Raman Interferometry between Autoionizing States to Probe Ultrafast Wave-Packet Dynamics with High Spectral Resolution.

Photoelectron interferometry with femtosecond and attosecond light pulses is a powerful probe of the fast electron wave-packet dynamics, albeit it has practical limitations on the energy resolution. We show that one can simultaneously obtain both high temporal and spectral resolution by stimulating Raman interferences with one light pulse and monitoring the modification of the electron yield in a separate step. Applying this spectroscopic approach to the autoionizing states of argon, we experimentally resolved its electronic composition and time evolution in exquisite detail. Theoretical calculations show remarkable agreement with the observations and shed light on the light-matter interaction parameters. Using appropriate Raman probing and delayed detection steps, this technique enables highly sensitive probing and control of electron dynamics in complex systems.

Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H(2)SO(4)/CH(3)CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC(50)'s > 1000 nM), but five (2, 6, 10, 11, 12) had IC(50)'s between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC(50)'s of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

Methyl-substituted dispiro-1,2,4,5-tetraoxanes: correlations of structural studies with antimalarial activity.

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethyl-substituted dispiro-1, 2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results.

A randomized British National Lymphoma Investigation trial of CHOP vs. a weekly multi-agent regimen (PACEBOM) in patients with histologically aggressive non-Hodgkin's lymphoma.

BACKGROUND: Between 1987 and 1991, the British National Lymphoma Investigation randomized 459 patients with non-Hodgkin's lymphoma with a large-cell component to either CHOP or the PACEBOM regimen. PATIENTS AND METHODS: Four hundred fifty-nine eligible patients were included in this trial, four hundred one with diffuse large-cell lymphoma and fifty-eight with diffuse mixed-cell lymphoma according to the Working Formulation. Two hundred twenty-six patients were randomized to receive CHOP and two hundred thirty-three to receive PACEBOM. The two arms of the trial were well balanced for all potential prognostic factors. RESULTS: The complete remission rate with PACEBOM was 64% and with CHOP 57% (NS). At eight years, the actuarial cause specific survival (CSS) in the PACEBOM arm is 59% compared to 49% in the CHOP arm (P = 0.09). Patients < 50 years of age fared significantly better in the PACEBOM arm both for CSS and overall survival (P = 0.002) and the CSS was also significantly improved in stage IV disease (P = 0.02). CONCLUSIONS: The mature data from this trial suggest that an etoposide-containing multi-agent weekly regimen can be superior to CHOP.

Laparoscopic splenectomy: a suitable technique for children and adults

Aims: Splenectomy retains an important role in the management of certain haematological conditions that fail to respond to conventional medical therapy, and has traditionally been performed through a midline or left subcostal incision with patients requiring 5-7 days in hospital. The well recognized benefits of laparoscopic surgery should also apply to splenectomy. This study aimed to develop a safe and effective technique suitable for all age ranges and without the requirement for expensive stapling devices. METHODS: An operative technique evolved over the 5-year period from 1994, from an initial six-port approach with the patient supine, to a four-port approach in a modified right lateral position, with locking surgical clips applied down a 5-mm port to vessels in the hilum, and removal of the spleen within a retrieval bag through a 4-6-cm Pfannanstiel incision. Data were collected prospectively for all patients undergoing laparoscopic splenectomy at Leicester Royal Infirmary, including demographic details, indication for surgery, duration of surgery, length of inpatient stay, transfusion requirement, postoperative complications and the response of the original condition to surgical intervention. RESULTS: A total of 40 patients underwent laparoscopic splenectomy (14 children, 26 adults) for a variety of conditions (idiopathic thrombocytopenia (ITP) (n = 24), haemolytic anaemia (n = 9) or malignancy (n = 7)) with a median operating time of 180 min for the first 20 patients and 100 min for the second 20 (P < 0.0001), and median inpatient stay of 3 days for the first 20 patients and 2 days for the second 20 (P < 0.0003). None of the operations was converted to open surgery, five patients required blood and/or platelet transfusion perioperatively, none of the patients had major postoperative complications, 23 of the 24 patients with ITP developed normal platelet counts after operation, and all nine patients with haemolytic anaemia maintained a normal haemoglobin concentration after operation. CONCLUSION: Laparoscopic splenectomy can be performed safely and effectively in adults and children without the need for stapling devices.

Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma.

Paroxysmal cold haemoglobinuria is an autoimmune haemolytic anaemia characterized by a biphasic polyclonal IgG autoantibody, the Donath-Landsteiner (D-L) antibody. Although classically described in association with chronic syphilis, it is most commonly seen after acute viral infections in children. We describe a case of high-grade B-cell non-Hodgkin's lymphoma which presented with paroxysmal cold haemoglobinuria. The lymphoma responded promptly to combination chemotherapy whilst, at the same time, the haemolytic process rapidly resolved. Subsequent investigations showed that the D-L antibody originated from the lymphoma cells.

Synthesis and antimalarial activity of 11 dispiro-1,2,4,5-tetraoxane analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes substituted at the 1 and 10 positions with unsaturated and polar functional groups.

