Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis.

A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P<0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P<0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P<0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome.

We investigated the hypothesis that gemtuzumab ozogamicin (GO), an anti-CD33 immunotoxin would improve the efficacy of fludarabine/melphalan as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. Toxicity was defined as grades III-IV organ damage, engraftment failure or death within 30 days. 'Response' was engraftment and remission (CR) on day +30. We sought to determine the GO dose (2, 4 or 6 mg m(-2)) giving the best trade-off between toxicity and response. All patients were not candidates for myeloablative regimens. Treatment plan: GO (day -12), fludarabine 30 mg m(-2) (days -5 to -2), melphalan 140 mg m(-2) (day -2) and HSCT (day 0). GVHD prophylaxis was tacrolimus and mini-methotrexate. Diagnoses were AML (n=47), MDS (n=4) or CML (n=1). Median age was 53 years (range, 13-72). All but three patients were not in CR. Donors were related (n=33) or unrelated (n=19). Toxicity and response rates at 4 mg m(-2) were 50% (n=4) and 50% (n=4). GO dose was de-escalated to 2 mg m(-2): 18% had toxicity (n=8) and 82% responded (n=36). 100-day TRM was 15%; one patient had reversible hepatic VOD. Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m(-2) can be safely added to fludarabine/melphalan, and this regimen merits further evaluation.

Videolaparoscopic treatment for isolated necrosis and abscess of the round ligament of the liver.

A case involving abcess and necrosis of the round ligament of the liver is described. This type of case is seldom reported in medical literature. Laparaoscopy is a very useful and feasible tool for the diagnosis and treatment of such cases. The video shows an oversized round ligament with necrotic appearance partially blocked by the epiplon, gallbladder, and stomach. (This online case report contains a video.).

Believe it or not--silver still poisons!

For centuries, silver has been endowed with therapeutic benefits. It is still used today as a "caustic" for superficial bleeding. Within 7days, we had 3 cases of "argyria" and then 2 more over the next month. The first 2 cases involved a husband and wife with a 3-y exposure to naturopathic hydrolyzed silver treatment. The third casewas a 37-y-old male in a state psychiatric facility noted to have darkly "discolored" skin probable obtained from herbal tea. The last 2 cases were a married couple into herbal medications who developed bluish discoloration of face and hands. Current cases due to "alternative medicine" may get worse as rumor reveals its popularity as prophylaxis against anthrax. The skin's grayish discoloration, made worse by sunlight, may persist for life.

Autologous stem cell transplantation for acute lymphocytic leukemia in adults.

Autologous bone marrow transplantation remains an investigational treatment for adult ALL. Despite many anecdotal studies showing efficacy, the rarity of ALL has prevented the large randomized trials necessary to confirm effectiveness. Candidates for autoBMT include adult patients in first CR with adverse risk factors and all patients who have experienced disease relapse. It remains debatable which preparative regimen is optimal, whether purging is necessary, or if chemotherapy or immunotherapy administered after transplantation can decrease disease relapse. Overall, every effort should be made to enter ALL patients on well-designed randomized multi-institutional trials. These trials should compare autologous transplantation to newer more intensive chemotherapy regimens and should take into account the heterogeneity of ALL. A quality of life analysis should be performed as one high-dose treatment may be less toxic and better tolerated than multiple cycles of consolidation chemotherapy. Strategies aimed at enhancing an autologous graft-versus-leukemia effect after transplantation may enhance long-term survival. Many more studies are needed to further define the optimal role of autoBMT in adult ALL.

Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults.

Acute lymphocytic leukemia remains a difficult disease to treat in adults. Allogeneic bone marrow transplantation can cure some patients with ALL, but GVHD transplant-related mortality and disease relapse remain problematic. Immunotherapeutic approaches aimed at eliminating minimal residual disease and enhancing the GVL effect may decrease relapse rates and improve overall survival. Because of the rarity of this disease in adults, every new patient should be entered in well-designed, peer-reviewed, investigational trial.

A comparative study of once-daily versus twice-daily filgrastim administration for the mobilization and collection of CD34+ peripheral blood progenitor cells in normal donors.

Eighty-one first-time normal donors underwent leukapheresis for peripheral blood progenitor cell (PBPC) collection after mobilization with filgrastim administered either twice-daily (6 microg/kg every 12 h; n = 40) or once-daily (12 microg/kg; n = 41) subcutaneously for 3 d. The groups were similar for age, donor blood volume and target CD34+ cell dose to be collected (>/= 4 x 106 CD34+ cells/kg recipient). There was no statistically significant difference in the apheresis yield of CD34+ PBPCs (x 106) per kg recipient weight (5.6 +/- 3.3 vs. 5.6 +/- 4.3; P = 0.94) and per litre of blood processed (30 +/- 17.2 vs. 30.4 +/- 19.5; P = 0.92).

