Production of cytokines by bone marrow cells obtained from patients with multiple myeloma

Previous work with continuously cultured multiple myeloma lines suggested that cytokine production by tumor cells may mediate some of the medical complications of this disease. To further investigate this issue, we assayed freshly obtained bone marrow (BM) cells from myeloma patients for the in vitro production of cytokines and the presence of cytokine RNA. Production of cytokine protein was assessed by bioassays with the aid of specific neutralizing anticytokine antibodies. These assays detected interleukin-1 (IL-1) and tumor necrosis factor (TNF) secretion by myeloma BM cells, which was significantly greater than secretion from similarly processed BM cells of control individuals. In contrast, lymphotoxin and interleukin-2 (IL-2) production could not be detected. The levels of IL-1 and TNF produced in vitro peaked at 24 hours of culture and correlated with stage and the presence (or absence) of extensive osteolytic bone disease. Northern blot analysis demonstrated the presence of IL-1 beta and TNF RNA in uncultured myeloma BM cells but no detectable IL-1 alpha or lymphotoxin RNA. In addition, the amount of cytokine RNA correlated with protein production, being significantly greater in patients' BM cells than in control marrow. These data suggest a role for IL-1 beta and/or TNF in the pathophysiology of multiple myeloma and argue against a role for lymphotoxin or IL-2.     

Rare detection of hepatitis B and hepatitis C virus genomes by polymerase chain reaction in seronegative donors with elevated alanine aminotransferase

BACKGROUND: Since screening for antibody to hepatitis C virus (HCV) was introduced in 1990, posttransfusion hepatitis has been reduced to nearly background levels. This has led to reconsideration of the value of testing donated blood for elevated alanine aminotransferase (ALT). The contribution of ALT testing in detecting seronegative infection was evaluated by the performance of polymerase chain reaction (PCR) for hepatitis B virus (HBV) or HCV in plasma from ALT-elevated blood units. STUDY DESIGN AND METHODS: Testing was performed on 375 units of plasma, derived from an equivalent of 47,500 blood donations, with a highly sensitive hemi-nested PCR procedure. Using a triplet of primers directed at the conserved regions of HBV DNA and 5'-noncoding regions of HCV RNA, the hemi-nested PCR assay can reliably amplify 10 viral molecules to levels detectable in ethidium bromide-stained agarose gels. Pools of plasma from groups of four donors were screened with hemi-nested PCR. For any reactive pools, the plasma from individual donors was retested twice on different aliquots. RESULTS: Two of 375 units, both with midrange ALT elevation, were repeatedly reactive in hemi-nested PCR (one each for HBV DNA and HCV RNA). However, samples from the two suspect donors tested 9 and 5 months later revealed no seroconversion, elevated ALT, or viral genomes in hemi-nested PCR. CONCLUSION: The lack of confirmed HBV or HCV infection in this study representing an estimated 47,500 voluntary blood donations suggests that routine ALT testing for further prevention of posttransfusion hepatitis after exclusion of HBV- and/or HCV-seropositive blood may be superfluous.     

Chronic Arsenic Poisoning From Burning High-Arsenic-Containing Coal In Guizhou, China

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.     

Cutaneous lymphomas showing prominent granulomatous component: clinicopathological features in a series of 16 cases

Background  The presence of a prominent granulomatous tissue reaction in skin biopsies from primary cutaneous or systemic malignant lymphomas with secondary cutaneous involvement is a rare but well-known phenomenon.
Objective  This paper aims to characterize and study a series of cutaneous lymphomas showing a prominent granulomatous component.
Patients and methods  The clinical, histopathological and evolutive features of granulomatous variants of mycosis fungoides (5 patients, 2 of them associating 'granulomatous slack skin' features), Sézary syndrome (1 patient), CD30⁺ cutaneous T-cell lymphoma (2 patients), CD4⁺ small/medium pleomorphic cutaneous T-cell lymphoma (1 patient), primary cutaneous B-cell lymphoma (3 patients) and peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement (4 patients) were reviewed.
Results  The observed features were clinically non-distinctive. Only those cases presenting with granulomatous slack skin features were clinically suspected (2 patients). Non-necrotizing granulomata (11 patients) and granuloma annulare-like (4 patients) were the most frequently observed histopathological patterns. In five cases, no diagnostic lymphomatous involvement was initially observed. From our series, no definite conclusions regarding prognosis could be established.
Conclusion  The diagnosis of cutaneous lymphoma may be difficult when a prominent cutaneous granulomatous inflammatory infiltrate obscures the true neoplastic nature of the condition. However, the presence of concomitant lymphoid atypia may help to suspect the diagnosis. In doubtful cases, the clinical evolution and the demonstration of a monoclonal lymphoid B- or T-cell population may lead to a definite diagnosis.

