggests that glucocorticoids may normally contribute to steady-state regulation of lymphopoiesis. Finally, parallel studies revealed that the earliest events in human lymphopoiesis are susceptible to injury during glucocorticoid therapy.