Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis.

BACKGROUND: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. AIM: To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). METHODS: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). RESULTS: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). CONCLUSIONS: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals.

Pharmacokinetics, safety, and tolerability of atomoxetine and effect of CYP2D6*10/*10 genotype in healthy Japanese men.

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

Spectral processing deficits in belt auditory cortex following early postnatal lesions of somatosensory cortex.

Induced or genetically based cortical laminar malformations in somatosensory cortex have been associated with perceptual and acoustic processing deficits in mammals. Perinatal freeze-lesions of developing rat primary somatosensory (S1) cortex induce malformations resembling human microgyria. Induced microgyria located in parietal somatosensory cortex have been linked to reduced behavioral detection of rapid sound transitions and altered spectral processing in primary auditory cortex (A1). Here we asked whether belt auditory cortex function would be similarly altered in rats with S1 microgyria (MG+). Pure-tone acoustic response properties were assessed in A1 and ventral auditory (VAF) cortical fields with Fourier optical imaging and multi-unit recordings. Three changes in spectral response properties were observed in both A1 and VAF in MG+ rats: 1) multi-unit response magnitudes were reduced 2) optical and multi-unit frequency responses were more variable; 3) at high sound levels units responded to a broader range of pure-tone frequencies. Optical and multi-unit pure-tone response magnitudes were both reduced for low sound levels in VAF but not A1. Sound level "tuning" was reduced in VAF but not in A1. Finally, in VAF frequency tuning and spike rates near best frequency were both altered for mid- but not high-frequency recording sites. These data suggest that VAF belt auditory cortex is more vulnerable than A1 to early postnatal induction of microgyria in neighboring somatosensory cortex.

Two thalamic pathways to primary auditory cortex.

Neurons in the center of cat primary auditory cortex (AI) respond to a narrow range of sound frequencies and the preferred frequencies in local neuron clusters are closely aligned in this central narrow bandwidth region (cNB). Response preferences to other input parameters, such as sound intensity and binaural interaction, vary within cNB; however, the source of this variability is unknown. Here we examined whether input to the cNB could arise from multiple, anatomically independent subregions in the ventral nucleus of the medial geniculate body (MGBv). Retrograde tracers injected into cNB labeled discontinuous clusters of neurons in the superior (sMGBv) and inferior (iMGBv) halves of the MGBv. Most labeled neurons were in the sMGBv and their density was greater, iMGBv somata were significantly larger. These findings suggest that cNB projection neurons in superior and iMGBv have distinct anatomic and possibly physiologic organization.

The multi-element content of the lichen Parmelia sulcata, soil, and oak bark in relation to acidification and climate.

Understanding how biodiversity is influenced by changing atmospheric conditions is important for conservation, public policy and environmental health. In a recent study, an impact on two of the most abundant lichens in Europe (Parmelia sulcata and Hypogymnia physodes) was recorded at Burnham Beeches lying 40 km west of London (UK) during unusual atmospheric conditions whilst other species remained unaffected. Bark and soil chemistry also influence lichen vitality and community composition. Correlations between element concentrations and element ratios in different samples help understand element cycling. To study this further, the multi-element content of the lichen P. sulcata and bark sampled in 2000 from 16 oak (Quercus robur) trees at Burnham Beeches was compared with the same elements determined in 24 surface soils sampled in 2005 from beneath the same trees. Soil pH ranged from 4.1 to 6.7. Highly significant correlations (p<0.001) for Mn/Ca ratios in lichen versus bark, soil versus bark and soil versus lichen samples confirmed cycling via the soil-tree-lichen system. Similar Mn/Ca ratios were reported in coniferous forests where high Mn concentrations were shown to limit epiphytic lichen abundance. Soil acidification influences element bioavailability and bark chemistry in Burnham Beeches with implications for lichen diversity and health. Recovery was recorded in P. sulcata, including regeneration within monitoring quadrats. Biological systems are well known to be influenced by pollution episodes.

Early cortical damage in rat somatosensory cortex alters acoustic feature representation in primary auditory cortex.

