Amorphous silicon nanowires combining high nonlinearity, FOM and optical stability.

We demonstrate optically stable amorphous silicon nanowires with both high nonlinear figure of merit (FOM) of ~5 and high nonlinearity Re(γ) = 1200W(-1)m(-1). We observe no degradation in these parameters over the entire course of our experiments including systematic study under operation at 2 W coupled peak power (i.e. ~2GW/cm(2)) over timescales of at least an hour.

Electrically driven hybrid Si/III-V Fabry-Pérot lasers based on adiabatic mode transformers.

We report the first demonstration of an electrically driven hybrid silicon/III-V laser based on adiabatic mode transformers. The hybrid structure is formed by two vertically superimposed waveguides separated by a 100-nm-thick SiO2 layer. The top waveguide, fabricated in an InP/InGaAsP-based heterostructure, serves to provide optical gain. The bottom Si-waveguides system, which supports all optical functions, is constituted by two tapered rib-waveguides (mode transformers), two distributed Bragg reflectors (DBRs) and a surface-grating coupler. The supermodes of this hybrid structure are controlled by an appropriate design of the tapers located at the edges of the gain region. In the middle part of the device almost all the field resides in the III-V waveguide so that the optical mode experiences maximal gain, while in regions near the III-V facets, mode transformers ensure an efficient transfer of the power flow towards Si-waveguides. The investigated device operates under quasi-continuous wave regime. The room temperature threshold current is 100 mA, the side-mode suppression ratio is as high as 20 dB, and the fiber-coupled output power is ~7 mW.

High contrast 40Gbit/s optical modulation in silicon.

Data interconnects are on the verge of a revolution. Electrical links are increasingly being pushed to their limits with the ever increasing demand for bandwidth. Data transmission in the optical domain is a leading candidate to satisfy this need. The optical modulator is key to most applications and increasing the data rate at which it operates is important for reducing power consumption, increasing channel bandwidth limitations and improving the efficiency of infrastructure usage. In this work silicon based devices of lengths 3.5mm and 1mm operating at 40Gbit/s are demonstrated with extinction ratios of up to 10dB and 3.5dB respectively. The efficiency and optical loss of the phase shifter is 2.7V.cm and 4dB/mm (or 4.5dB/mm including waveguide loss) respectively.

Functional connectivity between motor cortex and globus pallidus in human non-REM sleep.

Recent evidence suggests that the motor system undergoes very specific modulation in its functional state during the different sleep stages. Here we test the hypothesis that changes in the functional organization of the motor system involve both cortical and subcortical levels and that these distributed changes are interrelated in defined frequency bands. To this end we evaluated functional connectivity between motor and non-motor cortical sites (fronto-central, parieto-occipital) and the globus pallidus (GP) in human non-REM sleep in seven patients undergoing deep brain stimulation (DBS) for dystonia using a variety of spectral measures (power, coherence, partial coherence and directed transfer function (DTF)). We found significant coherence between GP and fronto-central cortex as well as between GP and parieto-occipital cortex in circumscribed frequency bands that correlated with sleep specific oscillations in 'light sleep' (N2) and 'slow-wave sleep' (N3). These sleep specific oscillations were also reflected in significant coherence between the two cortical sites corroborating previous studies. Importantly, we found two different physiological activities represented within the broad band of significant coherence between 9.5 and 17 Hz. One component occurred in the frequency range of sleep spindles (12.5-17 Hz) and was maximal in the coherence between fronto-central and parieto-occipital cortex as well as between GP and both cortical sites during N2. This component was still present between fronto-central and parieto-occipital cortex in N3. Functional connectivity in this frequency band may be due to a common input to both GP and cortex. The second component consisted of a spectral peak over 9.5-12.5 Hz. Coherence was elevated in this band for all topographical constellations in both N2 and N3, but especially between GP and fronto-central cortex. The DTF suggested that the 9.5-12.5 Hz activity consisted of a preferential drive from GP to the fronto-central cortex in N2, whereas in N3 the DTF between GP and fronto-central cortex was symmetrical. Partial coherence supported distinctive patterns for the 9.5-12.5 and 12.5 and 17 Hz component, so that only coherence in the 9.5-12.5 Hz band was reduced when the effects of GP were removed from the coherence between the two cortical sites. The data suggest that activities in the GP and fronto-central cortex are functionally connected over 9.5-12.5 Hz, possibly as a specific signature of the motor system in human non-REM sleep. This finding is pertinent to the longstanding debate about the nature of alpha-delta sleep as a physiological or pathological feature of non-REM sleep.