Biomarkers of liver regeneration allow early prediction of hepatic recovery after acute necrosis.

Acute toxic hepatic necrosis is common and may be fatal. Predicting clinical outcome may be aided by following serum markers that could indicate recovery or may signify massive (substantial) destruction of functional liver mass. Previously, in a published case of chloroform poisoning, we serially assayed serum biomarkers of hepatocellular necrosis (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase) and markers of hepatocellular regeneration (alpha-fetoprotein, retinol-binding protein, gamma-glutamyl transferase, and des-gamma-carboxyprothrombin). We noted a decline in necrotic markers and a synchronous elevation in regenerative markers, which could be suggestive of a favorable outcome in similar cases. We now report 6 Amanita mushroom poisonings with favorable outcome and 2 fatal acetaminophen poisonings in which the same markers were observed. Our results further support our hypothesis that a sustained decline in serum markers of hepatocyte necrosis with a concurrent elevation in regenerative markers could aid in prediction of favorable outcome in patients with acute liver injury.

Health and growth performance of barrows reared in all-in/all-out or continuous flow facilities with or without a chlortetracycline feed additive.

OBJECTIVE: To compare health and growth performance in barrows reared in all-in/all-out (AIAO) or continuous flow (CF) management systems. ANIMALS: 400 barrows. PROCEDURE: Barrows (approx 2 months old) were allotted to 4 replications (100 barrows each); barrows were housed in AIAO or CF rooms (10 pens/room), and 50 pigs/replicate received chlortetracycline (CTC, 110 mg/kg of feed). Barrows from each pen were slaughtered at 3, 4, 5, and 6 months old. RESULTS: Barrows in the AIAO room had greater total daily gain (TDG) and lean daily gain (LDG) than did barrows in the CF room. Addition of CTC did not improve TDG or LDG in either environment. Barrows in the AIAO room reached body weight of 104.5 kg in 169.7 days, compared with 177.3 days for barrows in the CF room. Feed-to-gain ratio was not affected by management or CTC. Lungs from barrows reared in AIAO facilities had a lower percentage of lesions than did lungs of barrows reared in CF facilities (1.74% vs 9.52%). Addition of CTC did not affect prevalence and extent of lung lesions. Extent of lung lesions was positively correlated with change in serum optical density (OD) to Mycoplasma hyopneumoniae (r = 0.35), but not with change in serum OD to Actinobacillus pleuropneumoniae. Lean growth and serum OD to M. hyopneumoniae and A. pleuropneumoniae were not correlated. CONCLUSIONS: Health and growth performance were better for barrows in an AIAO facility, compared with a CF facility, but addition of CTC to feed failed to enhance health or performance of barrows in either facility.

Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation.

BACKGROUND: Thrombocytopenia is a common manifestation of cirrhosis. OBJECTIVES: To determine plasma thrombopoietin levels in cirrhotic patients with thrombocytopenia, monitor those levels before and after orthotopic liver transplantation, and compare thrombopoietin messenger RNA (mRNA) levels in liver samples from cirrhotic patients and controls. DESIGN: A cross-sectional study of patients with cirrhosis, including a small subset of patients who had orthotopic liver transplantation. SETTING: University-affiliated hospital. PATIENTS: 44 patients with cirrhosis, including 17 patients who had orthotopic liver transplantation. INTERVENTION: Orthotopic liver transplantation. MEASUREMENTS: Plasma thrombopoietin levels in all patients, platelet counts in all patients, and thrombopoietin mRNA levels in liver samples from nine patients with cirrhosis and eight controls. RESULTS: Thrombopoietin levels were undetectable in 39 of 44 patients with cirrhosis. In 16 of 17 patients, the levels became detectable after liver transplantation. Thrombopoietin mRNA levels were decreased in liver samples from patients with cirrhosis compared with controls (P = 0.0103). CONCLUSIONS: The low thrombopoietin levels in cirrhotic patients with thrombocytopenia and the increased levels after orthotopic liver transplantation suggest that impaired production of thrombopoietin may contribute to thrombocytopenia associated with cirrhosis.

Lack of a nocturnal rise in serum concentrations of melatonin as gilts attain puberty.

