Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study.

Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396.

Trends of mortality and causes of death among HIV-infected patients in Taiwan, 1984-2005.

BACKGROUND: The aim of this study was to analyse the trends of mortality and causes of death among HIV-infected patients in Taiwan from 1984 to 2005. METHODS: Registered data and death certificates for HIV-infected patients from Taiwan Centers for Disease Control were reviewed. Mortality rate and causes of deaths were compared among patients whose HIV diagnosis was made in three different study periods: before the introduction of highly active antiretroviral therapy (HAART) (pre-HAART: from 1 January 1984 to 31 March 1997), in the early HAART period (from 1 April 1997 to 31 December 2001), and in the late HAART period (from 1 January 2002 to 31 December 2005). A subgroup of 1161 HIV-infected patients (11.4%) followed at a university hospital were analysed to investigate the trends of and risk factors for mortality. RESULTS: For 10 162 HIV-infected patients with a mean follow-up of 1.97 years, the mortality rate of HIV-infected patients declined from 10.2 deaths per 100 person-years (PY) in the pre-HAART period to 6.5 deaths and 3.7 deaths per 100 PY in the early and late HAART periods, respectively (P<0.0001). For the 1161 patients followed at a university hospital (66.8% with CD4 count <200 cells/microL), HAART reduced mortality by 89% in multivariate analysis, and the adjusted hazard ratio for death was 0.28 (95% confidence interval 0.24, 0.33) in patients enrolled in the late HAART period compared with those in the pre-HAART period. Seventy-six per cent of the deaths in the pre-HAART period were attributable to AIDS-defining conditions, compared with 36% in the late HAART period (P<0.0001). The leading causes of non-AIDS-related deaths were sepsis (14.7%) and accidental death (8.3%), both of which increased significantly throughout the three study periods. Compared with patients acquiring HIV infection through sexual contact, injecting drug users were more likely to die from non-AIDS-related causes. CONCLUSIONS: The mortality of HIV-infected patients declined significantly after the introduction of HAART in Taiwan. In the HAART era, AIDS-related deaths decreased significantly while deaths from non-AIDS-related conditions increased.

Surrogate estimates of insulin sensitivity in subjects with hypertension.

The purpose of the study is to compare surrogate estimates of insulin sensitivity with a directly measured insulin sensitivity index, steady-state plasma glucose (SSPG) from insulin suppression test (IST), in subjects with hypertension. Two hundred and twenty-eight hypertensive patients who received IST for SSPG were included for analysis. Estimates from fasting measurements alone, homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)), and indices from fasting and/or 2 h samples (ISI(0,120) and ISI(TX)) were calculated. In addition to Pearson and partial correlations, variance-component models were used to test the relationship between surrogate estimates of insulin sensitivity and SSPG. A large proportion of variance owing to covariates in the variance-component models indicated the goodness of model fit, irrespective of the independence among variables. SSPG was positively correlated with logarithmic transformation (Log) (HOMA-IR) and negatively correlated with QUICKI, Log (ISI(0,120)) and ISI(TX) (all P<0.0001). Log (ISI(0,120)) seemed to have a better correlation with SSPG (r=-0.72) than other measures in partial correlation. The proportion of variance owing to all covariates of Log (ISI(0,120)) and ISI(TX) were larger than those of Log (HOMA-IR) and QUICKI in the variance-component models. After adjustments for demographic and obesity covariates, the proportion of variance explained by Log (ISI(0,120)) were largest among the surrogate measures in the variance-component models. Our results showed that ISI(0,120) and ISI(TX) correlated better with SSPG than those used fasting measures alone (HOMA-IR and QUICKI). Log (ISI(0,120)) currently showing the strongest association with SSPG than other estimates is adaptable for use in large studies of hypertension.

Endemic fungal infections caused by Cryptococcus neoformans and Penicillium marneffei in patients infected with human immunodeficiency virus and treated with highly active anti-retroviral therapy.