Conflicts of interest

None declared.     

SELECTIVE ENDOSCOPY IN MANAGEMENT OF INGESTED FOREIGN BODIES OF THE UPPER GASTROINTESTINAL TRACT: IS IT SAFE?

During a four-year period, 308 patients presented following ingestion of foreign bodies. Ingestion was accidental in 272 cases (88.3%) and deliberate in the remainder. Symptoms at presentation included dysphagia, odynophagia, nausea and vomiting, chest pain and pharyngeal discomfort. Sixty-eight patients were asymptomatic. A policy of expectant management and selective endoscopy was employed. Following initial assessment 202 patients (65.6%) were discharged without treatment, 30 (9.7%) of whom were later reviewed as outpatients and did not require admission. Forty-nine patients (16%) were admitted for treatment; 27 had oesophagoscopy, five bronchoscopy and two had foreign body extraction with direct laryngoscopy. In nine patients who were endoscoped, no foreign body was identified. Twenty-seven others were referred to the otorhinolaryngology service in another hospital. There were no deaths in the group and morbidity was 1.2%. We conclude that a policy of selective endoscopy is safe and effective in the management of patients following ingestion of foreign bodies.     

15The effect of Lower Esophageal Sphincter (LES) electrical stimulation on LES pressure

Background: Electrical stimulation (ES) of the stomach has been shown to modulate LESP. Electrical stimulation, using neural high frequency stimulation (NGES) can induce contractions of the smooth muscle of the gut. The purpose of this study was to determine if electrical stimulation of the LES can affect LESP. Methods: Four female hound dogs, weight: 20–25 kg, underwent an esophagostomy that allowed the introduction of a sleeve manometry catheter into the esophagus. They were also implanted with a pair of electrodes along the longitudinal axis of the LES. After 3 weeks of recovery, they underwent esophageal manometry recording during control and ES, performed randomly on separate days, using 4 different stimulations: 1‐Low frequency: freq: 6 cycles/min, pulse: 350 milisec, amp: 5 mAmp; 2 High‐frequency: freq: 50 Hz, pulse: 1 milisec, amp: 5 mAmp; 3‐ NGES: freq: 50 Hz, pulse:20 milisec, amp:10 volts; 4‐ High‐frequency, circular: freq: 20 Hz, pulse:1 milisec, amp:5 mAmp. All recordings were performed 1 hour after consumption of 3 ounces of canned dog food, to prevent fluctuations in LESP and under mild sedation (acepromazine 0.5 mg kg^­1). Tests consisted, during ES days, of 3 periods of 20 minutes each: control , stimulation and post stimulation. The effect of NGES was also tested under anesthesia and following administration of L‐NAME 50 mg kg^­1 IV. and also atropine 0.05 mg kg^­1 IV. Analysis: area under the curve (AUC) and pressure were compared among the 3 periods. Data shown as mean ± SD, ANOVA and t‐test, p < 0.05. Results: Sustained increase in LESP was observed during low frequency stimulation, 32.1 ± 12.8 vs. 42.4 ± 18.0 vs. 50.1 ± 23.6, control vs. stimulation vs. post stimulation respectively, p = 0.013. AUC also significantly increased during and after stimulation, 39,320.3 ± 15,722 vs. 51,294 ± 21,826 vs. 59,823.6 ± 28,198.4 mmHgxsec, control vs. stimulation vs. post stimulation respectively, p = 0.01. There was no significant change with other types of ES. NGES induced an initial rise in LESP followed within few seconds by relaxation with slow resumption of pressure over a 1 minute period. L‐NAME increased LESP and augmented the initial rise in LESP following NGES but markedly diminished or abolished the relaxation phase. Atropine lowered LESP and abolished the initial rise in LESP induced by NGES. Conclusions: Low frequency ES of the LES increases LESP in conscious dogs. NGES has dual effect on LESP: an initial stimulation, cholinergically mediated, followed by relaxation mediated by nitric oxide.