Diffusion modeling of percutaneous absorption kinetics: 3. Variable diffusion and partition coefficients, consequences for stratum corneum depth profiles and desorption kinetics

Stratum corneum (SC) desorption experiments have yielded higher calculated steady-state fluxes than those obtained by epidermal penetration studies. A possible explanation of this result is a variable diffusion or partition coefficient across the SC. We therefore developed the diffusion model for percutaneous penetration and desorption to study the effects of either a variable diffusion coefficient or variable partition coefficient in the SC over the diffusion path length. Steady-state flux, lag time, and mean desorption time were obtained from Laplace domain solutions. Numerical inversion of the Laplace domain solutions was used for simulations of solute concentration-distance and amount penetrated (desorbed)-time profiles. Diffusion and partition coefficients heterogeneity were examined using six different models. The effect of heterogeneity on predicted flux from desorption studies was compared with that obtained in permeation studies. Partition coefficient heterogeneity had a more profound effect on predicted fluxes than diffusion coefficient heterogeneity. Concentration-distance profiles show even larger dependence on heterogeneity, which is consistent with experimental tape-stripping data reported for clobetasol propionate and other solutes. The clobetasol propionate tape-stripping data were most consistent with the partition coefficient decreasing exponentially for half the SC and then becoming a constant for the remaining SC. (C) 2004 Wiley-Liss, Inc.

Sagittal movement of the medial longitudinal arch is unchanged in plantar fasciitis

Background: Although a lowered medial longitudinal arch has been cited as a causal factor in plantar fasciitis, there is little experimental evidence linking arch motion to the pathogenesis of the condition. This study investigated the sagittal movement of the arch in subjects with and without plantar fasciitis during gait. Methods: Digital fluoroscopy was used to acquire dynamic lateral radiographs from 10 subjects with unilateral plantar fasciitis and 10 matched control subjects. The arch angle and the first metatarsophalangeal joint angle were digitized and their respective maxima recorded. Sagittal movement of the arch was defined as the angular change between heel strike and the maximum arch angle observed during the stance phase of gait. The-thickness of the proximal plantar fascia was determined from sagittal sonograms of both feet. ANOVA models were used to identify differences between limbs with respect to each dependent variable. Relationships between arch movement and fascial thickness were investigated using correlations. Results: There was no significant difference in either the movement or maximum arch angle between limbs. However, subjects with plantar fasciitis were found to have a larger metatarsophalangeal joint angle than controls (P < 0.05). Whereas the symptomatic and asymptomatic plantar fascia were thicker than those of control feet (P < 0.05), significant correlations were noted between fascial thickness and peak arch and metatarsophalangeal joint angles (P < 0.05) in the symptomatic limb only. Conclusions: Neither abnormal shape nor movement of the arch are associated with chronic plantar fasciitis. However, arch mechanics may influence the severity of plantar fasciitis once the condition is present. Digital flexion, in contrast, has a protective role in what might be a bilateral disease process.

Quadriceps activity and movement reactions in response to unpredictable sagittal support-surface translations in women with patellofemoral pain

Patellofemoral pain (PFP) may be related to unfavorable knee joint loading. Delayed and/or reduced activity of vastus medialis obliquus (VMO) and different movement patterns have been identified in individuals with PFP in some studies, whereas other studies have failed to show a difference compared to non-affected controls. The discrepancy between study results may depend on the different tasks that have been investigated. No previous study has investigated these variables in postural responses to unpredictable perturbations in PFP. Whole body three dimensional kinematics and surface EMG of quadriceps muscles activation was studied in postural responses to unpredictable support surface translations in 17 women with PFP who were pain free at the time of testing, and 17 matched healthy controls. The results of the present study showed earlier onset of VMO activity and associated changes in kinematics to anterior platform translation in the PFP subjects. We suggest that the relative timing between the portions quadriceps muscles may be task specific and part of an adapted response in attempt to reduce knee joint loading. This learned response appears to remain even when the pain is no longer present.

A new crocodilian from the Lower Cretaceous Crato Formation of north-eastern Brazil

A new mesosuchian crocoddian from the Nova Olinda Member of the Crato Formation (Lower Cretaceous, Aptian) of north-eastern Brazil is described. Susisuchus anatoceps gen. et sp. nov. is the first crocodillan to be reported from this formation. It is represented by an incomplete, partially articulated skeleton: the skull and mandible, partial postcranial axial skeleton, forelimbs and portions of the osteodermal skeleton. Preservation of soft tissues includes the skin surrounding both forelimbs and the digits of the right hand. The state of preservation of the specimen suggests that it was incorporated into the basin as a desiccated carcass. Susisuchus anatoceps is one of the oldest crocodilians with a eusuchian-type dorsal shield, comprising a tetraserial paravertebral shield and, either side of this, two sagittal rows of accessory osteoderms. It also possesses amphicoelous thoracic, lumbar and caudal vertebrae. This combination of postcranial features have never before been seen in a crocodilian and warrant the erection of a new family within Mesosuchia: Susisuchidae. Taxonomically, S. anatoceps is similar to a number of Lower Cretaceous mesosuchians previously considered to have given rise to eusuchians, most notably the Glen Rose crocodilian and a new, but as yet undescribed crocodillan from the Lower Cretaceous Winton Formation of western Queensland, Australia. Preliminary preparation of the Winton crocodilian indicates that it may belong to Susisuchidae, supporting the hypotheses of interchange between the vertebrate faunas of South America and Australia during the Lower Cretaceous.

