Mode locking in a tapered two-section quantum dot laser: design and experiment.

In this Letter, the pulse generation and pulse train stability of a tapered two-section InAs/InGaAs quantum dot laser emitting at 1250 nm are numerically predicted and experimentally verified. Simulations based on a multi-section delayed differential equation model are used to properly design a laser source able to generate stable mode-locked pulses at a 15 GHz repetition rate with picosecond width and output power larger than 1 W, and to identify the device stability regions depending on the bias conditions. Possible instabilities are associated with the existence of a leading or trailing edge net gain window outside the optical pulse. Experimentally, we confirm the existence of different stability regions where instabilities manifest in broadband or multi-periodic pulse train amplitude modulations. Our results confirm the correctness to the design and may be helpful in achieving high-power pulses while avoiding detrimental pulse train instabilities, both being important for time-critical applications.

High peak-power picosecond pulse generation at 1.26 µm using a quantum-dot-based external-cavity mode-locked laser and tapered optical amplifier.

In this paper, we present the generation of high peak-power picosecond optical pulses in the 1.26 µm spectral band from a repetition-rate-tunable quantum-dot external-cavity passively mode-locked laser (QD-ECMLL), amplified by a tapered quantum-dot semiconductor optical amplifier (QD-SOA). The laser emission wavelength was controlled through a chirped volume Bragg grating which was used as an external cavity output coupler. An average power of 208.2 mW, pulse energy of 321 pJ, and peak power of 30.3 W were achieved. Preliminary nonlinear imaging investigations indicate that this system is promising as a high peak-power pulsed light source for nonlinear bio-imaging applications across the 1.0 µm - 1.3 µm spectral range.

Direct observation of the coherent spectral hole in the noise spectrum of a saturated InAs/InP quantum dash amplifier operating near 1550 nm.

We demonstrate a direct observation of the coherent noise spectral hole in a saturated quantum dash amplifier. Its width 500-600 GHz is determined by the response time and is responsible for high speed regeneration properties.

Very compact external cavity diffraction-coupled tapered laser diodes.

To maintain the same beam quality as that of a single emitter and to be close to diffraction limit, we have combined a phase corrected array, emitting at lambda = 975 nm, coherently using the Talbot effect. First, to improve the beam quality of the array, a phase correcting system was added. The FWHM divergences of the array (which is approximately the same as that of the single emitter since the emitters within the array are not optically coupled to each other) were reduced from 34 degrees to 0.17 degrees in the fast axis and from 3.5 degrees to 0.7 degrees in the slow axis at 6 A. Then, to be close to the diffraction limit, we have combined this corrected array coherently using the Talbot effect. We have obtained a quasi-monolobe slow axis far field profile for the in-phase mode with a central peak divergence of only 0.27 degrees at 1.5 A, 315 mW under cw operation, and of only 0.20 degrees at 2.5 A, 787 mW under pulsed operation. To our knowledge, this is the first demonstration of coherent coupling of a corrected tapered laser diode array in an external Talbot cavity.

IFN-gamma overexpression within the pancreas is not sufficient to rescue Pax4, Pax6, and Pdx-1 mutant mice from death.

In the presence of interferon-gamma (IFN-gamma), pancreatic ductal epithelial cells grow continuously, and islets undergo neogenesis. To determine whether these new islets are derived from conventional precursors, we tested whether IFN-gamma can complement the loss of transcription factors known to regulate pancreatic development. We analyzed the effect of a transgene on lethality in mice lacking the transcription factors Pax4, Pax6, or Pdx-1, by intercrossing such mice with transgenic mice whose pancreatic cells make IFN-gamma (ins-IFN-gamma mice). However, IFN-gamma expression did not rescue these mice from the lethal mutations, because no homozygous knockout mice carrying the IFN-gamma transgene survived, despite the survival of all other hemizygous gene combinations. This outcome demonstrates that the pathway for IFN-gamma regeneration requires the participation of Pax4, Pax6, and Pdx-1. We conclude that the striking islet regeneration observed in the ins-IFN-gamma NOD strain is regulated by the same transcription factors that control initial pancreatic development.

Transcription factor expression during pancreatic islet regeneration.

