Effects of Different Cold Preservation Solutions on the Functions of Cultured Isolated Human Hepatocytes.

BACKGROUND: Hepatocyte transplantation using isolated human hepatocytes is an alternative source that can be used for the treatment of metabolic diseases and acute liver failure as a time bridge to liver transplantation. These cells can also be used for bioartificial liver systems and in vitro study of drug toxicity. OBJECTIVE: To determine which cold preservation solution is better maintain the liver function. METHODS: We prepared 4 cold preservation solutions made of different combination of antioxidants, chelating, membrane protective, and anti-apoptotic agents as well as inhibitor of cyclophilin D. For hepatocyte isolation, we used livers obtained from unused deceased donor livers and the liver of patients with Crigler-Najjar syndrome who were candidates of partial liver transplantation. After culture and cold preservation, the level of albumin, and urea production were measured as indices of liver functionality. RESULTS: We found that albumin production significantly decreased after cold preservation in solution 1. There was no significant difference in urea production after cold preservation in solution 1 compared with control 24 h. No significant differences in albumin production were found after cold storage in solution 2 and solution 4 compared with control 24 h. Urea production significantly decreased after cold storage in solutions 2 and 4 compared with control 24 h. As a whole albumin and urea production were significantly decreased after cold preservation. Although albumin and urea production were decreased after cold preservation, but the results of albumin production of two solutions were not significantly different from that of the control group (p=0.109 and 0.951). CONCLUSION: Cold preservation of cultured human hepatocytes in solution 2 and solution 4 could maintain the function of albumin production better than other cold preservation solutions in our experiments; solution 1 was more effective on urea production of cultured human hepatocytes at 4 °C for 24 h. To determine if these hepatocytes are suitable candidates for transplantation, further studies should be performed.

The Effects of Cold Preservation Solutions Supplemented with UDCA and α-Lipoic Acid on the Viability and Function of Isolated Human Hepatocytes.

BACKGROUND: Liver transplantation is the only treatment for end-stage and genetic liver diseases. The main burden of this treatment is the shortage of both living and cadaveric liver donors. An alternative treatment is using liver cell transplantation, which can be obtained from unused livers for transplantation. These hepatocytes should be kept ready in viable and functional situation in a frozen state to be instantly used when they would be needed. In our previous experience, we had isolated hepatocytes from unused livers. OBJECTIVE: To find a preserving solution for increasing viability and function of the isolated hepatocytes that are stored to be transplanted. METHODS: 9 cadaveric donor livers, which were not used for transplantation due to various causes such as severe steatosis, were selected to isolate hepatocytes. Various cold storage solutions were tried to find the best temperature for more viability and functionality for preservation of hepatocytes. University of Wisconsin (UW) solution and Williams E media were used as control media. 2 anti-apoptotic and anti-oxidative solutions, i.e., α-lipoic acid and ursodeoxycholic acid (UDCA), were used as cold preservatives solutions. The numbers of viable hepatocytes were estimated by trypan blue method; the functionality was assessed by the cells ability to produce urea. RESULTS: The highest number of viable and functional hepatocytes was obtained from freshly isolated cells. However, after preservation, the number of these viable hepatocytes and their functionality were not significantly different in cold storage solutions comparing to the control media used. Functionality of the isolated hepatocytes stored in UW with and without UCDA solution was similar to freshly isolated hepatocytes. CONCLUSION: Preservatives with anti-apoptotic and antioxidant activity could not increase the number of viable hepatocytes. Functionality of cold storing hepatocytes could be preserved similar to freshly isolated hepatocytes by UW solution with and without UCDA.

Comparison of Human Mesenchymal Stem Cells Derived from Various Compartments of Human Adipose Tissue and Tunica Adventitia Layer of the Arteries Subsequent to Organ Donation.