Early postnatal freeze-lesions to the cortical plate result in malformations resembling human microgyria. Microgyria in primary somatosensory cortex (S1) of rats are associated with a reduced behavioral detection of rapid auditory transitions and the loss of large cells in the thalamic nucleus projecting to primary auditory cortex (A1). Detection of slow transitions in sound is intact in animals with S1 microgyria, suggesting dissociation between responding to slow versus rapid transitions and a possible dissociation between levels of auditory processing affected. We hypothesized that neuronal responses in primary auditory cortex (A1) would be differentially reduced for rapid sound repetitions but not for slow sound sequences in animals with S1 microgyria. We assessed layer IV cortical responses in primary auditory cortex (A1) to single pure-tones and periodic noise bursts (PNB) in rats with and without S1 microgyria. We found that responses to both types of acoustic stimuli were reduced in magnitude in animals with microgyria. Furthermore, spectral resolution was degraded in animals with microgyria. The cortical selectivity and temporal precision were then measured with conventional methods for PNB and tone-stimuli, but no significant changes were observed between microgyric and control animals. Surprisingly, the observed spike rate reduction was similar for rapid and slow temporal modulations of PNB stimuli. These results suggest that acoustic processing in A1 is indeed altered with early perturbations of neighboring cortex. However, the type of deficit does not affect the temporal dynamics of the cortical output. Instead, acoustic processing is altered via a systematic reduction in the driven spike rate output and spectral integration resolution in A1. This study suggests a novel form of plasticity, whereas early postnatal lesions of one sensory cortex can have a functional impact on processing in neighboring sensory cortex.

The impact of a supplementary medication review and counselling service within the oncology outpatient setting.

The impact on the care of breast cancer patients, of a pharmacy technician-led medication review and counselling clinic, provided in an outpatient setting, was investigated using a controlled randomised study. Compared to the controls, clinic patients showed a significantly improved level of understanding of their chemotherapy support medication (95% CI for difference in mean knowledge rating scores=2.165-2.826, P<0.001) and a significant reduction in the median number of support items required (two compared to five in the control, P<0.001). This resulted in a significant reduction in mean medication expenditure per patient (26.70 vs 10.20 British Pound, 95% CI for the mean difference in cost 6.72 - 26.26 British Pound, P<0.001). The clinic was also associated with significant reductions in chemotherapy delays (P<0.001) and dose reductions due to side effects (P=0.003). Other benefits from the clinic were a reduction in pharmacy dispensing time and a highly significant reduction in pharmacy time spent resolving post-clinic prescription queries (P<0.001). Taking into account the initial technician training cost, the scheme represented an annual saving to the Trust of over 15,000 British Pound. The clinic serves as a model for those wishing to improve outpatient services to breast cancer patients.

Identification of acyl-homoserine lactone signal molecules produced by Nitrosomonas europaea strain Schmidt.

Nitrosomonas europaea strain Schmidt produces at least three acyl homoserine lactone (AHL) signal molecules: C(6)-homoserine lactone (HSL), C(8)-HSL, and C(10)-HSL. These compounds were identified in extracts of chemostat culture effluent by three independent methods. The concentrations of AHL in effluent were low (0.4 to 2.2 nM) but within the range known to induce AHL-responsive systems. The absence of LuxI and LuxM homologs from the genome of N. europaea strain Schmidt suggested that AHL synthesis occurs by an alternate pathway, possibly mediated by an HdtS homolog. To the best of our knowledge, the present report is the first to document the types and levels of AHLs produced by N. europaea.

Which factors are responsible for the changing lichen floras of London?

SO(2) is no longer the principal factor influencing the vitality and composition of lichen assemblages in London. We provide direct evidence for an impact on lichen growth during episodic high exhaust emissions coupled with unusual climatic conditions. This suggests a combination of particles and nitrogen plays a major role in influencing lichen growth. Nitrogen from traffic emissions may be at least as important as agriculture in influencing the composition of lichen assemblages.

Functional convergence of response properties in the auditory thalamocortical system.

One of the brain's fundamental tasks is to construct and transform representations of an animal's environment, yet few studies describe how individual neurons accomplish this. Our results from correlated pairs in the auditory thalamocortical system show that cortical excitatory receptive field regions can be directly inherited from thalamus, constructed from smaller inputs, and assembled by the cooperative activity of neuronal ensembles. The prevalence of functional thalamocortical connectivity is strictly governed by tonotopy, but connection strength is not. Finally, spectral and temporal modulation preferences in cortex may differ dramatically from the thalamic input. Our observations reveal a radical reconstruction of response properties from auditory thalamus to cortex, and illustrate how some properties are propagated with great fidelity while others are significantly transformed or generated intracortically.

Deterministic dynamics emerging from a cortical functional architecture.

Cerebral cortex has a range of interconnected functional architectures. Some appear random and without structure, while others are geometrical. Although the biological details certainly constrain spatial temporal patterns in neural networks, the influence that the laws of deterministic dynamics bring to bear on even isolated simple geometries are unknown. Layer II/III of primary visual cortex has long range horizontal connections with projections to and from other layers. The long range excitatory connections were modeled in isolation as an isolated laterally connected functional architecture. The Hodgkin-Huxley or Pinsky-Rinzel equations were used to simulate the neuronal elements. Waves of activity could propagate through the functional architecture; depending on the synaptic kinetics, the system could settle down into quiescence, oscillations, or seemingly random behavior. Order could be found in random-looking behavior by the application of techniques from chaos theory. Furthermore, the range and transitions of the temporal patterns in the modeled collection of neurons are similar to those found in other non-linear systems. The possibility that the temporal patterns of neurons in situ are also constrained by these mathematical laws is discussed.

