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Cryogenian cap carbonates that overlie Sturtian glacial deposits were formed during a post-glacial transgression. Here, we describe microfossils from the Kakontwe Formation of Zambia and the Taishir Formation of Mongolia-both Cryogenian age, post-Sturtian cap carbonates-and investigate processes involved in their formation and preservation. We compare microfossils from these two localities to an assemblage of well-documented microfossils previously described in the post-Sturtian Rasthof Formation of Namibia. Microfossils from both new localities have 10 ± 1 μm-thick walls composed of carbonaceous matter and aluminosilicate minerals. Those found in the Kakontwe Formation are spherical or ovoid and 90 ± 5 μm to 200 ± 5 μm wide. Structures found in the Taishir Formation are mostly spherical, 50 ± 5 μm to 140 ± 5 μm wide, with distinct features such as blunt or concave edges. Chemical and mineralogical analyses show that the walled structures and the clay fraction extracted from the surrounding sediments are composed of clay minerals, especially muscovite and illite, as well as quartz, iron and titanium oxides, and some dolomite and feldspar. At each locality, the mineralogy of the microfossil walls matched that of the clay fractions of the surrounding sediment. The abundance of these minerals in the walled microfossils relative to the surrounding carbonate matrix and microbial laminae, and the presence of minerals that cannot precipitate from solution (titanium oxide and feldspar), suggests that the composition represents the original mineralogy of the structures. Furthermore, the consistency in mineralogy of both microfossils and sediments across the three basins, and the uniformity of size and shape among mineral grains in the fossil walls indicate that these organisms incorporated these minerals by primary biological agglutination. The discovery of new, mineral-rich microfossil assemblages in microbially laminated and other fine-grained facies of Cryogenian cap carbonates from multiple localities on different palaeocontinents demonstrates that agglutinating eukaryotes were widespread in carbonate-dominated marine environments in the aftermath of the Sturtian glaciation. [ABSTRACT FROM AUTHOR]

Although macroscopic plants, animals, and fungi are the most familiar eukaryotes, the bulk of eukaryotic diversity is microbial. Elucidating the timing of diversification among the more than 70 lineages is key to understanding the evolution of eukaryotes. Here, we use taxon-rich multigene data combined with diverse fossils and a relaxed molecular clock framework to estimate the timing of the last common ancestor of extant eukaryotes and the divergence of major clades. Overall, these analyses suggest that the last common ancestor lived between 1866 and 1679 Ma, consistent with the earliest microfossils interpreted with confidence as eukaryotic. During this interval, the Earth's surface differed markedly from today; for example, the oceans were incompletely ventilated, with ferruginous and, after about 1800 Ma, sulfidic water masses commonly lying beneath moderately oxygenated surface waters. Our time estimates also indicate that the major clades of eukaryotes diverged before 1000 Ma, with most or all probably diverging before 1200 Ma. Fossils, however, suggest that diversity within major extant clades expanded later, beginning about 800 Ma, when the oceans began their transition to a more modern chemical state. In combination, paleontological and molecular approaches indicate that long stems preceded diversification in the major eukaryotic lineages., Earth and Planetary Sciences, Accepted Manuscript

When producing chemical sensors, especially in thin film form, there are often a large variety of processing variables that are believed to impact the ultimate performance of the materials. It is thus advantageous to find methods for simultaneous, high-throughput characterization of many process variables. Here, we report on a method for using MEMS-based microhotplates to create and characterize arrays of chemiresistive SnO thin films. The microhotplates are used both to control the thermal process variables at each element of the array during film growth by CVD as well as subsequently to operate the sensors. Example chemiresistive properties of the films at 200°C were characterized during exposure to CH OH and NO . Through the use of a fractional factorial experiment design, the effects of 4 different process variables (growth temperature, thickness, presence of a dopant and use of rapidly pulsed heating during growth) were reliably determined using only 8 films and the associated statistical modeling of the results . [ABSTRACT FROM PUBLISHER]