BACKGROUND: Mesenchymal stem cells are one of the most interesting cell sources used in regenerative medicine. OBJECTIVE: In the present study, we isolated and characterized the mesenchymal stem cells from various compartments of human adipose tissue and tunica adventitia layer of the arteries. METHODS: Tissue explant culture was done from various compartments of the human adipose tissue and tunica adventitia layer of the arteries, including adipose tissue far from the vessels, perivascular tissues that are completely attached to the vessels, and tunica adventitia layer of the arteries. After the cell culture, characterization of the cells was determined at 3rd-5th passages. Flow cytometry was performed for antigen expression analysis of CD34, CD45, CD44, CD90, CD29, CD73, and CD105. For the evaluation of cell differentiation potential, adipogenic and osteogenic differentiation was conducted under appropriate protocols. RESULTS: The cells were positive for CD44, CD90, CD29, and CD73 and negative for CD34, CD45, and CD105. Adipogenic and osteogenic differentiation potentials were different among the cells from various compartments. The cells derived from perivascular tissue demonstrated better adipogenic and osteogenic differentiation. CONCLUSION: It is essential to characterize the cells from different tissues and compartments for different purposes in regenerative medicine.

Stem Cell-Based Therapies and Tissue Engineering of Trachea as Promising Therapeutic Methods in Mustard Gas Exposed Patients.

Tissue engineering and cell-based therapies are promising therapeutic approaches in structural and functional defects of the trachea. Researchers have focused on these approaches to overcome the complications related to such diseases. Patients exposed to mustard gas suffer from massive damage to the respiratory system. Current treatment plans are only palliative and include anti-inflammatory drugs, broncholytics, long-acting ß2-agonists, and inhaled corticosteroids. As mustard gas exposure leads to chronic airway inflammation, it seems that tracheobronchomalacia, because of chronic inflammation and weakness of the supporting cartilage, is an important factor in the development of chronic and refractory respiratory symptoms. The previous studies show that regenerative medicine approaches have promising potential to improve the life quality of patients suffering from tracheal defects. It seems that the engineered tracheal graft may improve the respiratory function and decrease symptoms in patients who suffer from asthma-like attacks due to mustard gas exposure. There are several successful case reports on the transplantation of stem cell-based bioartificial grafts in structural airway diseases. Therefore, we hope that the reconstruction of tracheobronchial structure can lead to a decrease in respiratory difficulties in mustard gas-exposed patients who suffer from tracheomalacia. In the present review, we summarize the main aspects of tracheal tissue engineering and cell-based therapies and the possibilities of the application of these approaches in mustard gas-exposed patients.

The effect of consuming low- versus high-glycemic index meals after exercise on postprandial blood lipid response following a next-day high-fat meal.

BACKGROUND/OBJECTIVES: Exercise performed shortly before (that is, within half a day of) a high-fat meal is beneficial for stimulating fat oxidation after the meal and reducing postprandial triglycerides (TG). This benefit of exercise is unfortunately negated if the after-exercise food choice to replace the calories expended during exercise is one containing high-glycemic index (HGI) carbohydrates. We determined the effect of consuming low-glycemic index (LGI) carbohydrates after an exercise session on fat oxidation and TG after a subsequent high-fat meal. SUBJECTS/METHODS: Using a randomized, counterbalanced crossover design, 23 overweight or obese individuals (body mass index ⩾25 kg m(-2)) performed: walking exercise (90 min) at 1800 h followed by no meal (EX); exercise followed by a meal with LGI carbohydrates (that is, lentils, EX-LGI); exercise followed by a meal with HGI carbohydrates (that is, instant potatoes, white bread, EX-HGI); and a control condition with no exercise or meal. After a 10-h overnight fast, participants were given a standardized high-fat meal. Fat oxidation was estimated before and for 6 h after this meal from respiratory gas measures and TG determined from blood samples. RESULTS: Fat oxidation (mean±s.d.) was higher with EX (6.9±1.7 g h(-1)) than EX-HGI (6.3±1.6 g h(-1); P=0.007) and Control (5.9±1.7 g h(-1); P=0.00002), and EX-LGI (6.6±1.7 g h(-1)) was higher than Control (P=0.002). TG total area under the curve was 18-32% lower with EX and EX-LGI compared with control (P=0.0005 and P=0.0001, respectively) and EX-HGI (P=0.05 and P=0.021, respectively). CONCLUSIONS: A meal containing HGI carbohydrates consumed after an evening exercise session cancels the beneficial effect of exercise for stimulating fat oxidation and lowering TG after a subsequent high-fat meal, whereas consuming a post-exercise meal with LGI carbohydrates retains the positive effect of exercise.

