Bcl-2 antisense oligonucleotides are effective against systemic but not central nervous system disease in severe combined immunodeficient mice bearing human t(14;18) follicular lymphoma.

The t(14;18) is present in 85-90% of follicular lymphomas. It results in overexpression of the Bcl-2 protein, which inhibits apoptosis and plays a role in lymphomagenesis. Bcl-2 antisense oligonucleotides (ODNs) down-regulate Bcl-2 expression and inhibit growth of the follicular lymphoma cell line WSU-FSCCL. In this study, we have established a human lymphoma xenograft model in severe combined immunodeficient (SCID) mice using the WSU-FSCCL cell line. s.c., i.v., or i.p. injection of WSU-FSCCL cells into SCID mice results in the development of disseminated tumors, with the liver, spleen, bone marrow, and lymph nodes as major sites of disease. Tumors were fatal in 7-14 weeks, depending on cell inoculum and route of administration. Immunohistochemistry, flow cytometry, and cytogenetic analysis confirmed the human B-cell origin of tumor cells in the xenograft. Phosphorothioate ODNs against the translation initiation site of bcl-2 mRNA in the antisense and mismatched antisense sequences were administered i.v. or i.p. to the xenograft models three times a week for 2 weeks, starting on day 7 after tumor injections. Antisense-treated animals had significantly longer survival (mean, 11.6 weeks) compared with 7.6 weeks for the control group and 7.5 weeks for the mismatched antisense-treated animals (P = 0.002 and 0.004, respectively). More significantly, a pathological examination showed no tumor in the liver, spleen, or bone marrow of the antisense group. However, subsequent experiments showed that the central nervous system was involved, causing mice to die although other sites were disease free. We conclude that bcl-2 antisense ODN therapy is effective against systemic FSCCL disease in SCID mice xenografts; however, it does not prevent disease dissemination into the central nervous system causing animal death.     

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma.

Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3) + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.     

A voluminous vascular leiomyoma of the pancreas treated by personal technique of resection of the pancreatic head without duodenectomy

A new technique variation of complete resection of the pancreatic head with preservation of the duodenum is described. The steps of this intervention are the partial mobilization of the duodenum, the mobilization of the gastric antrum, the section of the pancreatic neck and the complete resection of the pancreatic head with a meticulous dissection/section of the small blood vessels connecting the duodenum and the head of the pancreas. The terminal part of choledochus is removed with the specimen of the pancreas. The intervention is completed with cholecystectomy, end-to-side pancreaticojejunostomy, end-to-side choledocho-jejunostomy and side-to-side jejunojejunal anastomosis. The authors carried out this intervention on a 74-year old woman with a voluminous vascular leiomyoma of the pancreatic head. The patient, two years after the operation, is well with a normal clinical and laboratory follow-up.     

Effects of lingual nerve afferents on swallowing in sheep

We investigated in sheep the effects of stimulation of the thick afferent fibers running through the lingual nerve (LN) upon the activity of some of the muscles and medullary interneurons or motoneurons which are active during swallowing. Using electromyography (EMG), and extra- and intracellular neuronal recording, we demonstrated that LN stimulation inhibited triggering and/or distal progression of deglutition reflexly induced by stimulation of the superior laryngeal nerve (SLN). This inhibition appeared as a delay, or the interruption or total suppression, of the EMG and neuronal swallowing activities, depending on the interval between SLN and LN stimulation. It was apparent at the level of the muscles and motoneurons of the nucleus ambiguus, as well as at the level of the interneurons of the dorsal medulla within or around the nucleus of solitary tract, which are assumed to be the core of the organizing system for swallowing, the so-called central pattern generator (CPG). Taking into account the stimulation parameters used in our experiments, it was likely that only LN-mechanosensitive fibers were excited. These fibers were involved in the jaw-opening reflex, and possibly in mastication regulation. Therefore, inhibition of swallowing could result from interactions between the hindbrain mastication and swallowing CPGs. However, it was also possible that mechanosensitive afferents acted upon the swallowing CPG directly or indirectly through supramedullary, especially cortical, loops.     

Quantitative analysis of uvular muscles in cases of simple snoring and obstructive sleep apnea: an image analysis study

Studies on the histopathological changes of the palatine muscles in cases of obstructive sleep apnea (OSA) and simple snoring are controversial, while some authors confirm the presence of muscle hypertrophy and increase in total muscle bulk (obstructive theory), others deny this confirming the presence of muscle atrophy and decrease in the muscle bulk (neurogenic theory), but all these studies depended on subjective observer dependent methods to calculate the muscle bulk. We are carrying a unique study to calculate the muscle bulk in uvular specimens in ten cases of OSA comparing it to ten cases with simple snoring and controls using digital computer dependent software (image analysis). Cases of OSA are associated with definite increase in the total muscle bulk of the palatine muscles when compared to cases of simple snoring and controls. Uvular muscular hypertrophy and the obstructive theory seem to explain the pathophysiology of OSA.     