Correlates of disability in multiple sclerosis detected by transcranial magnetic stimulation.

OBJECTIVE: To study the usefulness of corticospinally mediated excitatory responses and transcallosal inhibition (TI) elicited by transcranial magnetic stimulation (TMS) as a surrogate marker of disability in patients with different courses of MS. METHODS: Focal TMS of the motor cortex was performed in 118 patients with MS (96 with relapsing-remitting, 19 with primary progressive, and three with secondary progressive disease) who had an Expanded Disability Status Scale (EDSS) score between 0 and 6.5 and in 35 normal subjects. Central motor latencies (CML) and TI (onset latency, duration) were investigated. The Spearman rank correlation was used for statistical analysis. RESULTS: TMS disclosed prolonged CML in 52.5% and abnormal TI in 61% of the patients. In all patients the EDSS correlated with the frequency of abnormal TI (r = 0.58, p < 0.01) and abnormal CML (r = 0.51, p < 0.01). In patients with primary progressive MS (EDSS 1.5 to 6.5) the frequency of TI abnormalities correlated with EDSS (r = 0.65, p < 0.01) whereas CML did not. Delayed corticospinal responses in hand muscles always led to abnormal TI. CONCLUSIONS: The combination of central motor latencies and transcallosal inhibition evoked by transcranial magnetic stimulation yields objective data to estimate disease progression in MS as assessed by the EDSS.

Corticospinal excitability in human sleep as assessed by transcranial magnetic stimulation.

The excitability of the corticospinal system was studied in 23 healthy subjects in sleep stages NREM2, NREM4, REM, and wakefulness using transcranial magnetic stimulation. Assessment of motor thresholds, stimulus-response curves, and latencies of motor evoked potentials shows activation of the fast-conducting corticospinal fibers in all sleep stages and a neuronal recruitment pattern similar to wakefulness, however, at a lower level of excitability and with significant differences between sleep stages.

MRI study of human brain exposed to high-dose repetitive magnetic stimulation of visual cortex.

T1-, T2-, and diffusion-weighted MRI was used to determine whether repetitive transcranial magnetic stimulation (rTMS) affects the blood-brain barrier or induces localized brain edema. In 11 healthy individuals, 1,200 to 3,800 stimuli were applied over the visual cortex of one hemisphere in series of 5-, 10-, or 20-Hz stimulus trains. MRI performed 6 minutes to 6 hours after rTMS did not show pathologic changes in conventional MRI sequences, after application of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), or by determining apparent diffusion coefficients.

In vitro modulation of doxorubicin and docetaxel antitumoral activity by methyl-beta-cyclodextrin.

Methyl-beta-cyclodextrin (MEBCD) was investigated for its effect on the antitumoral activity of various antineoplastic agents (doxorubicin (DOX), docetaxel (DXL), 5-fluorouracil (5-FU) and cisplatin (CDDP)) in three different human parental sensitive cancer cell lines (K562 S, MCF7 S and A2780 S) and their multidrug resistant variant sublines (K562 R, MCF7 R and A2780 R). At non-cytotoxic concentrations, MEBCD was able to increase significantly DOX and DXL cytotoxic activity in all the cell lines tested. The sensitisation ratios (IC50 drug control/IC50 drug-MEBCD treated) ranged from 3l1 to 14.3. Moreover, intracellular DOX accumulation, determined by high-performance liquid chromatography, was also increased when cells were treated with MEBCD combined with DOX (approximately 2-3 fold). The effects of MEBCD in resistant sublines were greater than in their parental sensitive cell lines. Other experiments demonstrated that the action of the MEBCD was independent of DOX. These data provided a basis for the potential therapeutic application of MEBCD in cancer therapy.

Methyl-beta-cyclodextrin in HL-60 parental and multidrug-resistant cancer cell lines: effect on the cytotoxic activity and intracellular accumulation of doxorubicin.