Twenty prepubertal crossbred gilts (Yorkshire x Hampshire x Duroc) weighing 98.1 +/- 4.2 kg at 5 mo of age were placed in an environmentally controlled room having a temperature of 18 degrees C and light:dark cycle of 12 h:12 h. Light intensity measured 700 lx at eye level to the gilts. Three mature ewes were penned adjacent to the gilts to serve as positive controls for the light-dark cycles. After a 30-d acclimation period, 10 gilts from the pool determined to be prepubertal (serum progesterone < 500 pg/mL) were fitted with surgically implanted jugular catheters. Blood samples were drawn at 1100 (4 h after onset of light), 1130, 1200, 2300 (4 h after onset of darkness), 2330, and 2400 for 4 d. On d 5 of sampling, gilts were transported in an open-bed truck for 15 min, returned to their original environment, and exposed to boars for 20 min. Boar exposure was repeated every day throughout the remainder of the experimental period. Blood samples were drawn from each gilt until 7 d after estrus or for 12 d in those gilts that did not exhibit estrus. Blood samples were drawn by venipuncture from the ewes during the entire experimental period. For each sampling day, within an individual gilt or ewe, means of serum concentrations of melatonin (MEL) for night (scotophase) and day (photophase) samples were calculated. After three replications were conducted, four classes of animals were obtained: ewes (n = 9); nonpubertal gilts (n = 10); and two classes of gilts that ultimately reached puberty (prepubertal [n = 16] and postpubertal [n = 16]). Across all gilts, only 65 of 406 bleeding periods (16.0%) had a nocturnal (scotophase) rise in serum MEL. The proportion of gilts expressing a nocturnal rise in serum MEL did not differ as gilts approached puberty (P > .05). Incidence of nocturnal rises of MEL was similar (P > .05) in gilts that attained puberty and gilts that did not attain puberty. Nocturnal rises in MEL were observed in 86.2% of the bleeding periods of ewes housed in the same environment. These data indicate clearly that nocturnal rises in serum MEL are not necessary for a gilt to attain puberty.

Serotonin syndrome due to venlafaxine and maintenance tranylcypromine therapy.

A number of novel serotonergic antidepressants have been introduced to clinical practice over the last decade. These medications are felt to be safe alternatives to the traditional tricyclic antidepressants and monoamine oxidase inhibitors, particularly in the overdose setting. Serious adverse reactions and drug interactions have been appreciated and fatalities have been reported. We describe the development of the serotonin syndrome in a 60 year old female on chronic tranylcypromine treatment following the inadvertent ingestion of a single dose of venlafaxine. Manifestations included and altered mental status that progressed to hyperthermia and coma. She recovered quickly and without complications. Health care providers and poison specialists need to be aware that this potentially serious syndrome can be precipitated by a single dose of a serotonin reuptake inhibitor in patients being treated with a monoamine oxidase inhibitor.

Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation.

Thrombopoietin, the ligand for the c-mpl receptor, promotes proliferation and maturation of megakaryocytes. An ELISA using a chimaeric receptor, mpl-IgG, for capture, and rabbit antibody to thrombopoietin for detection was developed for the quantitation of thrombopoietin in human serum or plasma. This ELISA preferentially detects full-length thrombopoietin compared to the bioactive N-terminal half of the molecule which has homology to erythropoietin. Thrombopoietin was not detected (< 0.16 ng/ml) in 88/89 healthy individuals. However, elevated thrombopoietin concentrations of up to 3 ng/ml were detected in 59/63 thrombocytopenic patients, including cancer patients following chemotherapy. In cancer patients receiving chemotherapy with (n = 12) or without (n = 6) peripheral blood progenitor cell transplantation, thrombopoietin concentrations varied inversely with platelet counts throughout the treatment period. In general, patients who received myeloablative chemotherapy on days -7 to -2 and peripheral blood progenitor cell transplantation on day 0 had high thrombopoietin levels (0.6-2.9 ng/ml) around day 5. Low platelet counts (< 20 x 10(9)/l) occurred between days 4 and 9. Patients who received high-dose chemotherapy on day 1 (equivalent to day -7 for transplantation patients) to day 6 without transplantation had high thrombopoietin concentrations (1.4-2.3 ng/ml) around day 13 and low platelet counts occurred between days 7 and 17.

Serotonin syndrome.

Selective serotonin reuptake inhibitors (SSRIs) are replacing tricyclic antidepressants (TCAs) with increasing frequency in the United States. Although SSRI poisoning tends to be less serious that TCA poisoning, the incidence of adverse side effects and drug interactions may be greater. The serotonin syndrome is a potentially severe adverse drug interaction characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities. The serotonin syndrome is similar to the neuroleptic malignant syndrome, leading to misdiagnosis. Although serotonin syndrome may result in death, most patients recover completely with supportive care alone. The main pathophysiologic mechanism appears to be excessive 5-hydroxytryptophan stimulation; this finding is supported by reports of beneficial effects with serotonin-antagonist treatment. The incidence of the serotonin syndrome may increase as SSRIs continue to replace TCAs. Morbidity and costly diagnostic procedures may be avoided if prompt diagnosis and appropriate treatment are provided.

Influence of mastitis on D-amino acid content of milk.