Major lineages of modern eukaryotes, represented primarily by microscopic taxa, are thought to have originated during the Neoproterozoic, but microfossils older than 635 Ma rarely have unambiguous relationships to modern microscopic eukaryotes. Here we report exceptionally preserved 715-635 m.y. old eukaryotic tests in limestone strata of Mongolia. The ~100-µm-long organic-rich three-dimensional tests have flask-like shapes, constricted necks, distinct and often thickened collars, and flexible walls composed of densely packed alveolar structures. The combined morphological and ultrastructural characters of these Cryogenian tests are remarkably similar to the tests of tintinnids, modern planktonic ciliates. Eukaryotes forming recalcitrant organic or mineral-rich tests before 635 Ma may have increased export and burial fraction of organic carbon, driving an increase in atmospheric oxygen and the subsequent radiation of metazoans. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy of a specialized inpatient rehabilitation program in patients with newly diagnosed epilepsy (NDE), who had been referred within 1 year after diagnosis., Methods: We performed an open, prospective, controlled study comparing a 1-year follow-up assessment of patients with NDE after completing a rehabilitation program at an epilepsy center (rehabilitation group) with a control group of patients with similar epilepsy duration, but without rehabilitation in the first year after diagnosis. Primary outcome measures comprised emotional adaptation to epilepsy, depression and anxiety; and secondary outcome measures were overall quality of life (QoL), overall health, perceived restrictions because of epilepsy, level of information about epilepsy, and employment status., Results: Comparison of the admission data of 74 rehabilitation group patients (mean age and SD 47.7 ± 13.0 years) with the pre-rehabilitation assessment of 56 control patients (45.5 ± 12.1 years) revealed no significant differences concerning sociodemographic and health data. Comparison of the follow-up assessment of the rehabilitation group and the pre-rehabilitation assessment of the control group showed significantly better values for the rehabilitation group on emotional adaptation to epilepsy (p = .003), overall QoL (p = .006) and overall health (p = .011), perceived restrictions because of epilepsy, and subjective level of information about epilepsy (both p's < .001). There were no statistically significant differences concerning depression and anxiety or employment status (all p's > .50). One year after rehabilitation, patients in the rehabilitation group were more often seizure-free and less often on sickness absence than control group patients (both p's < .001)., Significance: Since reduced QoL shortly after diagnosis of NDE is associated with seizure recurrence, an early identification of patients with a greater need for support seems important. This epilepsy-related rehabilitation program showed lasting effects on several aspects of adaptation to epilepsy and QoL., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To evaluate the efficacy of a specialized inpatient rehabilitation program in patients with early in comparison with chronic epilepsy., Methods: We performed a prospective, open pre/post study using a parallel group design. Patients with early epilepsy (EE, treatment with anti-seizure medication [ASM] ≤ 1 year) or with chronic epilepsy (CE, ASM treatment > 5 years) completed questionnaires at the time of their admission to the rehabilitation program and at discharge. Outcome measures comprised scales from the PESOS questionnaire (PErformance, SOciodemographic aspects, Subjective estimation; e.g., emotional adaptation to epilepsy) as well as screening instruments for depression (Neurological Disorders Depression Inventory for Epilepsy, NDDI-E) and anxiety (Generalized Anxiety Disorder Scale, GAD-7). Linear mixed models (LMMs) were used to determine the effects of the program in the total group and to compare the effects between patients with EE and CE., Results: The analyses included 79 patients with EE and 157 patients with CE. Baseline comparisons revealed differences in disease-related and sociodemographic variables (e.g., patients with EE were older, those with CE had a higher seizure frequency and a higher rate of unemployment; all p < .01). LMMs showed significant improvements in emotional adaptation to epilepsy, depression, anxiety, overall quality of life and overall health as well as in perceived overall restrictions because of epilepsy and the subjective level of information about epilepsy (all p < .001). Despite the different duration of epilepsy, baseline levels as well as improvements did not differ between patients with EE and CE (all p > .05) except for the perceived level of information, which was significantly lower in patients with EE at admission and improved to a higher extent in this group (both p < .001)., Conclusion: Both patients with EE and patients with CE who are referred to a specialized comprehensive rehabilitation program benefit from the participation in this program with respect to emotional adaptation to epilepsy, aspects of quality of life, and level of information about epilepsy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rab GTPase is a paralog-rich gene family that controls the maintenance of the eukaryotic cell compartmentalization system. Diverse eukaryotes have varying numbers of Rab paralogs. Currently, little is known about the evolutionary pattern of Rab GTPase in most major eukaryotic 'supergroups'. Here, we present a comprehensive phylogenetic reconstruction of the Rab GTPase gene family in the eukaryotic 'supergroup' Amoebozoa, a diverse lineage represented by unicellular and multicellular organisms. We demonstrate that Amoebozoa conserved 20 of the 23 ancestral Rab GTPases predicted to be present in the last eukaryotic common ancestor and massively expanded several 'novel' in-paralogs. Due to these 'novel' in-paralogs, the Rab family composition dramatically varies between the members of Amoebozoa; as a consequence, 'supergroup'-based studies may significantly change our current understanding of the evolution and diversity of this gene family. The high diversity of the Rab GTPase gene family in Amoebozoa makes this 'supergroup' a key lineage to study and advance our knowledge of the evolution of Rab in Eukaryotes.