Modular organization of intrinsic connections associated with spectral tuning in cat auditory cortex.

Many response properties in primary auditory cortex (AI) are segregated spatially and organized topographically as those in primary visual cortex. Intensive study has not revealed an intrinsic, anatomical organizing principle related to an AI functional topography. We used retrograde anatomic tracing and topographic physiologic mapping of acoustic response properties to reveal long-range (> or = 1.5 mm) convergent intrinsic horizontal connections between AI subregions with similar bandwidth and characteristic frequency selectivity. This suggests a modular organization for processing spectral bandwidth in AI.

Modular organization of frequency integration in primary auditory cortex.

Two fundamental aspects of frequency analysis shape the functional organization of primary auditory cortex. For one, the decomposition of complex sounds into different frequency components is reflected in the tonotopic organization of auditory cortical fields. Second, recent findings suggest that this decomposition is carried out in parallel for a wide range of frequency resolutions by neurons with frequency receptive fields of different sizes (bandwidths). A systematic representation of the range of frequency resolution and, equivalently, spectral integration shapes the functional organization of the iso-frequency domain. Distinct subregions, or "modules," along the iso-frequency domain can be demonstrated with various measures of spectral integration, including pure-tone tuning curves, noise masking, and electrical cochlear stimulation. This modularity in the representation of spectral integration is expressed by intrinsic cortical connections. This organization has implications for our understanding of psychophysical spectral integration measures such as the critical band and general cortical coding strategies.

Histological appearances in post-partum de Quervain's disease.

Six patients who developed de Quervain's disease during pregnancy or within 12 months of childbirth were treated surgically. Histopathological examination of the tendon sheaths using alcian blue stain showed that myxoid degeneration was responsible for the thickening observed in the sheath. Characteristic intramural deposits of mucopolysaccharides were present, predominantly in the subsynovial region. Acute or chronic inflammatory changes were not seen. These findings were the same as those described in patients with de Quervain's disease unrelated to pregnancy or childbirth.

Etiologic factors associated with Achilles tendinitis in runners.

PURPOSE: The purpose of this study was to determine whether relationships exist between selected training, anthropometric, isokinetic muscular strength, and endurance, ground reaction force, and rearfoot movement variables in runners afflicted with Achilles tendinitis. METHODS: Specifically, we examined differences in selected measures between a noninjured cohort of runners (N = 58) and a cohort of injured runners with Achilles tendinitis (N = 31). Isokinetic, kinetic, and kinematic measures were collected using a Cybex II+ isokinetic dynamometer (Medway, MA), AMTI force plate (500 Hz), and Motion Analysis high-speed videography (200 Hz), respectively. Separate discriminant function analyses were performed on each of the five sets of variables to identify the factors that best discriminate between the injured and control groups. RESULTS: Years running, training pace, stretching habits (injured runners were less likely to incorporate stretching into their training routine), touchdown angle, plantar flexion peak torque at 180 degrees x s(-1) and arch index were found to be significant discriminators. CONCLUSION: A combined discriminant analysis using the above mentioned significant variables revealed that plantar flexion peak torque, touchdown angle, and years running were the strongest discriminators between runners afflicted with Achilles tendinitis and runners who had no history of overuse injury.

Modulation of responses to optic flow in area 7a by retinotopic and oculomotor cues in monkey.

Perception of two- and three-dimensional optic flow critically depends upon extrastriate cortices that are part of the 'dorsal stream' for visual processing. Neurons in area 7a, a sub-region of the posterior parietal cortex, have a dual sensitivity to visual input and to eye position. The sensitivity and selectivity of area 7a neurons to three sensory cues - optic flow, retinotopic stimulus position and eye position - were studied. The visual response to optic flow was modulated by the retinotopic stimulus position and by the eye position in the orbit. The position dependence of the retinal and eye position modulation (i.e. gain field) were quantified by a quadratic regression model that allowed for linear or peaked receptive fields. A local maximum (or minimum) in both the retinotopic fields and the gain fields was observed, suggesting that these sensory qualities are not necessarily linearly represented in area 7a. Neurons were also found that simply encoded the eye position in the absence of optic flow. The spatial tuning for the eye position signals upon stationary stimuli and optic flow was not the same, suggesting multiple anatomical sources of the signals. These neurons can provide a substrate for spatial representation while primates move in the environment.