The efficacy of balloon dilation in achalasia is the result of stretching of the lower esophageal sphincter, not muscular disruption.

Pneumatic dilation (PD) of the lower esophageal sphincter (LES) in achalasia is a major palliative treatment. It is generally believed, although never substantiated, that therapeutic efficacy of ballooning in achalasia is the result of the disruption and tearing of the muscular layers of the LES. To clarify this issue, we investigated the frequency of muscular disruption at the LES, 24 hours after PD, by employing the endoscopic ultrasound (EUS), in a group of 43 consented patients with achalasia. Between July 2009 and March2012, 51 consecutive adult patients with tentative diagnosis of achalasia, some with recurrence of symptoms after an earlier treatment with balloon dilation, were evaluated and underwent PD, using Rigiflex balloon without major adverse effect. Out of the 51 evaluated, 43 eligible and consenting patients who underwent EUS, 24 hours after PD, using Olympus GF-UE 160 echoendoscope and an Aloka Prosound probe at 7.5 MHZ, are the subjects of this study. The EUS in 43 eligible patients revealed an intact LES in 36 (83.7%), small area of muscular disruption in 5 (11.6%) and small hematoma in 2 patients (4.6%). Our data convincingly demonstrate that the clinical effectiveness of balloon dilation in achalasia is not the result of muscular disruption, but of circumferential stretching of the LES. Our findings on the mechanism of action of PD in achalasia could result in modifying the current method of dilation for a safer procedure, by slowing the rate of inflation and allowing the sphincter to slowly stretch itself to the distending balloon.

Cross cultural adaptation of the menopause specific questionnaire into the persian language.

BACKGROUND: The menopause-specific quality-of-life (MENQOL) was developed as a specific tool to measure the health-related quality-of-life in menopausal women. Recently, it has been translated into about 15 languages. AIM: This study was performed to develop the Persian version of the MENQOL questionnaire from the original English language version. SUBJECTS AND METHODS: This was a cross-sectional study that evaluated 300 menopausal women attending five primary health-care centers in Shiraz. The "forward-backward" procedure was applied to translate the questionnaire from English to Persian by two independent translators and then back translated into English and was checked to ensure the correct translation. Then, participants were interviewed and the questionnaire filled out. RESULTS: Over all Cronbach's alpha was 0.9 and in subscales of vasomotor, psychosocial, physical and sexual were 0.8, 0.7, 0.8 and 0.3, respectively. However, the major items were acceptable (Cronbach's alpha > 0.7), but internal consistency in sexual item was poor (Cronbach's alpha = 0.3). The result of internal consistency was acceptable in subgroups of age, disease, education, marital status and smoking habit. CONCLUSIONS: The Persian MENQOL questionnaire demonstrates good internal consistency in vasomotor, physical and psychosocial domains, but not sexual. Therefore we suggest that, the items: "Vaginal dryness during intercourse" and "weight gain" should be deleted in Persian version of the MENQOL. This questionnaire can be used in Persian language and Iranian culture in different subgroups of age, marital status and educational level as well as in individuals with hypertension and diabetes.

First Report of Pear Decline Caused by 'Candidatus Phytoplasma pyri' in Ontario, Canada.