Topiramate (TPM) is an effective antiepileptic drug (AED). A high proportion of patients, however, experiences cognitive adverse events (CAEs), especially in verbal fluency, memory spans, and working memory. To our knowledge, CAEs of TPM have not been studied systematically in patients with intellectual disability (ID). This may be due to the fact that many of those patients are not able to follow test instructions properly and that neuropsychological instruments are not validated for that group. Cognitive deterioration in patients with ID may thus easily be overlooked. Topiramate is in frequent use in persons with ID. We included 26 consecutive patients with epilepsy and ID in this observational study who had undergone neuropsychological examinations as part of clinical routine before and after the introduction of TPM into the therapeutic regimen (n=4) or before and after the withdrawal of TPM (n=22). Examinations under TPM showed reduced cognitive speed, reduced verbal memory, reduced verbal fluency, and reduced flexibility compared to examinations without TPM. Despite some limitations (especially small sample size, high interindividual variation of the results dependent on the degree of ID, effects of other - limited - changes in the therapeutic regimen), our study indicates that TPM in persons with epilepsy and ID may lead to CAEs comparable to those in persons with normal intelligence. Neuropsychological testing is mandatory in order not to miss CAEs that might severely impair quality of life., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Patients with major depression report on severe cognitive deficits but objective neuropsychological test results indicate rather mild problems. In the present study we aimed at investigating neuropsychological performance, subjective complaints, and observer ratings of cognitive abilities in everyday life., Methods: Fifteen patients with major depression were studied in the acute state of illness and after remission. Fifteen healthy control subjects were investigated, too. A comprehensive neuropsychological battery, questionnaires for self and observer rating of cognitive abilities, and clinical questionnaires were administered., Results: As expected problems reported in self and observer ratings exceeded neuropsychological deficits in tests. Neuropsychological test results tended to be improved at the second test session, with patients showing a more pronounced improvement in flexibility., Conclusions: The data support the hypothesis that cognitive problems in everyday life indeed exceed results in standardised tests. However, it seems also likely from our data that results are additionally influenced by patients negative self perception.

Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.

