75 MW few-cycle mid-infrared pulses from a collinear apodized APPLN-based OPCPA.

We present an ultra-broadband optical parametric chirped-pulse amplification (OPCPA) system operating at 3.4 µm center wavelength with a peak power of 75 MW. The OPCPA system is split into a pre- and a power-amplifier stage. Both stages are based on apodized aperiodically poled MgO:LiNbO3 (APPLN). The collinear mixing configuration allows us to manipulate the spectral phase of the output mid-infrared pulses by sending the near-infrared seed pulses through a pulse shaper. The system delivers clean 75-fs pulses with record-high 700 mW average power, corresponding to 7 µJ of pulse energy at a repetition rate of 100 kHz.

Role of apodization in optical parametric amplifiers based on aperiodic quasi-phasematching gratings.

We experimentally demonstrate and analyze two different techniques for apodizing the nonlinear coupling in aperiodically poled MgO:LiNbO(3) (APPLN) used in an ultrabroadband optical parametric chirped pulse amplifier (OPCPA). With an adiabatic increase of the nonlinear coupling, a smooth gain spectrum and spectral phase is preserved during amplification in such media. The two approaches we explore are poling period apodization (PPA) and duty cycle apodization (DCA). For the first implementation of the apodized APPLN amplifier we use a constant chirp-rate in the grating k-vector. The nonlinear coupling is apodized over 10% of the total length at each side of the APPLN chip. This allows us to achieve high-intensity output pulses with clean temporal structure.

Ultrabroadband, highly flexible amplifier for ultrashort midinfrared laser pulses based on aperiodically poled Mg:LiNbO3.

We present an amplification medium for optical parametric chirped-pulse amplification that allows for ultrabroadband gain in a collinear configuration. Our approach is based on aperiodic quasi-phase-matching (QPM). For the first demonstration of this method in a mid-IR optical parametric chirped-pulse amplifier, we chose a QPM grating design with a linear chirp of its associated spatial frequencies. The resulting 7.4-mm-long, aperiodically poled Mg:LiNbO(3) amplification crystal has a chirp rate of kappa'=-250 cm(-2) and provides gain over the 800 nm bandwidth centered at 3.4 microm. We were able to generate pulses as short as 75 fs and the pulse energy at the output of the optical parametric amplifier before compression was 1.5 microJ. Low thermal load on the amplification medium allows for operation at a high repetition rate, 100 kHz in our case, and high average power limited only by the available pump power.

High-repetition-rate optical parametric chirped-pulse amplifier producing 1-microJ, sub-100-fs pulses in the mid-infrared.

We present a high-repetition-rate, femtosecond optical parametric chirped pulse amplifier (OPCPA). Its seed signal is obtained by difference frequency generation from the two-branch output of a commercially available Er:fiber laser amplifier. The optical parametric amplifier is pumped by a commercially available diode-pumped solid-state laser. In a two-stage amplification setup we have achieved a gain of 100'000, resulting in approximately 1 microJ femtosecond mid-infrared pulses in the wavelength range between 3 and 4 microm and an amplification bandwidth of >300 nm at a repetition rate of 100 kHz. The pulses have been compressed to 92 fs by a 4-prism compressor.

Cytomegalovirus encephalomyelomeningoradiculitis in acquired immunodeficiency syndrome (AIDS).

Acute inflammatory polyradiculitis represents an uncommon peripheral nerve complication during HIV infection. The case of an HIV-seropositive patient who was admitted to hospital for a cauda equina syndrome is reported. Despite early application of anticytomegalic medication, a cytomegalovrirus (CMV) infection spread out to the central nervous system (CNS), causing the patient's death. A post-mortem examination confirmed the diagnosis of CMV-encephalomyelomeningoradiculitis. To the authors' knowledge, such a progress of a CMV-related polyradiculitis to an encephalomyelomeningoradiculitis has not yet been described. The clinical features of this case will aid in the recognition of CMV-related neurological complications, and may permit earlier and perhaps more successful treatment.

Immunoglobulin deposition in sural nerves of AIDS patients with distal-symmetric HIV-associated polyneuropathy.

