Modulation of immunoglobulin production and cytokine mRNA expression in peripheral blood mononuclear cells by intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) has the potential to regulate Ig production, but the mechanism(s) responsible for this effect is unknown. In experiments reported here, we examined the ability of IVIG to regulate Ig production in human peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed mitogen (PWM). IVIG (2–10 mg/ml) showed a potent (80–85%) inhibition of PWM-stimulated IgG, IgM, and IgA production. To determine more precisely how IVIG mediated the inhibition of Ig production, we studied Ig promoting cytokine gene expression after PWM stimulation with or without IVIG (2 and 10 mg/ml) using dot-blot techniques. RNA was isolated from PBMCs at predetermined time points and probed with cDNAs specific for human cytokines (IL-1-, IL-2, IL-2R, IL-4, IL-5, IL-6, -IFN, and TNF-). IL-6 mRNA accumulation was maximal at 4.5 hr post-PWM stimulation and was inhibited 64–75% when IVIG (10 mg/ml) was present. -IFN mRNA levels peaked at 72 hr poststimulation and were also 68–75% inhibited by IVIG. IL-2 mRNA levels peaked at 4.5 hr and were 23–46% inhibited by IVIG. The inhibitory effect of IVIG on production of these cytokines (IL-6 and -IFN) was also observed at the protein level in sonicated PBMCs after incubation with PWM and IVIG. The mRNA levels for other cytokines were not or only minimally inhibited by IVIG. Addition of IL-6, -IFN, or IL-2 partially restored Ig production in IVIG-treated PWM-stimulated cultures, suggesting that inhibition of other cytokines or another mechanism(s) independent of cytokine inhibition might also be involved, although inhibition of IL-6, -IFN, and IL-2 may be one of the critical factors in the suppression of Ig production by IVIG.     

The proximo-distal spread of axonal degeneration in the dorsal columns of the rat

Summary The pivotal event in Wallerian degeneration is the breakdown of the axon. Establishing the pathophysiology of axonal degeneration has implications for the understanding of the pathogenesis of other types of nerve degenerations. A key aspect of the pathophysiology is the spatiotemporal pattern of spread after transection, an issue that has remained controversial. We have studied the progression of axonal degeneration in the dorsal columns of the rat following L₄L₅L₆ dorsal radiculotomy. Axonal degeneration proceeds in a proximo-distal fashion, beginning near the site of transection and spreading up the dorsal columns at a net rate of about 3 mmh^–1. In addition, there was early degeneration of the preterminal axons in the gracile nuclei. This pattern suggests that the clearing of axonally transported materials from the distal stump by continued anterograde transport may underlie axonal breakdown after transection.     

Cerebral spinal fluid involvement by Hodgkin's disease diagnosed by CSF cytology and immunocytochemistry

A 39-yr-old man with stage IV Hodgkin's disease (HD) involving bone marrow was being evaluated for autologous bone marrow transplantation when he developed diplopia, prompting a lumbar puncture tap for cerebral spinal fluid (CSF) examination. Cytologic examination of the CSF revealed numerous Reed-Sternberg (RS) cells in a polymorphous inflammatory background of small lymphocytes, monocytes, rare plasma cells, and eosinophils. However, magnetic resonance imaging (MRI) studies of the brain and spinal cord failed to reveal evidence of leptomeningeal disease or intracranial masses. Repeat CSF examination again demonstrated cytologic evidence of HD. Immunocytochemical stains established that the RS cells and mononuclear Hodgkin's cells were positive for CD30 and CD20 but negative for CD15; this phenotype was identical to that of RS cells in the initial diagnostic bone marrow biopsy, confirming CSF involvement by HD. The patient was treated with intrathecal methotrexate, 15 mg, 6 days after his bone marrow transplant. After treatment, all subsequent CSF cytology specimens were negative for tumor. In this case of disseminated HD, cytologic examination allowed for early detection of CNS involvement by lymphoma prior to development of radiographically detectable lesions.     

Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'

An impairment of prefrontal cortical functioning in schizophrenia ('hypofrontality') has been suggested by clinical, neuroimaging, and postmortem brain tissue studies. We used Western immunoblot and Northern hybridization analyses of postmortem brain tissue obtained from 14 schizophrenic patients and 12 control patients of similar ages to measure tissue levels of synaptophysin (a structural synaptic vesicle protein) and of SNAP-25 (a 25-kDa presynaptic protein), and their encoding mRNAs, in Brodmann's area 10 of prefrontal cortex. There were significant decreases in tissue levels of both of these proteins in prefrontal cortex of schizophrenic patients relative to controls. In contrast, tissue levels for the mRNAs encoding these proteins were not decreased in schizophrenic patients. Subsequent labeling of the same Western immunoblots showed no difference in tissue levels of glial fibrillary acidic protein (GFAP) in schizophrenic and control patients. Similarly, subsequent hybridization of the same Northern hybridization membranes showed no difference in tissue levels of GFAP mRNA or of 28S rRNA in schizophrenic and control patients. These alterations in tissue levels of synaptophysin and SNAP-25 are consistent with the idea that the clinically observed 'hypofrontality' of schizophrenia arises from abnormalities of synaptic number or structural integrity in prefrontal cortex.     

Transhiatal approach to total gastrectomy for adenocarcinoma of the gastric cardia

BACKGROUND: A thoracoabdominal approach has traditionally been described for the resection of tumours of the gastric cardia. The aim of this study was to evaluate a transhiatal approach for resection of cancers of the gastric cardia. METHODS: Twenty consecutive patients undergoing transhiatal gastro-oesophagectomy for cancer of the gastric cardia were studied. Data were collected prospectively with regard to operating time, operative blood loss, intensive care unit (ICU) stay, analgesia use, duration of hospital stay, and pathological details of resection margin clearance and lymph node yield. Results were compared with those of the 20 preceding patients for whom the same prospective information had been recorded following resection via the standard thoracoabdominal approach. RESULTS: The transhiatal approach required a shorter operating time (median 190 (range 105-255) versus 280 (225-330) min; P = 0.004). It resulted in less blood loss (median 405 (180-2000) versus 1000 (420-3200) ml; P = 0.03) and fewer days in the ICU (median 0 (0-31) versus 2 (1-8) days; P = 0.005) despite being performed in an older patient population (median 71 (43-78) versus 63 (59-70) years; P = 0.016). There was no difference in either the lymph node harvest or length or involvement of upper resection margins. CONCLUSION: The transhiatal approach to the resection of tumours at the gastric cardia is a valid and safe alternative to the standard thoracoabdominal technique. This technique avoids thoracotomy and its associated morbidity and is accompanied by reduced blood loss, decreased operating time and a shorter ICU stay.     

Comparison of adenosine and remifentanil infusions as adjuvants to desflurane anesthesia

BACKGROUND: Because adenosine has been alleged to produce both anesthetic and analgesic sparing effects, a randomized, double-blinded study was designed to compare the perioperative effects of adenosine and remifentanil when administered as intravenous adjuvants during general anesthesia for major gynecologic procedures. METHODS: Thirty-two women were assigned randomly to one of two drug treatment groups. After premedication with 0.04 mg/kg intravenous midazolam, anesthesia was induced with 2 micro/kg intravenous fentanyl, 1.5 mg/kg intravenous propofol, and 0.6 mg/kg intravenous rocuronium, and maintained with desflurane, 2%, and nitrous oxide, 65%, in oxygen. Before skin incision, an infusion of either remifentanil (0.02 microg x kg(-1) x min(-1)) or adenosine (25 microg x kg(-1) x min(-1)) was started and subsequently titrated to maintain systolic blood pressure, heart rate, or both within 10-15% of the preincision values. RESULTS: Adenosine and remifentanil infusions were effective anesthetic adjuvants during lower abdominal surgery. Use of adenosine (mean +/- SEM, 166+/-17 microg x kg(-1) x min(-1)) was associated with a significantly greater decrease in systolic blood pressure and higher heart rate values compared with remifentanil (mean +/- SEM, 0.2+/-0.03 microg kg(-1) x min(-1)). Total postoperative opioid analgesic use was 45% and 27% lower in the adenosine group at 0-2 h and 2-24 h after surgery, respectively. CONCLUSIONS: Adjunctive use of a variable-rate infusion of adenosine during desflurane-nitrous oxide anesthesia was associated with acceptable hemodynamic stability during the intraoperative period. Compared with remifentanil, intraoperative use of adenosine was associated with a decreased requirement for opioid analgesics during the first 24 h after operation.