Introduction: In its guideline on intrapartum fetal surveillance, the Society of Obstetricians and Gynaecologists of Canada (SOGC) recommended the availability of 1:1 nursing care (1 nurse to 1 patient) for women in active labour. The common perception is that the majority of women in labour and delivery units are in active labour. Identifying the proportion of women in active labour versus those who are not in active labour is crucial for the allocation of nursing care resources., Objectives: We sought to obtain a quantitative description of our obstetrical population to determine the distribution of women in the labour and delivery (L&D) unit, the obstetrical triage unit, and the labour, delivery, recovery, and postpartum (LDRP) unit and to determine the proportion of women in active labour who were receiving 1:1 nursing care., Methods: We randomly sampled and surveyed nursing care activities and patient distribution in a 1-hour period each day over a period of 4 months; each hour of the day was assessed on 5 separate occasions. The 3 units (L&D, LDRP, and obstetrical triage) were surveyed simultaneously., Results: In the L&D unit, 31% of women were in active labour; of those, 92% received 1:1 nursing care. The remaining women (69%) were either in the early phase of labour, had significant obstetrical complications, were undergoing Caesarean section, or had just delivered. In the LDRP unit, 13% of women were in active labour, and 87% were postpartum. Almost one-half the women (45%) in the obstetrical triage unit were being assessed for possible labour or possible rupture of membranes, while the remainder were being assessed for other pregnancy-related problems., Conclusion: Contrary to common perception, the majority of women in the L&D unit were admitted for reasons other than active labour but required care in that unit. The concept of providing 1:1 nursing care solely to women in active labour would leave the labour units understaffed. We recommend that institutions use a more precise classification system, rather than the presence or absence of labour, to determine individual patient risk and the appropriate nursing resource requirements.

Objective: To assess the safety and efficacy of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after autologous bone marrow transplantation (ABMT)., Patients and Methods: Two randomized, double-blind, placebo-controlled studies were done. In the phase 1/2 study, 75 breast cancer patients underwent a bone marrow harvest and myeloablative STAMP V chemotherapy and were randomized to receive placebo or one of three doses of PEG-rHuMGDF. In the phase 3 study, 64 patients were randomized to receive placebo or the minimally effective dose of PEG-rHuMGDF. The study drug was administered daily starting on the day of bone marrow infusion until the platelet count was greater than or equal to 50 x 10(9)/L (without transfusion) or for a maximum of 28 days. All patients received 10 microg/kg/day filgrastim starting on day 2 until neutrophil count recovery., Results: PEG-rHuMGDF appeared to be safe and well tolerated. No significant differences were noted in mortality or disease progression rates. Antibodies to MGDF were not observed. In the phase 1/2 study, the time to platelet recovery to greater than or equal to 20 x 10(9)/L and platelet transfusion requirements were significantly reduced for patients treated with PEG-rHuMGDF compared with placebo (p < 0.05). In the phase 3 study, no significant differences in the kinetics of early thrombopoiesis or platelet transfusions after ABMT were observed., Conclusions: PEG-rHuMGDF was not consistently efficacious in reducing the duration of severe thrombocytopenia. The maximum platelet counts for PEG-rHuMGDF-treated patients occurred a median of 2 weeks after the last dose of drug, suggesting that the biologic effects of this hematopoietic cytokine are delayed compared with other hematopoietic cytokines.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct disease entity that has a relatively short history. The prognosis and therapy of patients with PMLBCL is still controversial. We summarize our experience with PMLBCL at the Medical University of South Carolina between 1997 and 2000.

The Medical University of South Carolina is currently participating in clinical trials of 131I radiolabeled Anti-B1 antibody for treatment of Non-Hodgkin's lymphoma. Under current South Carolina Department of Health and Environmental Control regulatory guidelines,; these patients are required to be admitted to the hospital and to remain as inpatients until the whole body burden is <30 mCi or the exposure rate measured 1 m from the patient is <5 mR h(-1). We demonstrate that these patients can be released in accordance with the new recommended guidelines of the Nuclear Regulatory Commission for the release of patients containing radioactive materials in compliance with all radioactive material and public dose standards. This benefits these patients by reducing their risk of infection and other hospital insults and by reducing the length of hospitalizations. Further, unnecessary hospital admissions are decreased, and the overall cost of healthcare delivery for these patients is significantly reduced.