Pear decline (PD) is a serious disease of pear (Pyrus communis L.) caused by 'Candidatus Phytoplasma pyri', which belongs to the subgroup 16SrX-C of the apple proliferation (AP) group of phytoplasmas (3). Pear seedlings from the Agriculture and Agri-Food Canada (AAFC) pear breeding program, which have been selected for advanced test and grower trials, are routinely submitted to the Canadian Food Inspection Agency (CFIA) Sidney Laboratory (formerly, CFIA Centre for Plant Health, Saanichton, BC) for virus testing at the same time that propagation is initiated to produce trees for further evaluations. In early 2007, the CFIA reported that samples of two seedling selections submitted in 2005 tested positive for phytoplasmas by a nested PCR assay with phytoplasma universal primers P1/P7 (1), followed by phytoplasma universal primers fU5/rU3 (2) and real time PCR with universal phytoplasma primers developed by the CFIA-Sidney (personal communication). Phytoplasmas present in both selections were subsequently identified as 'Ca. P. pyri' strains by nested PCR with the P1/P7 primers followed by PD/peach yellow leaf roll (PYLR)-specific primers fPD/rPDS (2,4). These were the first PD-positive results from many samples submitted over the years for testing. Following PD-positive diagnoses for the seedling trees, others propagated from these seedling trees were removed from the nursery. When tested by PD-specific nested PCR (P1/P7 then fPD/rPDS), one selection had 39 of 79 nursery trees (49%) that were PD positive, while the other selection had 27 of 96 trees (28%) testing as PD positive. PCR amplification of DNA isolated from leaves of six of the propagated trees, with primer pair fPD/rPDS, yielded an ~1,400-bp product that was sequenced. A consensus sequence of 1,313 bp (GenBank Accession No. GU565959) was subjected to a nucleotide BLAST search of the NCBI database and showed 100% nt identity with sequences of phytoplasmas PD1 (AJ542543) and PYLR (Y16394). Subsequently, the PD-positive results from leaf, dormant shoot, and root tissues from the original seedling trees were confirmed by PD-specific nested PCR. On the original seedling trees, visible symptoms typical of PD, especially premature leaf coloration, were observed in late summer 2008 and samples taken of green and red leaves were subjected to PD-specific PCR. Red leaves were PD-positive, while green leaves were mostly PD-negative. Pear leaves, dormant shoots, and roots collected from research and commercial orchards in southern Ontario in 2007 and 2008 were subjected to PD-specific nested PCR (P1/P7 then fPD/rPDS), AP-specific nested PCR (P1/P7 then fO1/rO1) (2), as well as the universal phytoplasma nested PCR (P1/P7 then fU5/rU3), resulting in the identification of PD-positive trees of several cultivars. The sequence of the 1,057-bp amplicon from accession PYR0190 (selection HW615), with AP-specific primers fO1/rO1, was deposited in GenBank (GU475131). Although there have been no previous reports of PD in Ontario, Canada, it would appear that PD has been present for some time based on the number and distribution (both geographic and cultivar) of positive samples. References: (1) S. Deng and C. Hiruki. J. Microbiol. Methods 14:53, 1991. (2) K.-H. Lorenz et al. Phytopathology 85:771, 1995. (3) E. Seemüller et al. J. Plant Pathol. 80:3, 1998. (4) C. D. Smart et al. Appl. Environ. Microbiol. 62:2988, 1996.

Histopathological screening of tonsillectomy and/or adenoidectomy specimens: a report from southern Iran.

BACKGROUND: The need for pathologic examination of all tonsillectomy and/or adenoidectomy (T&A) specimens is controversial. Microscopic pathologic examination of these specimens is costly, but neglecting this step may miss diagnoses of significant diseases, especially malignancies. This study was designed to determine the rate of unexpected malignancies among patients who underwent T&A. METHODS: All patients who underwent T&A at Shiraz University of Medical Sciences between February 2004 and February 2008 were included in a prospective study. Gross and microscopic pathologic examinations were done on all the specimens. The charts of the patients with significant pathological finding were reviewed. Information about pre-operative signs, symptoms, and risk factors were used to verify unexpected pathologic findings. RESULTS: A total of 5058 patients were included. The age distribution was 10 months to 92 years (mean 14.0 years). There were 2498 males (49.4) and 2560 females (50.6%). Significant pathological findings were detected in 54 patients (1%). One unexpected malignancy (0.019%) was found in an adult patient. No unexpected malignancies were found in pediatric patients. CONCLUSIONS: All T&A specimens in the adult population should be sent for microscopic pathological examination. Also specimens of nonroutine T&A in children (with positive findings in the medical history or on physical examination) should be sent for microscopic pathological examination. In children without positive findings in their history or on physical examination, gross pathological evaluation of routine T&A specimens by a pathologist is sufficient.

Meningococcal carrier rate before and after hajj pilgrimage: effect of single dose ciprofloxacin on carriage.