The California Mastitis Test was used as an indicator of mastitis in this study. Five cows were chosen for each of the five test scores (from 0 = healthy to 4 = severe mastitis). Milk samples were analyzed for free AA and free D-AA. The contents of free AA, free D-AA, and the ratio of free D-AA to free AA increased significantly as the California Mastitis Test score increased. The free D-AA content of foremilk (first milk jets) from healthy cows (test score = 0) was approximately five times that in samples drawn later from the same udders. Contents of free AA and free D-AA were highly associated with test score and udder inflammation. Very low concentrations of free D-AA are normal for raw milk. Higher concentrations of free D-AA could be attributed to inclusion of foremilk and milk from cows having subclinical mastitis in the bulk tank milk.

Multistage selection for maximum economic return with an application to beef cattle breeding.

Methodology for selection index updating was developed to allow multistage selection. The program determines truncation points for each stage of selection that will maximize either profit or the ratio of aggregate economic gain to cost (R = delta H/C). Either maximum profit or R may be attained by reducing the cost of performance testing in later stages of a multistage program. In order to eliminate the need for multiple integration and assure convergence, a piecewise algorithm was developed. Examples of beef bull selection compared single-stage selection at 1 yr of age, two-stage selection at birth and 1 yr, two-stage selection at 205 d and 1 yr, and three-stage selection at birth, 205 d, and 1 yr. Selection based on three traits (birth weight, gain birth to 205 d, and gain 205 to 365 d) was compared with selection based on four traits (the above three plus ultrasound fat depth) and selection based on five traits (the above four plus feed:gain ratio). Five scenarios were used that allowed variation in proportion of candidates selected for breeding, number of progeny per selected bull, and proportion of profit returned to the nucleus herd. General conclusions based on the examples were 1) multistage selection reduced aggregate economic gain relative to that attained by single-stage selection, 2) inclusion of feed conversion in the index of traits resulted in reduced profit and aggregate economic gain, 3) measurement of feed conversion could be justified when selected bulls produced a large number of progeny, and 4) three-trait selection produced greater profit in all five scenarios than did four- or five-trait selection. Use of the selection updating program described here provides a new source of information that can be used in developing economically sound performance testing and selection programs.

Hemodynamic effects of 3,4-diaminopyridine in a swine model of verapamil toxicity.

STUDY HYPOTHESIS: 3,4-Diaminopyridine (3,4-DAP) may reverse the hemodynamic effects of severe verapamil toxicity. DESIGN: A nonblinded acute animal preparation. INTERVENTIONS: Eighteen chloralose-anesthetized and instrumented swine were poisoned with verapamil at 10 mg/kg/hr for five minutes and then 5 mg/kg/hr until a systolic blood pressure of 55 mm Hg was achieved. Heart rate, lead II ECG, mean arterial pressure, left ventricular dP/dT max, and cardiac index were monitored. Nine control animals received 0.2 mL/kg/min infusion of normal saline, and nine treatment animals received similar volumes of 1 mg/kg/min 3,4-DAP until systolic blood pressure reached 100 mm Hg, an elapsed time of 30 minutes, or death. RESULTS: Verapamil toxicity was produced in all animals following an average dose of 1.38 +/- 0.44 mg/kg verapamil, and resulted in diminished mean arterial pressure, dP/dT max, cardiac index, and heart rate to average values of 47%, 32%, 46%, and 88% of baseline values, respectively. Transient atrioventricular dissociation was noted in only 22% of cases. 3,4-DAP treatment (with an average dose of 14 +/- 5.6 mg/kg) resulted in significant increases in mean arterial pressure, dP/dT max, cardiac index, and heart rate to 136%, 298%, 149%, and 158% of baseline values, respectively. Mortality was unchanged (22% in both groups). 3,4-DAP treatment was complicated by muscle twitching, tachycardia (rate of more than 180) and hypertension (diastolic blood pressure of more than 110 mm Hg) each in 44% of cases. CONCLUSION: Although 3,4-DAP reversed the hypotensive and negative inotropic effects of verapamil toxicity, it failed to improve survival and resulted in several complications including muscle twitching, tachycardia, and hypertension.

Mixed fluoxetine/loxapine overdose and atrial flutter.

A 19-year-old man who attempted suicide by ingesting approximately 600 mg fluoxetine (Prozac) and 140 mg loxapine (Loxitane) had two episodes of atrial flutter shortly thereafter. Admission serum fluoxetine, norfluoxetine, and loxapine levels were 1,053 ng/mL, 702 ng/mL, and 40 ng/mL, respectively. This case of atrial flutter in association with an overdose of either of these drugs demonstrates the potential for cardiotoxicity with these agents in the overdose setting. Theoretical mechanisms of cardiotoxicity are presented.