Recent studies by a number of laboratories have identified transcription factors that are involved in pancreatic development. Indeed, marked abnormalities in pancreatic development result from deficiencies in these molecules, which include, among others, PDX-1, islet-1 (Isl-1), and Pax-6. These studies have prompted us to evaluate the expression of Isl-1 and Pax-6 in the pancreas of the interferon-gamma (IFNgamma) transgenic mouse, which exhibits new islet growth and expansion of ducts throughout the life of the animal. We have previously demonstrated that PDX-1 is strikingly expressed in the ducts of the IFNgamma transgenic mouse. This latter observation compelled us to examine expression of hepatocyte nuclear factor-3beta (HNF3beta), which mediates PDX-1 gene transcription, in the IFNgamma transgenic pancreas as well. As a result of these studies, we now demonstrate marked expression of these transcription factors in the pancreatic ducts of IFNgamma transgenic mice. These data suggest a role for these transcription factors during pancreatic regeneration in the IFNgamma transgenic mouse.

Naive T lymphocytes traffic to inflamed central nervous system, but require antigen recognition for activation.

Organ-specific autoimmune diseases may be induced by infiltration of the target tissue by CD4(+) T cells with specificity for self antigen(s). As disease progresses, T cells of other specificities appear in the tissue. Traffic of naive, antigen-inexperienced T cells to target tissues has not been shown, although many studies have shown extravasation of activated or memory T cells. We have used a novel experimental system to track naive T cells to the central nervous system (CNS) in TCR transgenic mice with adoptively transferred experimental autoimmune encephalomyelitis. Ovalbumin (OVA)-specific CD4(+) T cells were equivalent in number to disease-inducing myelin basic protein (MBP)-specific T cells at disease onset. Furthermore, OVA-specific T cells retained a naive phenotype and did not transcribe Th1 cytokines, in contrast to MBP-specific T cells. These findings demonstrate that the T cell pool in the CNS of animals with demyelinating disease contains potential recruits from the time of disease onset, and that T cells require more than an inflammatory milieu for their induction to the autoimmune attack.

PDX-1 and Msx-2 expression in the regenerating and developing pancreas.

We have observed pancreatic duct cell proliferation and islet regeneration in transgenic mice whose pancreata produce interferon gamma (IFNg mice). We have previously demonstrated that new islet cells derive from endocrine progenitor cells in the pancreatic ducts of this model. The current study was initiated to define these endocrine progenitor cells further and to identify novel markers associated with pancreatic regeneration. Importantly, we have found that PDX-1, a transcription factor required for insulin gene transcription as well as for pancreatic development during embryogenesis, is expressed in the duct cells of IFNg mice. This striking observation suggests an important role for PDX-1 in the marked regeneration observed in IFNg mice, paralleling its critical function during ontogeny. Also demonstrated was elevated expression of the homeobox-containing protein Msx-2 in the pancreata of fetal mice as well as in adult IFNg mice, identifying this molecule as a novel marker associated with pancreatic development and regeneration as well. The identification of PDX-1 and Msx in the ducts of the IFNg transgenic pancreas but not in the ducts of the non-transgenic pancreas suggests that these molecules are associated with endocrine precursor cells in the ducts of the IFNg transgenic mouse.

Course of violence in patients with schizophrenia: relationship to clinical symptoms.

To understand the heterogeneity of violent behaviors in patients with schizophrenia, one must consider underlying clinical symptoms of the illness and their change over time. The purpose of this study was to examine persistence and resolution of violence in relation to psychotic symptoms, ward behaviors, and neurological impairment. Psychiatric symptoms and ward behaviors were assessed in violent inpatients with schizophrenia or schizoaffective disorder and in nonviolent controls on entry into the study. Patients were followed for 4 weeks; those who showed resolution of assaults over this time were classified as transiently violent, and those who remained assaultive were categorized as persistently violent. At the end of the 4 weeks, psychiatric symptoms, ward behaviors, and neurological impairment were assessed. Overall, the two violent groups presented with more severe psychiatric symptoms and were judged to be more irritable than the nonviolent control subjects, but the transiently violent patients showed improvement in symptoms over time. At the end of 4 weeks, the persistently violent patients had evidence of more severe neurological impairment, hostility, suspiciousness, and irritability than the other two groups. Canonical discriminant analyses identified two significant dimensions differentiated the groups. The first, characterized by positive psychotic symptoms, differentiated the violent patients from the control subjects; the second, characterized by neurological impairment and high endpoint score for negative symptoms, differentiated the transiently from the persistently violent patients. Identification of certain symptoms associated with different forms of violence has important implications for the prediction and differential treatment of violent behavior in patients with schizophrenia.

Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes.