The purpose of this work was to determine the role of methyl-beta-cyclodextrin (MEBCD) in combination with doxorubicin (DOX) on the cellular proliferation of a sensitive parental and a multidrug-resistant human cancer cell line (HL-60 S and HL-60 R) and to study the effect of MEBCD on DOX intracellular accumulation. The cytotoxicity of DOX at five concentrations (50-50,000 nM) was evaluated with or without the coadministration of four fixed noncytotoxic concentrations of MEBCD (100, 200, 500, and 1,000 microM). Intracellular DOX concentrations were determined by a high-performance liquid chromatography (HPLC) method with fluorescence detection. MEBCD applied at 500 and 1000 microM in combination with doxorubicin (DOX) significantly potentiated the activity of DOX used alone on both sensitive and multidrug-resistant cell lines; 50% growth-inhibitory (IC50) ratios (IC50 MEBCD-DOX/IC50 DOX) were about 3:4 and 1.6:4 for HL-60 S and HL-60 R, respectively. Moreover, intracellular DOX accumulation, determined by HPLC during 6 h of drug exposure, was about 2-4 times higher for cells treated with MEBCD in combination with DOX than in those treated with DOX alone. Similar results were obtained using other paired MCF 7 sensitive and resistant cell lines. Correlation between these results and an MEBCD-cell membrane interaction was discussed. These initial data provide a basis for the potential therapeutic application of MEMBCD in cancer therapy.

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS: We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinson's disease and 17 healthy subjects. RESULTS: PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS: Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.

Tumor cell membrane as a potential target for methyl-beta-cyclodextrin.

The purpose of this work was to determine the role of methyl-beta-cyclodextrin (MEBCD) in combination with doxorubicin (DOX) on DOX intracellular accumulation and efflux, in comparison to verapamil in a sensitive parental and multidrug-resistant human cancer cell line (HL-60 S and HL-60 R). Moreover, cell membrane and nuclear modifications induced by MEBCD were investigated. At concentration of 10 mumol for 10(6) cells, MEBCD combined with doxorubicin (DOX), was able to significantly enhance the intracellular concentration of DOX in HL-60 S and HL-60 R cell lines during the period of exposure. In the resistant subline, MEBCD activity was higher than that of verapamil. Moreover, treatment of cells with MEBCD resulted in a modification in cell membrane integrity and cell morphology, but had no own activity in the distribution of the cells within cell cycle.

Pharmacokinetics of 5-fluorouracil (5-FUra) in patients with metastatic colorectal cancer receiving 5-FUra bolus plus continuous infusion with high dose folinic acid (LV5FU2).

The pharmacokinetics of 5-fluorouracil (5-FUra) were investigated in 16 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV 200 mg/m2) followed by 5-FUra bolus (400 mg/m2) and continuous infusion (600 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. The concentrations of 5-FUra at the end of the loading dose averaged 30.7 +/- 13.2 micrograms/ml (i.e., 236 microM). The steady-state plasma concentration averaged 0.31 +/- 0.11 microgram/ml (i.e., 2.4 microM). 5-FUra plasma levels declined rapidly after the end of infusion with an apparent elimination half-life of 7.08 +/- 3.21 minutes. Clearance ranged from 776 to 3023 ml/min/m2. Large patient-to-patient variations in plasma 5-FUra concentrations were observed. No toxicity greater than WHO grade 2 was seen. One patient experienced grade 1 stomatitis and two others experienced grade 1 and 2 myelosuppression. One patient developed diarrhoea and another suffered asthenia. Nausea and vomiting were observed in 5 patients.

Methyl-beta-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit.