Eleven novel dispiro-1,2,4,5-tetraoxanes 3 bearing unsaturated and polar functional groups were designed to enhance the oral antimalarial activity of the prototype tetraoxane 2 (WR 148999). With the exception of 3g and 3h, tetraoxanes 3 were available via the peroxidation of corresponding cyclohexanone derivatives in H2SO4/CH3CN. Tetraoxanes 3g and 3h were prepared by hydrolysis of ester tetraoxanes 3e and 3i, respectively. Five of the 11 tetraoxanes were inactive, but six tetraoxanes had IC50 values of 6-26 nM against the K1 and NF54 strains of Plasmodium falciparum compared to corresponding IC50 values of 28 and 39 nM for 2, and 10 and 12 nM for artemisinin (1). Ester tetraoxane 3e was the most active in vitro, some 2-fold more potent than 1. However, none of the six tetraoxanes active in vitro were as effective as either 1 or 2 in vivo; at single doses of 100 mg/kg most possessed little to no vivo activity in mice infected with Plasmodium berghei. Unsaturated tetraoxane 3a was uniquely more active when administered per os (po) than subcutan (sc). For this series of tetraoxanes, the discrepancy between vitro and vivo activities underscores the limitations of conclusions drawn solely from in vitro antimalarial data and illustrates a practical benefit of complementary single-dose in vivo antimalarial screens.

Lymphoma associated bone marrow necrosis with raised anticardiolipin antibody.

A case of high grade B cell lymphoma presented with bone marrow necrosis, followed by development of extensive marrow fibrosis, the evolution of which was documented by serial magnetic resonance imaging and bone marrow trephine histology. A markedly raised anticardiolipin antibody titre at diagnosis suggests that lymphoma associated antiphospholipid syndrome may have contributed to the aetiology of the bone marrow necrosis.

The presence of free infectious cytomegalovirus (CMV) in the plasma of donated CMV-seropositive blood and platelets.

An in vitro study was carried out to determine the presence of free infectious CMV in the supernatant of donated units of blood and platelets which were known to be CMV seropositive. One sample was taken from each of 10 units of CMV-seropositive platelet donations which were 4 days old. Ten units of seropositive blood were sampled at intervals over their storage lifespan. Each sample was divided into two and thrombin was added to one of them. The samples were all prepared by centrifugation. The resulting supernatant from the clotted samples was used in in vitro culture studies using the MRC-5 cell line to ascertain the infectivity of the samples. The anticoagulated supernatants were subjected to PCR analysis to detect the presence of free genomic CMV DNA. All of the units of blood and platelets tested positive for the presence of genomic CMV DNA by PCR. Seven out of the 10 units of blood were culture positive from samples taken 3-4 weeks into their shelf-life. None of the platelet samples was culture positive. The cultures of supernatants taken from seropositive blood were negative when the units were fresh, but further into their storage life, the cultures became positive, indicating that infectious material was released into the supernatant during storage, presumably due to the breakdown of intact white cells.

Splenectomy for haematological disease.

The role of splenectomy in haematological disease appears to be changing. This single centre, retrospective study was carried out to document the indications for splenectomy and its outcome over a 7-year period and to compare it with the preceding 7-year period. Sixty-four patients underwent splenectomy in the study period, the main indication being idiopathic thrombocytopenic purpura. There was one post-operative death and morbidity was seen in 40 (63%) patients. Splenectomy was successful in achieving the desired aim in 51 (80%) patients. Approximately 40% fewer patients underwent splenectomy in the study period compared with the preceding 7 years despite there being an overall increase of 123 (633 vs. 540) patients treated for haematological disease in this period. The reason for this observation was the fall in the number of splenectomies performed for Hodgkin's disease and auto-immune haemolytic anaemia.

A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report.

A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkin's lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis.

Evaluation of the Pall RC100 leucocyte removal filters and the effect of air introduction on its performance.

We evaluated the efficiency of Pall RC100 leucocyte removal filters in processing two units of concentrated red cells for transfusion. Our results show that the filter is very effective in processing the first unit. However, 32% (5/16) of the filters evaluated allowed a leak of substantial numbers of white cells towards the end of the transfusion of the second unit of blood. Air introduction experiments showed that as little as 2 ml of air in the filter may cause major deterioration of the filter function.

Thrombocytopenia following autologous bone marrow transplantation: evidence for autoimmune aetiology and B cell clonal involvement.

Thrombocytopenia outlasting anaemia and neutropenia is a well recognised sequel of autologous bone marrow transplantation (BMT) but the pathogenesis remains unclear. Autoimmune destruction of platelets has been suggested as a possible mechanism. We studied 5 patients who had undergone autologous BMT and were found to have persistent thrombocytopenia (< 150 x 10(9)/l) 6 months from transplantation with a normal haemoglobin level and granulocyte count. Apart from a mild reduction in the megakaryocyte numbers in one case, no other quantitative or qualitative defects of the megakaryocyte lineage were present to explain the peripheral thrombocytopenia. Two cases had positive anti-platelet autoantibodies. Immunoglobulin heavy chain gene rearrangement studies of peripheral blood and bone marrow mononuclear cells using the polymerase chain reaction showed evidence of clonal rearrangement in one of the two cases with positive anti-platelet autoantibodies. Our results support the previous reports that anti-platelet antibody-mediated destruction of platelets may play a role in the pathogenesis of post-autologous BMT thrombocytopenia. Furthermore, the demonstration of a clonal B cell expansion in one of the cases with anti-platelet antibodies suggests an aetiological link between clonal B cells, autoantibody production and thrombocytopenia.

Visual hallucinations following treatment with vincristine.

Peripheral neuropathy is a common side effect of vincristine therapy. However, side effects due to central nervous system (CNS) toxicity following intravenous administration are rare. We report two patients who developed visual hallucinations during treatment with vincristine.