The upregulation of a limited number of growth factors in our interferon-gamma transgenic model for regeneration within the pancreas lead us to propose that these factors are important during pancreatic regeneration. In this study, we have assessed the influence of two growth factors within the pancreas, epidermal growth factor (EGF) and keratinocyte growth factor (KGF), by ectopically expressing these proteins under the control of the human insulin promoter in transgenic mice. This beta-cell-targeted expression of either EGF or KGF resulted in significant morphological changes, including cellular proliferation and disorganized islet growth. Intercrossing the individual Ins-EGF and Ins-KGF transgenic mice resulted in more profound changes in pancreatic morphology including proliferation of pancreatic cells and extensive intra-islet fibrosis. Insulin-producing beta-cells were found in some of the ducts of older Ins-EGF and Ins-EGFxKGF transgenic mice, and amylase-producing cells were observed within the islet structures of the double transgenic mice. These data suggest that both EGF and KGF are capable of affecting pancreatic differentiation and growth, and that co-expression of these molecules in islets has a more substantial impact on the pancreas than does expression of either growth factor alone.

Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that specifies accumulation of inflammatory cells within the CNS in these conditions remains a subject of active investigation. Chemokines including IP-10, GRO-alpha, MCP-1 are produced in EAE tissues selectively by parenchymal astrocytes, but the regulatory stimuli that govern this expression remain undetermined. The unexpected occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IFN-gamma) offered an opportunity to examine the spectrum of chemokine expression during immune-mediated inflammation in the absence of a single regulatory cytokine. We found that chemokines MCP-1 and GRO-alpha were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is highly expressed in the CNS of mice with an intact IFN-gamma gene and EAE, was strikingly absent. In vitro experiments confirmed that IFNgamma selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-gamma for its upregulation during this model disease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-inflammatory cytokines.

Pancreatic expression of keratinocyte growth factor leads to differentiation of islet hepatocytes and proliferation of duct cells.

Keratinocyte growth factor, (KGF), a member of the fibroblast growth factor (FGF) family, is involved in wound healing. It also promotes the differentiation of many epithelial tissues and proliferation of epithelial cells as well as pancreatic duct cells. Additionally, many members of the highly homologous FGF family (including KGF), influence both growth and cellular morphology in the developing embryo. We have previously observed elevated levels of KGF in our interferon-gamma transgenic mouse model of pancreatic regeneration. To understand the role of KGF in pancreatic differentiation, we generated insulin promoter-regulated KGF transgenic mice. Remarkably, we have found that ectopic KGF expression resulted in the emergence of hepatocytes within the islets of Langerhans in the pancreas. Additionally, significant intra-islet duct cell proliferation in the pancreata of transgenic KGF mice was observed. The unexpected appearance of hepatocytes and proliferation of intra-islet duct cells in the pancreata of these mice evidently stemmed directly from local exposure to KGF.

Immune cell entry to the CNS--a focus for immunoregulation of EAE.

T-cell-derived cytokines are therefore individually unnecessary and collectively insufficient for microglial response. This somewhat provocative interpretation does not exclude a role for T-cell cytokines in induction of a microglial response in EAE, but it may be easier to show a non-requirement then to prove such a role. The point that emerges is that cytokine production in the CNS parenchyma is itself dependent on the prior infiltration of immune cells, and that without immune cell entry, EAE does not occur. This identifies events at the BBB, and in particular in the perivascular space, as critical immunoregulatory events in development and progression of EAE.

Characterization of the expression and immunogenicity of the ns4b protein of human coronavirus 229E.

Sequencing of complementary DNAs prepared from various coronaviruses has revealed open reading frames encoding putative proteins that are yet to be characterized and are so far only described as nonstructural (ns). As a first step in the elucidation of its function, we characterized the expression and immunogenicity of the ns4b gene product from strain 229E of human coronavirus (HCV-229E), a respiratory virus with a neurotropic potential. The gene was cloned and expressed in bacteria. A fusion protein of ns4b with maltose-binding protein was injected into rabbits to generate specific antibodies that were used to demonstrate the expression of ns4b in HCV-229E-infected cells using flow cytometry. Given a previously reported contiguous five amino acid shared region between ns4b and myelin basic protein, a purified recombinant histidine-tagged ns4b protein and (or) human myelin basic protein were injected into mice to evaluate whether myelin-viral protein cross-reactive antibody responses could be generated. Each immunogen induced specific but not cross-reactive antibodies. We conclude that ns4b is expressed in infected cells and is immunogenic, although this does not involve amino acids shared with a self protein, at least in the experimental conditions used.

Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE.