This study compared the clinical presentations of 58 episodes of cryptococcosis in 50 patients and 26 episodes of penicillosis in 25 patients infected with human immunodeficiency virus (HIV) between June 1994 and June 2004, and assessed the safety of discontinuation of secondary prophylaxis for endemic fungal infections in those patients responding to highly active anti-retroviral therapy (HAART). Neurological symptoms were seen more commonly in patients with cryptococcosis, whereas respiratory symptoms, lymphadenopathy, hepatomegaly and/or splenomegaly, and non-thrush-related oral presentations were seen more commonly in patients with penicillosis. Patients with penicillosis were more likely to have abnormal chest radiography results and radiographic presentations of interstitial lesions, cavitations, fibrotic lesions and mass lesions. At the end of the study, maintenance antifungal therapy had been discontinued in 27 patients with cryptococcosis and in 18 patients with penicillosis in whom the median CD4 count had increased to 186 cells/microL (range, 9-523 cells/microL) and 95 cells/microL (range, 15-359 cells/microL), respectively, after HAART. Only one episode of penicillosis recurred (a relapse rate of 1.72/100 person-years; 95% CI, 1.44-2.10/100 person-years) after a median follow-up duration of 35.3 months (range, 2.6-91.6 months). No relapses occurred in patients with cryptococcosis after a median follow-up duration of 22.3 months (range, 1-83.4 months). These findings suggest that there are differences in the clinical presentations between endemic cryptococcosis and penicillosis in patients with HIV infection, and that it is safe to discontinue secondary antifungal prophylaxis for cryptococcosis and penicillosis in patients responding to HAART.

Tunable nanoblock lasers and stretching sensors.

Reconfigurable, reliable, and robust nanolasers with wavelengths tunable in the telecommunication bands are currently being sought after for use as flexible light sources in photonic integrated circuits. Here, we propose and demonstrate tunable nanolasers based on 1D nanoblocks embedded within stretchable polydimethylsiloxane. Our lasers show a large wavelength tunability of 7.65 nm per 1% elongation. Moreover, this tunability is reconfigurable and reliable under repeated stretching/relaxation tests. By applying excessive stretching, wide wavelength tuning over a range of 80 nm (spanning the S, C, and L telecommunication bands) is successfully demonstrated. Furthermore, as a stretching sensor, an enhanced wavelength response to elongation of 9.9 nm per % is obtained via the signal differential from two nanoblock lasers positioned perpendicular to each other. The minimum detectable elongation is as small as 0.056%. Nanoblock lasers can function as reliable tunable light sources in telecommunications and highly sensitive on-chip structural deformation sensors.

Membrane resonance and subthreshold membrane oscillations in mesencephalic V neurons: participants in burst generation.

Trigeminal mesencephalic (Mes V) neurons are critical components of the circuits controlling oral-motor activity. The possibility that they can function as interneurons necessitates a detailed understanding of the factors controlling their soma excitability. Using whole-cell patch-clamp recording, in vitro, we investigated the development of the ionic mechanisms responsible for the previously described subthreshold membrane oscillations and rhythmical burst discharge in Mes V neurons from rats ages postnatal day (P) 2-12. We found that the oscillation amplitude and frequency increased during development, whereas bursting emerged after P6. Furthermore, when bursting was initiated, the spike frequency was largely determined by the oscillation frequency. Frequency domain analysis indicated that these oscillations emerged from the voltage-dependent resonant properties of Mes V neurons. Low doses of 4-aminopyridine (<100 microm) reduced the oscillations and abolished resonance in most neurons, suggesting that the resonant current is a steady-state K(+) current (I(4-AP)). Sodium ion replacement or TTX reduced substantially the oscillations and peak amplitude of the resonance, suggesting the presence of a persistent Na(+) current (I(NaP)) that functions to amplify the resonance and facilitate the emergence of subthreshold oscillations and bursting.

Prevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis in non-haemophiliac HIV-1-infected adults in Taiwan.

We assessed the seroprevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis (TE) in 844 non-haemophiliac HIV-infected patients in Taiwan between June 1994 and April 2003. Approximately 70% (69.3%) of them had a baseline CD4+ lymphocyte count of 200 x 10(6)/L or less, and more than 70% (73.9%) having initiated highly active antiretroviral therapy. The seroprevalence of T. gondii infection was 10.2%, which did not differ with sex,age,route of transmission, birth inside or outside of Taiwan, or CD4+ lymphocyte stratifications. After a median observation duration of 603 days (range, 1-3264 days), 10 (1.2%) patients developed 11 episodes of TE after a median interval of 30 days (range, 1-941 days) between enrolment and diagnosis of TE, with an incidence of 0.59 per 100 person-years (PY) (95% confidence interval, 0.56-0.63 per 100 PY). We concluded that the incidence of TE of HIV-infected patients in Taiwan was lower than that reported in western countries because of a lower seroprevalence of T. gondii infection and use of antimicrobial prophylaxis and antiretroviral therapy, although most of the patients were at the late stage of HIV infection.

Impact of chronic hepatitis C infection on outcomes of patients with an advanced stage of HIV-1 infection in an area of low prevalence of co-infection.