We determined the carriage rate of Neisseria meningitidis before and after hajj pilgrimage among a group (1) of 674 randomly selected Iranian pilgrims, and the effect of 500 mg of ciprofloxacin given 24 hours before return on the reduction of meningococcal carriers among another group (2) of 123 randomly selected Iranian pilgrims. Throat specimens taken 1 hour before departure on the hajj and immediately on return were cultured. Carriage rates of N. meningitidis in group 1 were 5.2% before and 4.6% after pilgrimage (P = 0.65); 3 new serogroups (Z, Z and A) were identified on return. In group 2, the carriage rate decreased from 8.1% to zero before and after pilgrimage.

Meningococcal carrier rate before and after hajj pilgrimage: effect of single dose ciprofloxacin on carriage

We determined the carriage rate of Neisseria meningitidis before and after hajj pilgrimage among a group [1] of 674 randomly selected Iranian pilgrims, and the effect of 500 mg of ciprofloxacin given 24 hours before return on the reduction of meningococcal carriers among another group [2] of 123 randomly selected Iranian pilgrims. Throat specimens taken 1 hour before departure on the hajj and immediately on return were cultured. Carriage rates of N. meningitidis in group 1 were 5.2% before and 4.6% after pilgrimage [P = 0.65]; 3 new serogroups [Z, Z' and A] were identified on return. In group 2, the carriage rate decreased from 8.1% to zero before and after pilgrimage

Diurnal nonstress test variations in the human fetus at risk.

OBJECTIVE: To compare the results of the nonstress test (NST) performed at 9:00 PM and 9:00 AM on women with high-risk pregnancies. METHOD: The NST was performed 2 h after a meal, at 9:00 AM and 9:00 PM, in a quiet room exposed to daylight, on 80 women with high-risk singleton pregnancies. Each session lasted 20 min. If the NST was nonreactive, the entire biophysical profile was immediately performed. The women's blood pressure was measured before, 10 min within, and at the end of the NST. Women who smoked or had uterine contractions were excluded from the study. RESULTS: Diurnal nonstress test variations were manifested by a higher incidence of reactive NSTs and an increased number of fetal heart accelerations after 9:00 PM (82.5%) than at 9:00 AM (68.8%) (p<0.027 P<0.001). CONCLUSIONS: Evening appointments for fetal assessments, except in emergency conditions, may eliminate the need for additional tests such as the entire biophysical profile because of the decreased incidence of nonreactive NSTs. Evening NSTs would save time and decrease maternal anxiety.

Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole.

BACKGROUND: Twenty four hour oesophageal pH monitoring is frequently used to quantify the association between a patient's symptom and gastro-oesophageal reflux. Three indices (symptom association probability (SAP), symptom index (SI), and symptom sensitivity index (SSI)) are used to quantify and establish this relation. AIMS: The aim of the present study was to compare these indices against the omeprazole test (OT) as an objective indicator of reflux induced symptoms. METHODS: Fifty two patients with a predominant symptom of heartburn were enrolled from gastroenterology and primary care clinics. Baseline symptom score was calculated at the fist visit. All patients underwent 24 hour oesophageal pH monitoring, and symptom-reflux association indices were calculated. All patients were placed on high dose omeprazole (40 mg in the morning, 20 mg at night) after completion of pH monitoring and symptom score was recorded again after one week. RESULTS: Thirty eight patients completed the study. All three indices were significantly related to each other (p<0.001). SAP and SSI (with a new cut off of 1.3, but not with the commonly used 5%) had statistically significant relations with OT (p<0.05 for both). SSI had the highest positive and negative predictive values and sensitivity. The specificity of SSI and SAP was equal and lower than SI. Areas under the receiver operating characteristic (ROC) curve for the three indices were not significantly different from each other or from a hypothetical non-discriminating test. Per cent time pH <4, sex, and age had no relation to OT and no effect on its correlation with association indices. No cut off point could be found at which the results of SI could be related significantly to the OT results. CONCLUSION: SAP and SSI are significantly related to symptomatic response to high dose omeprazole; however, they are far from perfect, with a significant number of discordant cases as well as relatively small areas under the ROC curves. We suggest that the new cut off of 1.3 be used for SSI in the future. Further research is needed to identify possible methods to improve the discrimination power of these indices or to identify possible patient characteristics that may affect this relation.

Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: a prospective, double-blind, randomized, clinical trial.