The AML1/ETO fusion transcript is expressed in virtually all patients with t(8;21) (q22;q22) acute myeloid leukemia (AML). The fusion transcript can be detected by reverse transcription-polymerase chain reaction (RT-PCR) in most of these patients in long-term complete remission (CR) following conventional chemotherapy or autologous bone marrow transplantation (BMT). However, AML1/ETO expression has not been analyzed in a series of patients following allogeneic BMT. We examined CR bone marrow (BM) samples and, in some cases, blood samples from 10 patients with t(8;21) leukemia who underwent allogeneic BMT in either first or second remission or first or second relapse. A variety of myeloablative regimens were used. Eight patients received non-T-cell depleted BM from matched sibling donors, one patient received a T-cell depleted haploidentical BM, and one patient received a non-T-cell depleted BM from a matched unrelated donor (MUD). Five patients developed acute and/ or chronic graft versus host disease (GVHD). The furthest time points analyzed for the AML1/ETO transcript in the 10 patients in CR following allogeneic BMT ranged from 7.5 to 83.0 months. Sufficient RNA was extracted from the most recent BM or BM and blood samples from nine patients to assay for presence or absence of the AML1/ETO fusion transcript by RT-PCR. The fusion transcript was detected by RT-PCR in all nine of these patient samples; eight were positive in BM and one was negative in BM, but positive in blood. The fusion transcript could not be detected in a BM sample from the tenth patient obtained 7.5 months after BMT, but the amount of RNA available was suboptimal. Hematopoietic chimerism could be demonstrated in sorted CD34+ BM cells from two of four patient CR BM samples with RT-PCR evidence of the fusion transcript. Additionally, in one of the two cases with chimerism, we demonstrated an abnormal clonal population of recipient cells in the CR BM sample by fluorescence in situ hybridization. One patient died of complications from GVHD, while the other nine patients remain alive without evidence of relapse, with a median follow-up time of 27 (range, 7.5 to 87) months post-BMT. These data suggest that allogeneic BMT, like conventional chemotherapy and autologous BMT, is not sufficient to eradicate cells expressing AML1/ETO, and that a positive RT-PCR for the fusion transcript post allogeneic BMT is compatible with continued CR.

Although numerous health benefits are associated with running, relatively little is known about long-term effects on the musculoskeletal system. Running places a great deal of repetitive stress on the joints and supporting structures of the lower extremities. Through animal and clinical studies, investigators have attempted to determine whether running exercise causes osteoarthritis. Available evidence indicates that moderate running in individuals without anatomical variances poses no increased risk for the development or acceleration of osteoarthritis. Runners with abnormal anatomy and those with significant previous injury are at increased risk for the development and progression of lower extremity osteoarthritis.

Regimens using cyclosporin (CSP) and either methylprednisolone (MP) or methotrexate (MTX) have been useful in the prophylaxis of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, CSP produces a number of side effects, including neurologic toxicity. A retrospective review of recipients of 239 BMTs given CSP-based prophylactic regimens revealed that 10 patients (4.2%, 95% confidence interval 0% to 10.4%) experienced a syndrome characterized by hypertension, severe visual disturbances, seizures and occipital lobe density changes on brain computed tomography (nine patients) or nuclear magnetic resonance imaging (one patient). Neurologic findings were reversible in all cases, usually after temporary discontinuation of CSP. Univariate analysis identified the following risk factors for neurotoxicity: use of unrelated or HLA-mismatched related donors, administration of etoposide (VP-16) or total body irradiation as part of conditioning, use of corticosteroids for prophylaxis or treatment of acute GVHD, or development of either acute GVHD or clinically significant microangiopathic hemolytic anemia (MAHA) post-BMT. In multivariate analysis, the most important predictors were the use of VP-16 (p = 0.008), the use of a continuous infusion CSP plus MP prophylactic regimen for GVHD (p = 0.003) and the development of MAHA after BMT (p less than 0.001). The strong association with MAHA suggests that endothelial damage is related to the development of this complication.