The purpose of this work was to determine the pharmacokinetics and the tissue concentrations of methyl-beta-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination. MEBCD (200 mg/kg) and DOX (1 mg/kg) were intravenously injected to white New Zealand rabbits and blood samples were obtained over a 48-h period after administration. After this period, administration was repeated and animals were killed 1, 2 or 4 h after injection. Heart, liver and kidney were then removed. MEBCD and DOX analysis in plasma and tissues was performed using two HPLC methods with fluorimetric detection. MEBCD pharmacokinetic profile was consistent with a two-compartment model (t1/2 alpha: 30 min; t1/2 beta: 7 h). Co-administration with DOX did not modify the main pharmacokinetic parameters of MEBCD. However, C5 min, t1/2 alpha, t1/2 beta and AUCinfinity were decreased by the co-administration of DOX with MEBCD compared to DOX alone. Assays of excised tissues showed that DOX enhanced the cardiac, renal and hepatic concentrations of MEBCD. On the other hand, MEBCD did not alter the cardiac distribution of DOX, while renal and hepatic distribution profiles were modified. In this study, the pharmacokinetic parameters of MEBCD injected intravenously were determined for the first time. DOX did not enhance MEBCD pharmacokinetic profile but MEBCD reduced the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX, which is auspicious for further in vivo experiments using the co-administration of DOX and MEBCD.

Prospective documentation and analysis of the pre- and early clinical management in severe head injury in southern Bavaria at a population based level.

Treatment of patients suffering from severe head injury is so far restricted to general procedures, whereas specific pharmacological agents of neuroprotection including hypothermia have not been found to improve the outcome in clinical trials. Albeit effective, symptomatic measures of the preclinical rescue of patients (i.e. stabilization or reestablishment of the circulatory and respiratory system) or of the early clinical care (e.g. prompt diagnosis and treatment of an intracranial space occupying mass, maintenance of a competent circulatory and respiratory system, and others) by and large constitute the current treatment based on considerable organizational and logistical efforts. These and other components of the head injury treatment are certainly worthwhile of a systematic analysis as to their efficacy or remaining deficiencies, respectively. Deficits could be associated with delays of providing preclinical rescue procedures (e.g. until intubation of the patient or administration of fluid). Delays could also be associated in the hospital with the diagnostic establishment of intracranial lesions requiring prompt neurosurgical intervention. By support of the Federal Ministry of Education and Research and under the auspices of the Forschungsverbund Neurotraumatology, University of Munich, a prospective system analysis was carried out on major aspects of the pre- and early clinical management at a population based level in patients with traumatic brain injury. Documentation of pertinent data was made from August 1998 to July 1999 covering a catchment area of Southern Bavaria (5.6 mio inhabitants). Altogether 528 cases identified to suffer from severe head injury (GCS < or = 8 or deteriorating to that level within 48 hrs) were enrolled following admission to the hospital and establishment of the diagnosis. Further, patients dying on the scene or during transport to the hospital were also documented, particularly as to the frequency of severe head injury as underlying cause of mortality. The analysis included also cases with additional peripheral trauma (polytrauma). The efficacy of the logistics and organization of the management was studied by documentation of prognosis-relevant time intervals, as for example until arrival of the rescue squad at the scene of an accident, until intubation and administration of fluid, or upon hospital admission until establishment of the CT-diagnosis and commencement of surgery or transfer to the intensive care unit, respectively. The severity of cases studied in the present analysis is evident from a mortality of far above 40% of cases admitted to the hospital, which was increased by about 20% when including prehospital mortality. The outcome data notwithstanding, the emerging results demonstrate a high efficacy of the pre- and early clinical management, as indicated by a prompt arrival of the rescue squad at the scene, a competent prehospital and early clinical management and care, indicative of a low rate of avoidable complications. It is tentatively concluded on the basis of these findings that the patient prognosis is increasingly determined by the manifestations of primary brain damage vs. the development of secondary complications.

Inhibitory and excitatory intracortical circuits across the human sleep-wake cycle using paired-pulse transcranial magnetic stimulation.

Studies using single-pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep-wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n=7; NREM 3/4: n=7; REM: n=7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.

Encephalomyelitis due to Cryptococcus neoformans var gattii presenting as spinal tumour: case report and review of the literature.

A 24 year old immunocompetent German resident is described who developed multifocal encephalomyelitis due to infection with Cryptococcus neoformans var gatti, commonly considered a disease of tropical regions. In the light of current knowledge on the epidemiology of C neoformans var gatti and the travel history of the patient it is assumed that the infection was acquired outside Europe. As exclusive intramedullary involvement is an outstandingly rare manifestation in spinal cryptococcosis, the particular diagnostic procedure and the therapeutic strategies are discussed