To ascertain whether hepatitis C (HCV) co-infection affects the progression of HIV infection, we initiated an eight-year prospective observational study at a university hospital in Taiwan where seroprevalences of HCV antibody and HIV antibody were low. Fifty-three (12.0%) consecutive non-haemophiliac HIV1-infected patients with HCV co-infection and 387 (88.0%) patients without HCV and hepatitis B co-infection were enrolled between June 1994 and June 2002 and observed until December 2002. Outcomes evaluated included the risk for acute hepatitis, hepatic decompensation, HIV disease progression and mortality, and changes of CD4+ count and plasma viral load (PVL) after initiation of highly active antiretroviral therapy (HAART) at the end of the study. The baseline CD4+ count, PVL and proportion of patients with AIDS-defining opportunistic illnesses (OI) at study entry were similar between patients with HCV co-infection and those without co-infection, but HCV-co-infected patients were older (39 versus 35 years, P = 0.01) and had a higher proportion of intravenous drug use (17.0% versus 0.8%, P < 0.001). After a total observation duration of 1137 patient-years (PY) (median, 791 days; range, 3-3053 days), the incidence of acute hepatitis in HCV-co-infected patients was 13.89 per 100 PY (95% confidence interval [CI], 13.31-14.49) and that in patients without co-infection was 6.39 per 100 PY (95% CI, 6.24-6.55 per 100 PY), with an adjusted odds ratio (OR) of 2.769 (95% CI, 1.652-4.640). At the end of the study, CD4+ count increased by 137 x 10(6) and 157 x 10(6)/L in patients with and without HCV co-infection, respectively, (P = 0.47). The proportions of achieving undetectable PVL (<400 copies/mL) after HAART was similar (76.7% versus 74.9%, P = 0.79). The adjusted OR for development of new AIDS-defining OI was 1.826 (95% CI, 0.738-4.522) in HCV-co-infected patients as compared with HCV- uninfected patients. The adjusted hazards ratio for death of HCV-co-infected patients when compared with those without co-infection was 0.781 (95% CI, 0.426-1.432). Our findings suggested that HCV co-infection was associated with a significantly higher risk for acute hepatitis in HIV-infected patients receiving antiretroviral therapy, but it had no adverse impact on virological, immunological and clinical responses to HAART and survival when compared with patients without HCV and HBV co-infection.

Characteristics of a fast transient outward current in guinea pig trigeminal motoneurons.

A fast transient voltage dependent outward current (TOC) in trigeminal motoneurons (TMNs) was studied in guinea pig brainstem slices by use of sharp electrodes in combination with single electrode voltage clamp techniques. In solutions containing TTX, low Ca2+/Mn2+ and 20 mM TEA this current activated around -55 to -60 mV from holding potentials negative to resting potential, obtained its peak amplitude within 5 ms and decayed as a single exponential with a time constant of 6-8 ms. Half maximal values for inactivation and activation were -72 and -37 mV, respectively. Bath application of 5 mM 4-AP suppressed this current by approximately 90% and eliminated the early depolarizing transient membrane rectification observed in response to a constant depolarizing current pulse, prolonged the action potential duration, and reduced the threshold voltage and delay to onset of the action potential. It is suggested that this current resembles the typical A-current observed in many CNS neurons and, as a result of its voltage and time dependent properties, could contribute to control of motoneuronal discharge and timing of burst onset during rhythmical jaw movements. Therefore, any cellular models of masticatory activity should include the properties of this current.

Plastic changes in the distribution and soma size of retinal ganglion cells after neonatal monocular enucleation in rats.

Using the method of retrograde labeling of ganglion cells with HRP, we studied in adult rats the plastic changes in the retinogeniculate projections due to monocular enucleations shortly after birth. Four normal and 6 neonatally enucleated rats were used. In two of the normal and 4 of the enucleated rats a small amount of HRP was injected into the dorsal lateral geniculate nucleus (LGd) and in 4 other rats massive injections were made into the optic tract near the LGd. Neonatally unilaterally eye-enucleated rats were characterized by an expanded distribution of ipsilaterally projecting ganglion cells all over the retina of the remaining eye and by a densely packed distribution of these cells in the lower temporal retina in which area these cells have only a moderate density in normal rats. On the contrary, in the lower temporal retina of monocularly enucleated rats the incidence of contralaterally projecting ganglion cells was decreased. Soma areas of ipsi- and contralaterally projecting ganglion cells were measured for the peripheral crescent in lower temporal and lower nasal retinas. As compared with normal rats, neonatally enucleated rats had a larger mean soma area of ipsilaterally projecting cells and a smaller mean soma area of contralaterally projecting cells. This result was interpreted as suggesting that after neonatal monocular enucleation medium to large cells had changed their side of axonal projection from the contralateral to ipsilateral LGd.