Seventy consecutive adult patients with acute myelogenous leukemia (AML), median age 44 years, received high-dose cytarabine (3 g/m2 every 12 hours for 12 doses) followed by daunorubicin (45 mg/m2 daily for three doses) for remission induction. A single, identical course was planned for postremission therapy. Complete remission (CR) was achieved in 63 patients (90%, 95% confidence interval [CI] 83% to 97%), 60 after a single course. Eight patients were selected to undergo elective bone marrow transplantation (BMT) during first CR. Of the remaining 55 patients, 40 (73%) underwent planned post-CR therapy; 15 patients did not, owing to early relapse, excessive toxicity from the induction chemotherapy, or refusal. Nineteen patients, including 13 who received planned post-CR therapy, remain in continuous CR at a median follow-up of 5.2 years (range 3.0 to 7.1 years). The 5-year actuarial leukemia-free survival was 30% (95% Cl, 19% to 42%) for all patients achieving CR and 32% (95% Cl, 19% to 47%) for the 40 patients who received the planned post-CR chemotherapy. Analysis of various putative prognostic factors for CR and overall and leukemia-free survival showed significance for a previous history of myelodysplasia, higher initial leukocyte counts, certain French-American-British (FAB) types, and certain abnormal karyotypes. None of these factors was consistently significant regarding the above parameters, although small patient numbers in certain analyses may have obscured significant associations. Myelosuppression was occasionally prolonged after remission induction and especially post-CR therapy. Severe cerebellar toxicity was observed in 13 patients; in 11 cases, this toxicity was fully reversible. Other serious complications were infrequent. Intensive chemotherapy with high-dose cytarabine and daunorubicin has substantial antileukemic activity in adult AML, and may represent an improvement over conventional therapy. Relapses were common, however, even in patients who received planned therapy, and substantial toxicity was observed. The optimum use of this regimen in AML remains to be determined.

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) is a rare and often fatal complication of bone marrow transplantation (BMT). In this study, we report eight such cases (seven allo and one auto) treated with plasma exchanges (PE), vincristine (six patients), and discontinuation of cyclosporin A (in allo BMT). This complication occurred in 6.3% of 112 allogeneic BMT and in 0.7% of 146 autologous BMT. In seven patients, the BMT preparatory regimens consisted of cyclophosphamide, etoposide, and total-body irradiation (TBI). Among the eight patients with HUS/TTP, one allogeneic BMT patient with reversible renal failure, but without central nervous system (CNS) involvement, or systemic mycotic infection, responded completely and is without evidence of disease for a period of greater than 3.5 years. Three patients showed hematologic improvement, and four did not respond. The median duration of survival was 17 days. Six of the seven deaths occurred in a setting of systemic infection, progressive renal failure, and worsening of graft-versus-host reaction. In spite of hematologic improvement to PE and vincristine, BMT patients in whom HUS/TTP developed usually succumbed to complications.

Clinical and laboratory data are described for two siblings who both developed adult T-cell leukemia/lymphoma resulting from infection by human T lymphotropic virus type I (HTLV-I). These findings suggest that genetic factors or virus-specific factors may determine which HTLV-I-infected individuals will develop leukemia.

N,N',N''-triethylenethiophosphoramide (thiotepa) is a polyfunctional alkylating agent similar in structure to nitrogen mustard. Thiotepa (synthesized by American Cyanamid Company, Wayne, NJ) underwent clinical trials in the 1960s that showed that it was active against a wide variety of tumors. At a standard dose level (10 to 30 mg/m2), the dose-limiting toxicity is myelosuppression; other toxicities are infrequent. Therefore, high-dose phase I evaluation was encouraged by these observations. Approximately 217 patients have been treated with single-agent high-dose thiotepa administered intravenously daily over 2 hours for 3 days followed by hematopoietic stem cell rescue to prevent prolonged myelotoxicity. The total doses administered ranged from 135 to 1,575 mg/m2. As anticipated, myelotoxicity was substantial, with 180 mg/m2 being the highest dose not requiring stem cell rescue to ensure hematopoietic recovery. Extramedullary toxicities consisted of stomatitis, dermatitis, hepatoxicity, and central nervous system (CNS) toxicity. CNS toxicity was dose-limiting; other toxicities were problematic, ie, dose-dependent but not truly dose-limiting. The maximal tolerated dose of thiotepa is 900 to 1,125 mg/m2, with the lower dose being the maximal dose for evaluation in combination chemotherapy. In high-dose phase I evaluation, the overall response rate was approximately 50% with responses seen in a wide variety of solid tumors, lymphomas, and pediatric tumors. High-dose thiotepa appears to be an alkylating agent with broad-spectrum antitumor efficacy, which should add to the cytoreductive regimens for both solid and hematopoietic tumors.

