Analysis of the relationship between age and treatment response in migraine

In migraine, headache severity varies with age. As a consequence, the effectiveness of medication may also depend on a patient's age. The purpose of this study was to assess the combined effect of age and drug treatment on headache characteristics. Using data from clinical trials of sumatriptan in adolescents and adults, we show how the interaction between age and drug exposure can be parameterised as a covariate on a Markov model that describes the decline of headache severity over three clinically defined stages (no relief, relief and pain-free status). The model explains important clinical observations: (i) the rates at which the pain relief and pain-free status were attained were found to be inversely related to age; (ii) in placebo-treated patients, the mean transit time from 'no relief' to 'relief' is 3 h for young adolescents and increases to 6 h for patients aged ≥ 30 years; and (iii) sumatriptan reduces the transit time to 2 h, irrespective of age. These findings indicate that the therapeutic gain over placebo increases with age. Prospective studies of antimigraine drugs should take this relationship into account when extrapolating efficacy data from adults to adolescents.     

Cochlear mechanisms from a phylogenetic viewpoint

The hearing organ of the inner ear was the last of the paired sense organs of amniotes to undergo formative evolution. As a mechanical sensory organ, the inner-ear hearing organ's function depends highly on its physical structure. Comparative studies suggest that the hearing organ of the earliest amniote vertebrates was small and simple, but possessed hair cells with a cochlear amplifier mechanism, electrical frequency tuning, and incipient micromechanical tuning. The separation of the different groups of amniotes from the stem reptiles occurred relatively early, with the ancestors of the mammals branching off first, approximately 320 million years ago. The evolution of the hearing organ in the three major lines of the descendents of the stem reptiles (e.g., mammals, birds-crocodiles, and lizards-snakes) thus occurred independently over long periods of time. Dramatic and parallel improvements in the middle ear initiated papillar elongation in all lineages, accompanied by increased numbers of sensory cells with enhanced micromechanical tuning and group-specific hair-cell specializations that resulted in unique morphological configurations. This review aims not only to compare structure and function across classification boundaries (the comparative approach), but also to assess how and to what extent fundamental mechanisms were influenced by selection pressures in times past (the phylogenetic viewpoint).     

Symptoms of ＂Heat＂ as a Pattern of Physiopathology

Objective： The guiding criteria are considered the backbone of Chinese medicine. They have previously been described as functional features （symptoms） leading to the overall assessment of human functions on the basis of a regulatory （cybernetic） model referring to the I Ging. Methods： The Heidelberg model can explain symptoms such as created by ＂heat＂ on a rational physiological level. Results ＆ Conclusion： The overall of physiological symptoms are shown as a schematic draft. The basis of ＂heat＂ is considered to be a general increase of microcirculation in the periphery. This leads to a couple of local pathophysiological consequences and sensations like 1） red tongue （the tongue is considered an embryological somatotopic system）. 2） Sensation of warmth （by increase of capillary flow）. 3） pre-inflammatory state, leading to pain modalities like ＂worse if pressed＂, as inflammations tend to be increasingly painful under pressure; 4） reddish skin, the mechanisms by which this is induced may include the release of substance P, therefore accompanied by burning sensation. Systemic pathophysiological consequences may include. Relative lack of fluid in the larger vessels, as fluid supplies peripheral capillary flow. This may lead to water saving mechanisms like thirst, dry mucosa with do, mouth, dry nose, dry lips, dry skin, and also dry stool, yellow and sparse urine.     

Activity patterns of primary auditory-nerve fibres in chickens: development of fundamental properties.

We have examined the activity patterns of single auditory-nerve fibers in the chicken and tested for possible changes during post-hatching development. For this purpose, we recorded from fibres in the cochlear ganglion of chickens of two age groups (about P2 and P21) and investigated their spontaneous and sound-evoked activity patterns under nembutal-chloralhydrate anaesthesia. The spontaneous activity of primary auditory neurones was irregular, the average rates were between 20.5 (P2) and 23 (P21) spikes/s. Many low-frequency fibres from both age groups showed preferred intervals in their spontaneous activity. Tuning characteristics, including the range of characteristic frequencies, the presence of primary and two-tone suppression, the slopes of tuning-curve flanks and Q10dB values were similar to those previously reported for the starling and were statistically indistinguishable between the two age groups. However, there was a difference in fibre thresholds at the highest frequencies. Systematic differences were also present between the two age groups with regard to some characteristics of the rate-intensity functions. These data indicate that whereas the tuning properties of primary auditory fibres of the chicken cochlea are mature as early as post-hatching day 2, the intensity functions are not.     

Infrared pupillometry during uncal herniation

Infrared pupillary scans have been used extensively as an objective measure of pupillary reflexes during pharmacological studies of human subjects, but no previous scans have documented the pupillary changes during transtentorial uncal herniation. We present infrared pupillary scans from three patients with brain stem compression secondary to expanding intracranial mass lesions. The scans were made with a portable device permitting infrared pupillometry at the patient's bedside. Portable infrared pupillometry records objective measurements of pupillary light reflexes, which provides information useful for diagnosing transtentorial herniation and affords objective measurements of an important endpoint in the management of patients with head trauma or supratentorial mass lesions.     

Distinct response of experimental neuroblastoma to combination antiangiogenic strategies

Background: The authors have shown previously that experimental neuroblastoma is partially inhibited (48%) by antivascular endothelial growth factor (anti-VEGF) antibody. The topoisomerase-I inhibitor, topotecan, has been shown to have antiangiogenic activity when administered in a low-dose, high-frequency regimen. We hypothesized that combining topotecan with anti-VEGF would suppress neuroblastoma more effectively than either agent alone. Methods: A total of 10⁶ neuroblastoma cells were implanted intrarenally in athymic mice. Animals received vehicle, topotecan, anti-VEGF, or topotecan plus anti-VEGF (n = 9, 20, 20, 20, respectively). All control and half the treated mice were killed at 6 weeks. Remaining (rebound) mice were maintained without treatment for 3 more weeks. Patterns of vasculature and apoptosis were determined immunohistochemically. Results: Tumor weights at 6 weeks were reduced significantly in topotecan-only (0.07g) and combination-treated animals (0.08 g), compared with controls or anti-VEGF[ndash ]treated mice (1.18 g, 0.53 g; P [lt ] .0007, all). At 9 weeks, rebound tumor weights were greatest in anti-VEGF (2.82 g), intermediate in topotecan (1.82 g), and least in combination-treated animals (1.47 g); however, the only significant difference was between anti-VEGF and combination therapy (P = 0.04). All treated tumors were vascularized sparsely in comparison with controls at 6 weeks, but exhibited brisk neoangiogenesis at 9 weeks. Conclusions: Topotecan either with or without anti-VEGF antibody significantly suppresses neuroblastoma xenograft growth in comparison with controls or anti-VEGF antibody alone. Combining topotecan with anti-VEGF antibody significantly inhibited rebound tumor growth in comparison with anti-VEGF antibody alone. Combination therapy may improve durability of antiangiogenic inhibition of neuroblastoma.