The most frequent neurological diagnosis in peripheral nerve function of HIV-positive individuals is distal-symmetric polyneuropathy (DSPN). In this study we investigated the histopathology as well as the immunohistochemical expression of immunoglobulins IgA, IgG and IgM in post-mortem sural nerve tissue gained from 11 patients who had suffered from DSPN in the clinical course of AIDS (CDC 3C). We found that all 11 sural nerves showed signs of demyelination while in 6 out of 11 cases axonal degeneration could also be detected. Immunohistochemical expression of at least one immunoglobulin was found in all but two cases with deposits uniformly being located immediately beneath the basement membrane of capillary blood vessels and within the perineurium while endoneurial staining was discernable in three cases. The most commonly expressed immunoglobulin was IgA which was identified in 7 cases, followed by IgG and IgM which were positive in 6 and 5 cases, respectively. All three immunoglobulins were found to be expressed simultaneously in only two cases. Thus, our study shows that immunoglobulin deposits among other factors may be implicated in altering the function of sural nerves or enhance their vulnerability. In peripheral nerves they may be responsible for some of the common alterations in the development of AIDS-associated distal symmetric polyneuropathy.

Alterations of intracellular calcium concentration in mice neuroblastoma cells by electrical field and UVA.

By using a FURA2 ratio imaging method, the intracellular free calcium concentration was investigated in cultured mice neuroblastoma cells under the influence of an amplitude-modulated (AM) field (5 kHz sine wave AM 16 Hz sinusoidal 800 V/m and 80 V/m), as well as of electric field pulses (300-ms unipolar pulses of 1000 V/m and 800 V/m, 5 pulses during 10 s and 50 pulses during 100 s). An increase in free intracellular calcium was found in about 50% of cells after field application, whereas in control experiments only about 20% of the cells showed similar increases. However, this effect depended on the amount of UV irradiation used for excitation of FURA2 fluorescence. Experiments with 1/30 to former total illumination no longer demonstrated an increase in control cells or in cells treated with AM fields. The number of cells showing calcium increase after the application of pulsed fields was reduced significantly. Therefore, the UV light itself, applied as double flashes for the fluorescence measurement, activates the cellular calcium regulation. These findings offer a possible explanation for the low reproducibility of field effects found in different laboratories, in which investigations were performed with different equipment using different intensities of UV excitation.

Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53.

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II isoform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation. We previously reported isolation of the proximal promoter of the Type II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathupala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270, 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma. Co-expression studies showed that p53 overexpression significantly and reproducibly activated the Type II hexokinase promoter. Two functional p53 motifs were identified within this promoter by footprint and gel retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing liver tumors, and perhaps in many other tumors as well, this highly abundant p53 protein plays a role in maintaining a high glycolytic rate. This is the first report of a possible link between loss of cell cycle control in rapidly growing cancer cells and their high glycolytic phenotype.

A new class of mutants deficient in dodecamerization of aminopeptidase 1 and vacuolar transport.

Vacuolar aminopeptidase 1 is transported to the vacuole by cytoplasmic double-membrane vesicles, the nonclassic Cvt pathway. The cytosolic protein dodecamerizes and is enclosed in a double-membrane vesicle, which is transported to and fuses with the vacuole releasing a single-membrane autophagic body into the vacuolar lumen. This is degraded and the precursor sequence of aminopeptidase 1 is removed. This pathway resembles autophagy, and most proteins identified to function in the Cvt pathway are also required for autophagy and vice versa. The cytosolic precursor protein and the matured vacuolar protein form a homododecameric complex, and only this complex has enzymatic activity. We developed a new genetic screen to isolate mutants in the biogenesis of vacuolar aminopeptidase 1 based on its enzymatic activity. The sensitivity of this assay made it possible for us to search for mutants under conditions where autophagy is down-regulated, and we describe two new mutants defective in the biogenesis pathway of vacuolar aminopeptidase 1. Mutants are defective in dodecamerization of pApe1p and in Cvt vesicle formation. Complex assembly and transport vesicle formation appear to be linked processes. This mechanism can control the potentially harmful cytoplasmic proteolytic activity and could be the driving force for this nonclassic mechanism of vacuolar enzyme transport.