In two trials, 47 and 54 Holstein cows were fed diets containing ensiled forages, ensiled and dry forages, or diets of different moisture contents. In trial 1, diets were fed during a preliminary dry period, early lactation, late lactation, a second dry period, and a second early lactation. In trial 2, four diets identical except for moisture content (78, 64, 52, and 40% dry matter) were fed for the first 200 days of lactation. Substitution of dry hay for alfalfa silage increased dry matter intake during the first early lactation, whereas partial substitution of corn silage with straw did not affect intake during dry periods. Dry matter intake increased linearly as dry matter content of diet increased in trial 2. Neither milk production nor body weight were affected by treatment in either trial. Percentage total solids increased linearly as dry matter content of diet decreased in trial 2. Volatile fatty acids differed slightly, but no trends were consistent. No differences of daily chewing time were observed. From these trials, diets of less than 60 to 65% dry matter may reduce intake by lactating dairy cows.

We evaluated thiotepa in escalating dose in a broad phase I and II study using cryopreserved autologous bone marrow transplantation to assure hematopoietic recovery. Thiotepa was administered intravenously (IV) over two hours daily for three consecutive days followed in three to four days by marrow transplantation. The daily dose ranged from 60 to 525 mg/m2 (total dose, 180 to 1,575 mg/m2). A total of 71 patients with malignant melanoma were treated. Forty-three patients (61%) had received prior cytotoxic therapy and 28 were untreated. Sixty-two patients (87%) had melanoma disseminated to at least one visceral site, nine patients had skin and/or lymphatic metastases only. As of January 1, 1988 one patient was too early to be evaluated, 15 patients were inevaluable for tumor response, four patients had a complete response (CR), and 25 patients had a partial response (PR) to treatment. The response rates (95% confidence interval) for the 55 evaluable patients and for all 71 treated patients were 53% (40% to 65%) and 41% (30% to 53%), respectively. The median duration of response was 3 months, with a range of 1 to 31 + months. Three patients were alive and well without evidence of tumor more than 1 year after treatment. Analysis of patient subsets indicated that neither total dose, previous cytotoxic therapy, or sites of metastases influenced response rate. In this study, high-dose thiotepa has demonstrated a high response rate in patients with metastatic malignant melanoma with both PRs and CRs noted. Although most of the responses were not durable, 10% of the responses lasted more than 1 year. Future studies will evaluate additional methods for increasing the response rate and improving the duration of response.

Three patients developed blastic transformation of essential thrombocythemia (tET). Morphological studies in all patients showed that the majority of blasts had either myeloblastic or myelomonoblastic differentiation. Immunologic assays of hematopoietic cells were performed in two patients. In patient 1, 86% of peripheral blood mononuclear cells (predominantly blasts) reacted with a monoclonal antibody specific for granulocytes and monocytes (MMA), and 15% of mononuclear cells reacted with Tab, a monoclonal antibody specific for megakaryocyte-platelet glycoproteins (PGP) IIb and IIIa. In patient 2, 41.5% of peripheral blood mononuclear cells (predominantly blasts) were MMA-positive, 22.5% were Tab-positive, and 40% reacted with rabbit anti-human PGP. These results suggest either that two subpopulations of blast cells exist in tET, or that blast cells simultaneously express surface markers of myeloblastic/monoblastic and megakaryoblastic differentiation. In these three and in nine previously reported cases of tET, neither age, sex, nor previous therapy were obvious etiologic factors. tET occurred 24.2 +/- 14.4 mo after diagnosis of essential thrombocythemia, and a majority of patients had hepatomegaly and/or splenomegaly, anemia, leukocytosis, and thrombocytopenia. Leukemic cell morphology was myeloblastic and/or monoblastic in 12/12 patients, 5/12 had marrow fibrosis. Despite various treatments, death occurred in 3.6 +/- 2.7 mo; one patient had a brief complete remission.