BACKGROUND: Endoscopic therapies and continuous intravenous omeprazole can decrease the morbidity and duration of hospital stay of patients with high-risk peptic ulcer. AIM: To evaluate the role of oral omeprazole in high-risk bleeders. METHODS: After injection therapy of 160 patients with high-risk peptic ulcer, 80 received oral omeprazole and 80 received placebo, and all were followed up. RESULTS: One hundred and forty-nine patients (71 omeprazole and 78 placebo) completed the study. Eleven patients were excluded from the study. Thirty-seven (25%) patients had gastric ulcer and 112 (75%) had duodenal ulcer. Fifty-seven (38%) ulcers showed visible vessels, 80 (54%) showed oozing of blood and 12 (8%) showed a spurting artery. Only one patient died (placebo group). The mean hospital stays were 62.8 +/- 28.6 h and 75 +/- 39 h in the omeprazole and placebo groups, respectively (P = 0.032). The mean amounts of blood transfused were 1.13 +/- 1.36 and 1.68 +/- 1.68 bags in the omeprazole and placebo groups, respectively (P = 0.029). The re-bleeding rate was lower in the omeprazole group than in the placebo group (12 vs. 26, respectively; P = 0.022). CONCLUSION: Oral omeprazole is effective in decreasing the hospital stay, re-bleeding rate and the need for blood transfusion in high-risk ulcer bleeders treated with endoscopic injection therapy.

Various durations of a standard regimen (amoxycillin, metronidazole, colloidal bismuth sub-citrate for 2 weeks or with additional ranitidine for 1 or 2 weeks) on eradication of Helicobacter pylori in Iranian peptic ulcer patients. A randomized controlled trial.

INTRODUCTION: One of the most economical and effective therapeutic regimens for eradication of Helicobacter pylori is the classic triple therapy with amoxycillin or tetracycline, metronidazole and a bismuth derivative. Addition of H2-receptor antagonists to these drugs may heighten the rate of eradication and shorten the duration. We therefore performed a randomized controlled trial comparing twice daily metronidazole, bismuth derivative and amoxycillin for 2 weeks with additional ranitidine for 1 or 2 weeks. PATIENTS AND METHODS: In total, 240 adult patients with duodenal ulcer and H. pylori infection were randomly assigned to one of the following regimens: (1) amoxycillin 1 g bid, metronidazole 500 mg bid, bismuth sub-citrate 240 mg bid and ranitidine 300 mg bid for 1 week; (2) triple therapy without ranitidine for 2 weeks; or (3) triple therapy plus ranitidine 300 mg bid for 2 weeks. Side-effects of the drugs were evaluated two weeks after starting the treatment. The rapid urease test and histology from antrum and corpus, and/or 14C- urea breath test were used to determine H. pylori eradication six weeks after starting the treatment. RESULTS: In total, 195 patients were followed up for 6 weeks. The most frequent drug side-effects were unpleasant taste (46%), dry mouth (41%) and fatigue (26%), which had an equal distribution in all treatment groups. Endoscopy and 14C- urea breath test were performed for 178 and 123 patients, respectively. Eradication of H. pylori was documented in 19/64 (29.7%), 29/63 (46%) and 50/68 (73.5%) of patients in groups 1, 2 and 3, respectively (P < 0.000001 for group 1 versus group 3; P < 0.0014 for group 2 versus group 3; difference not significant for group 1 versus group 2). An intention-to-treat analysis showed eradication rates of 19/80 (23.75%), 29/80 (36.25%) and 50/80 (62.5%) for groups 1, 2 and 3, respectively. At four weeks post-treatment, the most sensitive test for evaluation of eradication of H. pylori was histology. CONCLUSION: Although combined use of an H2-receptor antagonist and twice daily triple therapy in a two-week regimen is more effective than two-week triple or one-week quadruple therapy in Iranian patients, none of these regimens is ideal in countries with a probable high rate of resistant and strongly toxic strains of H. pylori.

Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis.