Bilateral changes in soma size of geniculate relay cells and corticogeniculate cells after neonatal monocular enucleation in rats.

Soma areas of relay cells of the lateral geniculate nucleus and of corticogeniculate cells of normal rats (n = 4) were compared with those of neonatally unilaterally eye-enucleated adult rats (n = 13). These cells were labeled by retrogradely transported HRP. Monocular enucleation was performed on postnatal days 1 (PND 1) (n = 4), 3 (PND 3) (n = 5) and 6 (PND 6) (n = 4). The results are summarized as follows. In PND 1 rats soma areas of relay cells were 12-16% smaller than those of normal rats, but only for the geniculate nucleus ipsilateral to the remaining eye. In PND 3 and 6 rats the areal shrinkage of relay cells was 27-39% of the normal control for both hemispheres, though it was less marked in the hemisphere contralateral to the remaining eye. The corticogeniculate cells were distributed in layers V and VI in eye-enucleated rats as well as in normal rats. Soma areas of both layer V and VI cells increased in PND 1 rats for both hemispheres by about 15-47% of the normal control. In PND 3 rats increase in soma size tended to occur for layer VI cells, although the data varied from animal to animal. In summary, it was established that unilateral eye-enucleation in rats at birth induced soma size changes of the geniculate relay cells and of the corticogeniculate cells in the non-deafferented as well as in the deafferented hemisphere. Possible mechanisms for the bilateral changes in soma area of central visual cells after neonatal monocular enucleation are discussed.

Two types of thalamic reticular cells in relation to the two visual thalamocortical systems in the rat.

We found in urethane-anesthetized rats that thalamic reticular (TR) cells responding to an electrical stimulus of the optic tract (OT) can be further subdivided into two types, viz. S- and L-type cells. S-type cells, which were selectively excited from area 17 of the visual cortex, were characterized by short latency responses (2.3-6.1 ms) to OT stimulation. TR cells activated antidromically from the dorsal lateral geniculate nucleus were all classified as S-type. Long OT latencies (5.2-15.3 ms) and selective excitation from area 18a were peculiar to L-type cells, which showed antidromic responses to the lateral posterior nucleus stimulation. Mapping studies documented that cells belonging to each type were segregated in the thalamic reticular nucleus; L-type cells were located in the most posterior part. It is suggested that S- and L-type cells are inhibitory interneurons modulating activity of geniculocortical and extrageniculocortical projection cells, respectively.

Temporary double representation in expanded ipsilateral retinocollicular projection of neonatally one-eye-removed rats.

Retinotopic representations of the expanded projection to the ipsilateral colliculus were studied in albino rats of various ages after neonatal unilateral eye removal. Besides the projection from the lower temporal retina the projection from the central retina was observed in 3-6 month-old one-eyed rats. Such double retinotopic representation was not observed in 1-month- or 1-year-old one-eyed rats. A postnatally growing temporary process was suggested for the expanded ipsilateral retinocollicular projection in rats.

Identification of cell types from action potential waveforms: cerebellar granule cells.

We have recorded 404 single units extracellularly in the cerebellar cortex of the rat with tungsten microelectrodes. Waveforms of action potentials were analyzed in order to develop criteria for on-line identification of cell types. Two of the four most frequently recorded waveforms were simple and complex spikes from Purkinje cells. The other two originated from granule cells and glomeruli. Presumed granule cells showed biphasic action potentials with half-widths (0.78 +/- 0.14 ms, n = 51) broader than those of the simple spikes of Purkinje cells (0.22 +/- 0.06 ms, n = 54), whereas presumed glomerular potentials had complex action potentials with narrower half-widths (0.14 +/- 0.05 ms, n = 35). The mean inter-spike interval of presumed granule cells (333.3 +/- 195.4 ms, n = 53) was longer than that of Purkinje cells (47.3 +/- 31.8 ms, n = 59) and the presumed glomerular potentials (77.7 +/- 50.8 ms, n = 20). Results were virtually identical from 17 cerebellar units recorded extracellularly in the cat. Intracellular recording and staining of 20 granule cells with HRP-filled microelectrodes provided further support for our assessment. These results suggest that action potentials from granule cells may be identified on-line by waveform.

The relation between axon diameter and axonal conduction velocity of Y, X and W cells in the cat retina.