The cytokine interferon-gamma (IFNgamma) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFNgamma plays in progression to chronic demyelination and neurological deficit. To address this issue, we have expressed IFNgamma in myelinating oligodendrocytes of transgenic mice. MHC I immunostaining and iNOS mRNA were upregulated in their CNS, but such transgenic mice showed no spontaneous CNS inflammation or demyelination, and the incidence, severity, and histopathology of experimental autoimmune encephalomyelitis (EAE) were similar to nontransgenic controls. In contrast to control mice, which remit from EAE with resolution of glial reactivity and leukocytic infiltration, transgenics showed chronic neurological deficits. While activated microglia/macrophages persisted in demyelinating lesions for over 100 days, CD4(+) T lymphocytes were no longer present in CNS. IFNgamma therefore may play a role in chronic demyelination and long-term disability following the induction of demyelinating disease. Because IFNgamma may have neural as well as immune-infiltrating origins, these findings generate a new perspective on its role in the CNS.

The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis.

In experimental allergic encephalomyelitis (EAE), CD4+ T cells infiltrate the central nervous system (CNS). We derived CD4+ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE to naive mice. Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines, whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines. Mononuclear cells isolated from the CNS, the majority of which were microglia, presented antigen to and stimulated MBP-specific T cell lines in vitro. Although CNS antigen-presenting cells (APC) supported increased production of interferon (IFN)-gamma mRNA by these T cells, there was no increase in the interleukin (IL)-4 signal, whereas splenic APC induced increases in both IFN-gamma and IL-4. mRNA for IL-12 (p40 subunit) was up-regulated in both infiltrating macrophages and resident microglia from mice with EAE. We have thus shown that a Th1 cytokine bias within the CNS can be induced by CNS APC, and that IL-12 is up-regulated in microglial cells within the CNS of mice with EAE. Microglia may therefore control Th1 cytokine responses within the CNS.

Violence in psychiatric patients: the role of psychosis, frontal lobe impairment, and ward turmoil.

The purpose of the study was to identify psychiatric symptoms, neurological impairments, and situational factors associated with the emergence of violence and with its persistence. Psychiatric symptoms were assessed in newly admitted physically assaultive psychiatric patients and nonviolent controls. Patients were than evaluated for 4 weeks to determine the persistence or resolution of these physical assaults. Patients who showed marked resolution of assaults were classified as transiently violent (n = 41), and those who remained assaultive throughout were categorized as persistently violent (n = 34). At the end of 4 weeks, all patients received a comprehensive psychiatric and neurological assessment. Physical assaults were associated initially with prominent positive psychotic symptoms. Both transiently and persistently violent patients were more psychotic than the nonviolent controls; however transiently violent patients showed better resolution of these symptoms over the 4 weeks. They also evidenced less frontal lobe impairment on the neurological examination than the persistently violent patients. The two violent groups differed in their susceptibility to environmental influences: the surrounding ward agitation fostered physical assaults in transiently but not in persistently violent patients. This differentiation between transiently and persistently violent patients has major implications for the comprehensive treatment of violent behavior.

Effect of neuroleptic treatment on depressive symptoms in acute schizophrenic episodes.

This study examined depressive symptoms in acute schizophrenic episodes and their relationship to neuroleptic treatment. Sixty-three depressed and 62 non-depressed acutely exacerbated schizophrenic patients were evaluated with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, the Simpson-Angus Extrapyramidal Scale, and the Hamilton Rating Scale for Depression. Subjects were then randomly assigned to different haloperidol plasma levels and followed for 3 weeks. Overall, depression improved with treatment of the acute psychosis, but a positive association between extrapyramidal side effects and depressive symptoms emerged over time. Depressive symptoms tended to be positively related to haloperidol plasma levels. The results suggest that depressive symptoms in schizophrenia are heterogeneous in origin; while neuroleptics can ameliorate depressive symptoms inherent in the acute schizophrenic episode, they can also contribute to depression.

Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) was induced in SJL/J mice by adoptive transfer of MBP-reactive T cells in order to investigate the role of astrocytes in pathology. GFAP protein and mRNA expression (analyzed using semiquantitative Western blot and RT-PCR techniques) were upregulated in the spinal cord of mice, which had developed a complete paralysis of hind- and fore-limbs and tail (grade 4 EAE), thus establishing that reactive gliosis occurred under these experimental conditions. Within the same samples and using similar techniques, we found that glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression were dramatically reduced. These two astrocytic enzymes are responsible for degradation of glutamate, the most abundant excitatory neurotransmitter in the brain. Since elevated levels of glutamate may be neurotoxic, we propose that the decreased capacity of astrocytes to metabolize glutamate may contribute to EAE pathology.