Autoimmune hepatitis (AIH), a chronic T-cell-mediated liver injury, is treated with corticosteroids with or without Azathioprine. Corticosteroids are not universally effective and have serious side effects. Cyclosporin A was effective in refractory cases. To assess efficacy and safety of Cyclosporin A (Neoral) in induction of remission in AIH patients this study was performed. Nineteen consenting AIH patients (nine treatment-naive) were treated with cyclosporin A in an open label trial and followed for 26 weeks. Liver biopsy was done and hepatitis activity index (HAI) determined at the beginning and end of treatment. Four patients did not complete the study for various reasons. Mean AST and ALT levels decreased from 948.7 +/- 103.5 and 454.8 +/- 354 to 100.6 +/- 111.8 and 78.5 +/- 40.3 (P < 0.03, P < 0.001) respectively. HAI decreased from 15.2 +/- 3.16 to 7.14 +/- 4.01 (P < 0.005). Serum creatinine did not change significantly. In conclusion, low-dose cyclosporin A appears to be safe and effective even in treatment-naive autoimmune hepatitis patients. Randomized controlled trials are warranted.

Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin.

We identified eight cases of T-cell lymphoma with evidence of a gamma delta phenotype over a 13-year period. Seven of these cases conformed to a distinct clinicopathologic entity of hepatosplenic gamma delta T-cell lymphoma. Nearly all of these patients were young adult males (five of seven), with a median age at presentation of 20 years. They presented with marked hepatosplenomegaly, without lymphadenopathy or significant peripheral blood lymphocytosis. Thrombocytopenia was seen in all patients, and five of seven were mildly anemic. The clinical course was aggressive, and despite multiagent chemotherapy, the median survival duration was less than 1 year. The morphologic findings were uniform; a monomorphic population of medium-sized lymphoid cells with moderately clumped chromatin and a rim of pale cytoplasm infiltrated the sinusoids of the spleen, liver, and bone marrow. The cells had a characteristic immunophenotype: CD2+, CD3+, CD4-, CD5-, CD7+, CD16+, CD57-, CD25-, T-cell receptor (TCR)delta +, beta F1-. CD8 was positive in four of seven cases tested, and CD56 was positive in five of six. All cases expressed the cytotoxic granule-associated protein, TIA1, but perforin was detected in only one case. All cases with assessable DNA had a TCR gamma gene rearrangement, and lacked Epstein-Barr virus sequences. Isochromosome 7q was identified in two cases with cytogenetic information. The one case of cutaneous gamma delta T-cell lymphoma differed in its clinical manifestations, histologic appearance, and immunophenotype. We conclude that hepatosplenic gamma delta T-cell lymphoma is a distinct clinicopathologic entity derived from cytotoxic gamma delta T cells, and should be distinguished from other lymphomas of T-cell and natural-killer cell (NK)-like T-cell derivation.

Thrombopoietic activity of recombinant human interleukin 11 (rHuIL-11) in normal and myelosuppressed nonhuman primates.

We have extensively characterized the hematological response of normal and myelosuppressed nonhuman primates to treatment with recombinant human interleukin 11 (rHuIL-11) in vivo. In normal cynomolgus monkeys, rHuIL-11 significantly increased peripheral platelet counts when administered at doses of 10 micrograms/kg/day to 100 micrograms/kg/day either by constant i.v. infusion or s.c. injection. As few as four days of rHuIL-11 treatment were sufficient to increase peripheral platelet counts significantly. In addition, extending the treatment period enhanced both the magnitude and the duration of the response. Bone marrow megakaryocytes from animals treated with 100 micrograms/kg/day of rHuIL-11 were increased in size compared to controls and were ultrastructurally normal. A nonhuman primate myelosuppression model using carboplatin, which causes severe thrombocytopenia with platelet counts of < or = 20 x 10(3) platelets/microliters, was developed. This novel model was used to evaluate the effectiveness of rHuIL-11 in platelet restoration. rHuIL-11, administered s.c. at a dose of 125 micrograms/kg/day either concurrently or following chemotherapy, prevented severe thrombocytopenia in addition to accelerating platelet recovery compared to control animals receiving no rHuIL-11. These data demonstrate that rHuIL-11 has potent in vivo thrombopoietic effects when administered to normal and myelosuppressed nonhuman primates, and that rHuIL-11 can be an important therapy to reduce the severity and duration of thrombocytopenia following chemotherapy.