Axon diameters of ganglion cells were measured electronmicroscopically from the cross-sections of the optic nerve fiber layer in the cat retina. The diameter distribution revealed 3 well-separated groups which correspond to axons of Y, X and W cells. Mean intraretinal axonal conduction velocities were estimated physiologically for the 3 classes. Between the means of axon diameter (D, micron) and conduction velocity (V, m/s) the following positive correlations were obtained: V = 3.85 square root D-2.3 when short axes of cross-sections were measured, and V = 3.33 square root D-2.3 when long axes were measured.

Electron microscopic analysis of amacrine and bipolar cell inputs on Y-, X-, and W-cells in the cat retina.

In the cat retina, bipolar and amacrine cell inputs were analyzed electron microscopically in 5 ganglion cells (two Y-cells, two X-cells and one W-cell) that were well-isolated and had clear morphological features. For Y- and X-cells, subtypes of a and b were further identified according to the sublamina of the inner plexiform layer in which their dendrites extended. Y-a and Y-b ganglion cells had large somas, thick axons, and several thick dendrites that branched extensively with a large dendritic field. X-a and X-b cells had medium-sized somas, medium-sized axons and extremely narrow dendritic fields. The W-cell studied had a medium-sized soma, a medium-sized axon, and extremely thin dendrites that extended widely. For each of the 5 ganglion cells, ultrathin serial sections were made to study relative occurrence of amacrine and bipolar synapses in whole length of dendrites. About 50% of the terminals were bipolar in the Y-a and Y-b cell dendrites, 36-38% in the X-a and X-b cell dendrites, whereas only 19.7% were bipolar in the W cell dendrites. Bipolar terminals tended to make synaptic contacts with the distal dendrites of Y- and W-cells.

Electrophysiology of nitrous oxide on cerebellar granule cells: a single-cell study.

We recorded 18 single cells in the granule cell layer of the cat. Each single cell was screened and identified as a granule cell based on a set of criteria derived from known electrophysiological properties of granule cells. We then monitored the effects of nitrous oxide on the spontaneous activities and the auditory responses of these cells. Nitrous oxide consistently caused a severe inhibition of spontaneous activities as well as responses to sound in these cells. Furthermore, the amplitudes of their action potentials decreased during the inhibition. Three of the 18 cells were subsequently injected intracellularly with HRP. All three were verified to be granule cells. In those granule cells we recorded intracellularly, nitrous oxide did not change the resting membrane potentials. The gradual decrease in the amplitudes of action potentials suggested that some of the mechanisms leading to the genesis of action potentials were being altered by nitrous oxide. It is also possible that nitrous oxide may act on synaptic transmission at a site located postsynaptically on the granule cells.

Sensitivity to GABA of neurons of the dorsal and ventral lateral geniculate nuclei in the rat.

GABA was applied iontophoretically to dorsal and ventral lateral geniculate (LGd and LGv) neurons in rats. Spontaneous discharges were readily suppressed in both species of neurons. While in LGd neurons, evoked discharges by optic nerve stimulation were suppressed as readily as were spontaneous discharges, LGv neurons were characterized in that evoked discharges were much more resistant than spontaneous discharges.

Retinotopic organizations of the expanded ipsilateral projection to the rat's superior colliculus; variations along its rostrocaudal axis.

The retinotopic organization of the expanded projection to the ipsilateral colliculus was studied electrophysiologically in 12 adult albino rats with one eye removed at birth. For comparison, the contralateral projection was rather variable in the representation of the nasotemporal axis of the retina along the rostrocaudal dimension of the colliculus; on the other hand, the representation of dorsal-to-ventral retinal axis onto the mediolateral dimension of the colliculus was relatively stable.

Auditory receptive area in the cerebellar hemisphere is surrounded by somatosensory areas.

We mapped the neuronal discharges in response to sound in the granule cell layer of the cerebellar hemisphere of the rat. An auditory receptive area was located in the lateral part of Crus IIb. The size of the auditory area was approx. 1 mm2. It was surrounded by somatosensory receptive areas representing the regions in and around the mouth, particularly the lips, the incisors, and areas inside the mouth. Frequency selectivity of neurons in the auditory area was so broad that it resembled the audiogram of the ear of the animal. The auditory responses were not particularly sensitive to binaural intensity differences. On the basis of the response properties of these neurons to sound and the receptive field properties of the adjacent somatosensory areas, we suggest that the function of the auditory area in the cerebellar hemisphere may be in the control of movements involved in vocalization.