[Immunosuppressive and cytostatic effectiveness of the poplar mushroom Tricholoma populinum LANGE]. / Untersuchungen zur immunsuppressiven und cytostatischen Wirksamkeit des Pappel-Ritterlings, Tricholoma populinum LANGE.

Dry powders or extracts of the fruit bodies of Tricholoma populinum given per as or injected intraperitoneally respectively caused a suppression of the number of plaque forming cells of mice as shown by the hemolysis-plaque-assay. Extracts of the fungi inhibited above that the incorporation of 3H-thymidine into mitogen-stimulated human lymphocytes as observed in the lymphocyte transformation test and retarded the proliferation of cultivated bovine aortic endothelial cells.

[Correlation between clinical apparatus-based differential diagnosis and neuropathological diagnosis in patients with AIDS]. / Zur Korrelation klinisch-apparativer Differenzialdiagnosen mit neuropathologischen Diagnosen bei Patienten mit AIDS.

BACKGROUND: During the course of HIV infection, the majority of patients develop opportunistic cerebral neuro-manifestations. If conventional diagnostic tools are not sufficient, a stereotactic biopsy is often necessary. PATIENTS AND METHODS: In order to evaluate the correctness of the clinical diagnosis of cerebral neuro-manifestations in HIV-infected patients, we compared the results of cerebral biopsy or autopsy with the previous clinical diagnosis. A total of 19 biopsies and 49 autopsies could be analyzed. RESULTS: Except for HIV-associated encephalopathy, we detected a very high conformity between the clinical and the neuropathological diagnoses. We obtained the best sensitivity for progressive multifocal leukoencephalopathy (PML), whereas for cerebral toxoplasmosis the worst sensitivity and specificity was identified. CONCLUSION: We conclude that the diagnosis of PML can be made on clinical grounds alone, whereas the diagnosis of cerebral toxoplasmosis and lymphoma often requires a biopsy, which should be performed early.

[Progressive multifocal leukoencephalopathy in AIDS. Overview and retrospective analysis of 17 patients]. / Progressive multifokale Leukoenzephalopathie im Verlauf der AIDS-Erkrankung. Ubersicht und retrospektive Analyse von 17 Patienten.

We describe retrospectively the course of 17 AIDS patients with progressive multifocal leukoencephalopathy (PML) and give a review of their clinical symptoms and survival times. The relative frequency of PML in our cohort of AIDS patients was 2.6%. The mean of CD4-positive cells was 80.5 +/- 82.5/microliter. CD4-positive cells were > 200/microliter only in one patient and increased significantly under a combination of three antiretroviral drugs whereas, with the other patients, CD4-positive cells did not increase with a maximum of two antiretroviral drugs. The mean survival time was 6.6 (1.5-20) months and correlated positively with the number of CD4-positive cells. The diagnosis of PML can be regarded as confirmed when JC-virus DNA is detectable in cerebrospinal fluid, typical changes can be seen in MRI and typical clinical symptoms occur. No effective therapy is known to date. Single case reports on therapy with cidofovir, as in one of the cases described here, showed positive results.

Screening for HIV-associated distal-symmetric polyneuropathy in CDC-classification stages 1, 2, and 3.

OBJECTIVES: A total of 670 patients were screened for distal symmetric HIV-associated polyneuropathy during CDC stages 1-3 and its correlation to immunological deterioration. MATERIAL AND METHODS: Clinical examinations of 670 patients admitted to the neurological outpatient clinic at the Department of Neurology, University of Munster. Neurophysiological investigations were performed on the sural and peroneal nerve for detection of axonal and myelin lesion. RESULTS: Clinical examination proved progressive clinical signs and symptoms indicating distal symmetric polyneuropathy from CDC 1 (32%) to CDC 3 (55%). At least one neurophysiological result was impaired in CDC 1 in 25% and in CDC 3 in 45%. Significant correlation between neurophysiological changes and CDC4(+)-cells and beta-microglobuline were detected for stage CDC 3 C. CONCLUSION: Results show stage related prevalence of distal symmetric polyneuropathy already in early stages. In late stages of HIV-infection prevalence of distal symmetric polyneuropathy seems to be directly correlated to immunodeficiency syndrome. The pathogenesis of distal symmetric polyneuropathy during HIV-infection is up to now incompletely understood, but results indicate a clear dependency between progressive immunological dysfunction and neuropathy. High active antiretroviral therapy in patients suffering from distal symmetric polyneuropathy is a main topic of future studies.