Comparison between aerobic and anaerobic co-composting of agricultural residues

Fertile soil is the most important resource for food production. The agricultural area in Egypt is limited to 6 million faddans. This limited area has derived many farmers to use several types of chemical fertilizers, to enhance the fertility of the land and hence the productivity. Excessive application of chemical fertilizer lead to the build up of these residuals because they are superfluous. This will cause waste of money and also soil pollution. Ultimately, this would adversely affect the ecological system in the soil and surrounding environment, especially water bodies. Composting of organic solid wastes will address some of the problems of solid waste disposal and gives a beneficial product which may replace the expensive chemical fertilizers. Other organic compostable solid wastes could be utilized to produce this compost. Agricultural residues are cheap raw materials for such compost and are available in vast quantities as well. This compost can be used as a soil conditioner to improve soil characteristics and its productivity. Crop residues mixed with manure, may be co-composted to give a soil conditioner. Agricultural residues, about 106 million tons/year, may produce about 55 million tons/year of compost. Three co-composting were carried out at the experimental station of the Faculty of Agriculture in Abis. Two aerobic co-composting of winter and summer crop residues and one anaerobic co-composting inter rop esidue were produced. The development of the co-composting processes controlled by the temperature, moisture content, and chemical composition was studied. The aerobic co-composting of winter crop residues was found to be the best experiment as it complied with the standards of the Ministry of Agriculture Decree No. 100/1967. This co-compost is expected to be free from pathogenic microorganisms as the dominant temperature was almost about 50 degrees C from the 42nd day till the 101st day of the experiment.     

Chemotherapy with High-Dose Cytosine Arabinoside and Mitoxantrone for Poor-Prognosis Myeloid Leukemias

Forty-seven patients with poor-prognosis myeloid leukemias received induction therapy with high-dose cytosine arabinoside (HDara-C), 1.5-3.0g/m² for 8-10 doses, and mitoxantrone (DHAD), 12-15 mglm² for 3 doses. Complete remissions were achieved in 21 [45%, 95% confidence interval (CI) 30.2-59.9%]of the patients, including 11 of 14 with acute myelogenous leukemia (AML) in first relapse (79%, 95% CI 49.2-95.3%), 4 of 8 with refractory anemia with excess blasts in transformation (RAEBiT) (50%, 95% CI 15.4-84.6%), and 4 of 6 (67%, 95% CI 22.3-95.7%) previously untreated elderly AML patients. Patients with secondary AML and advanced chronic myelogenous leukemia had a very low response rate. The incidence of reversible toxicity was low and only 3 treatment-related deaths occurred. After reinduction, 8 of 9 AML patients ≤ 60 years of age were ultimately able to undergo intensive therapy and either autologous 4-hydroperoxycyclo-phosphamide-purged bone marrow (7 patients) or peripheral blood stem cell (1 patient) transplantation with satisfactory hematological recovery. We conclude that HDara-C and DHAD is an effective antileukemic regimen in selected AML and RAEBiT patients, and that its use may allow subsequent successful autologous BMT in appropriate patients.     

Inflammation in the Uvula Mucosa of Patients With Obstructive Sleep Apnea

This study was conducted to determine whether inflammation is present in the uvula mucosa of patients with obstructive sleep apnea (OSA). Uvulas were obtained by uvulopalatopharyngoplasty in 21 patients with moderate OSA (mean apnea/hypopnea index and standard error of the mean: 32±4) and by autopsy in 5 individuals not known to have OSA. Using point counting in five randomly selected high-power microscopic fields (×100), the authors found that the number of leukocytes in the lamina propria of the uvula mucosa was significantly higher in patients with OSA than in the controls (179±12 cells vs. 71±4 cells, respectively;P<.05). This was due to a significant increase in the number of plasma cells in patients with OSA as compared with controls (89±15 cells vs. 21±5 cells, respectively; P<.05). The thickness of the lamina propria (an index of interstitial edema) was also significantly increased in patients with OSA compared with controls (0.99±0.12 mm vs. 0.27±0.02 mm, respectively; P<0.05). The authors conclude that inflammation, characterized by plasma cell infiltration and interstitial edema, is present in the uvula mucosa of patients with moderate OSA. They also suggest that soft palate inflammation contributes to upper airway occlusion observed during sleep in these patients.     

Intramuscular epithelioid hemangioma of the parapharyngeal space

A clinical case of epithelioid hemangioma of the scalene muscle that occupied the parapharyngeal space is reported. The patient was a 34 year old man with a 2-month history of sensation of pharyngeal foreign body and mild dysphagia. The exploration revealed a tumor of the posterior and lateral wall of the oropharynx that extended from the rhinopharynx to the hypopharynx. The diagnostic sequence included CT, MRI, Doppler echography, and arteriography, which identified a right post-styloid tumor located behind and medial to the jugular vein, internal carotid artery, and vagal nerve, but did not affect arterial blood flow. The patient underwent surgical treatment consisting of lateral cervicotomy, tumor excision, and histological study.