Coadministration of clozapine and fluvoxamine in psychotic patients--clinical experience.

Fluvoxamine (FLUVOX) is an inhibitor of the cytochrome P450 isoenzyme 1 A2 and thereby inhibits clozapine (CLOZ) metabolism. We performed an open clinical study to gather experience in necessary dosages, plasma levels, side effects and clinical efficiency of the coadministration of the two drugs. Eighteen psychotic patients were studied. 50 mg FLUVOX were given throughout the study period, while the CLOZ dosage was increased individually (week 5: 96.9+/-37.2 mg). After 5 weeks the plasma concentrations were as follows: CLOZ 252+/-174 ng/ml, N-desmethylclozapine (DM-CLOZ) 143+/-74 ng/ml and clozapine N-oxide (CLOZ N-OX) 30+/-14 ng/ml. There were no differences in side effects, especially sedation, after 5 weeks compared to the pretreatment condition. Moreover, we found a significant improvement in measures of cognitive speed which might be regarded as a measure of vigilance. The BPRS scores dropped continuously until week 5 (pretreatment: 53.3+/-13.4; week 5: 33.2+/-12.9) and 5 patients were considered treatment responders (BPRS reduction > 50%). Ten patients continued the combination treatment after the study period and 9 of these patients were in clinical remission when discharged. Given strict therapeutic drug monitoring, coadministration of FLUVOX and CLOZ seems to be a safe and efficient treatment strategy with a low occurrence of the side effects associated with CLOZ treatment. This might be due to additive effects of the two drugs and/or metabolic interaction.

[Primary central nervous system lymphoma as a neurological manifestation of AIDS stage]. / Primäres Lymphom des zentralen Nervensystems als Neuromanifestation im AIDS-Stadium.

In patients infected with human immunodeficiency virus (HIV), the risk of developing non-Hodgkin's lymphoma is over 100 times greater than with noninfected persons. Primary central nervous system lymphoma as a complication of the acquired immunodeficiency syndrome (AIDS) occurs in up to 2.4% of all cases and is strongly associated with the Epstein-Barr virus. The prognosis is very poor, with a mean survival time of 21 to 27 days without therapy and up to 119 days with radiation therapy. We describe the course of seven AIDS patients with histologically proven primary central nervous system lymphoma and present a review of clinical symptoms, diagnosis, and therapy. The main criteria for differential diagnosis from other secondary neuromanifestations such as cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, abscesses, and infarctions are described.

Elevated levels of activities of beta-hexosaminidase and alpha-mannosidase in human immunodeficiency virus-infected patients.

To determine their value as markers of the clinical stage of human immunodeficiency virus (HIV) disease, plasma activities of lysosomal glycosidases were determined in the plasma of 97 HIV-infected patients: molecular forms of cathepsin D were characterized by Western blot to examine the mode of enzyme release. In patients with Centers for Disease Control and Prevention stage II and III of HIV disease, plasma activity of beta-hexosaminidase was significantly increased. In patients with stage III infection, alpha-mannosidase activity was also significantly increased and cathepsin D was elevated and present only in its premature form. Thus, determination of plasma activities of beta-hexosaminidase and alpha-mannosidase in HIV-positive persons may be useful for distinguishing the clinical stage of disease. The elevation of precursors of cathepsin D in patients with stage III HIV disease indicates that secretion of lysosomal enzymes rather than leakage of enzymes from damaged cells is markedly elevated.