Redescription of the gnathostome fish fauna from the mid-Palaeozoic Silverband Formation, the Grampians, Victoria

Gnathostome vertebrate remains from fine-grained sandstones of the Silverband Formation in the Grampians, Victoria include dissociated fin spines, scales and teeth. These elements arc assigned herein to the acanthodians Sinacanthus? micracanthus (fin spines) and Radioporacanthodes sp. cf. R. qujingensis (scales and tooth whorls). This fauna indicates a Late Silurian (?late Ludlow) age for the vertebrate-beating Stratum. Under current systematic groupings, the two gnathostome taxa from the Silverband Formation belong to two different families, the Sinacanthidae and the Poracanthodidae. However. the preserved association could indicate that the three element types derived from the same biological species. The possibility that the Sinacanthidae is a sister group to the Climatiidae and the Poracanthodidae is raised by this scenario. The Sinacanthidae is tentatively reassigned to the Acanthodii, as it is considered to lack diagnostic chondrichthyan characters.

Factors affecting the formation of a skin reservoir for topically applied solutes

The reservoir function of the skin is an important determinant of the duration of action of a topical solute. The reservoir can exist in the stratum corneum, in the viable avascular tissue (viable epidermis and supracapillary dermis) and in the dermis. A steroid reservoir in the stratum corneum has been demonstrated by the reactivation of a vasoconstrictor effect by occlusion or application of a placebo cream to the skin some time after the original topical application of steroid. Other solutes have also been reported to show a reservoir effect in the skin after topical application. A simple compartmental model is used to understand why reactivation of vasoconstriction some time after a topical steroid application shows dependency on time, topical solute concentration and the product used to cause reactivation. The model is also used to show which solutes are likely to show a reservoir effect and could be potentially affected by desquamation, especially when the turnover of the skin is abnormally rapid. A similar form of the model can be used to understand the promotion of reservoir function in the viable tissue and in the dermis in terms of effective removal by blood perfusing the tissues. Copyright (C) 2004 S. Karger AG, Basel.

Molecular size as the main determinant of solute maximum flux across the skin

One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J(max), mol per cm(2) per h) from a given vehicle. In this work, J(max) values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k(p)) are optimally correlated to solute octanol-water partition coefficient (K-ow) and molecular weight (MW) was found to be the dominant determinant of J(max) for this literature data set: log J(max)=-3.90-0.0190MW (n=87, r(2)=0.847, p

Intra-abdominal pressure response to multidirectional support-surface translation

A complex response of the trunk muscles occurs to restore equilibrium in response to movement of the support surface. Intra-abdominal pressure (IAP) is considered to contribute to control of the trunk. This study investigated the contribution of IAP to the postural response to multidirection support-surface translation. IAP was recorded with a thin-film pressure transducer inserted via the nose into the stomach and trunk motion was recorded with an optoelectronic system with markers over the spinous process of L1. A pattern of trunk movement was recorded in response to the support-surface translations that was consistent with a 'hip' strategy of postural control. The trunk moved in a manner appropriate to move the centre of gravity over the new base of support. IAP was increased with movement in each direction, but varied in timing and amplitude between translation directions. In general, the IAP was greater with translations in the sagittal plane compared to the frontal plane and was initiated earlier for translations in the backward direction. These data indicate that IAP contributes to the postural response associated with support-surface translation and suggest that this is consistent with stiffening the spine. (C) 2003 Elsevier B.V. All rights reserved.

Transdermal delivery of a tetrapeptide: Evaluation of passive diffusion

Skin penetration of the tetrapeptide Ac-Ala-Ala-Pro-Val-NH2 was assessed. This peptide sequence fits the P-P-1 subsites of elastase and inhibits human neutrophil elastase competitively. Consequently this peptide may be therapeutically useful in a variety of inflammatory disorders, including psoriasis. in which elevated levels of human neutrophil elastase have been reported. Peptide penetration was assessed across whole human skin, whole skin with the stratum corneum removed by tape stripping and epidermis, which had been removed from the dermis by heat separation. The influence of 75% aqueous ethanol as a potential penetration enhancer of the tetrapeptide across epidermis was also assessed. The tetrapeptide did not penetrate whole human skin or epidermis, even under the influence of 75% aqueous ethanol. However, when the stratum corneum was removed tetrapeptide flux of 73.39 mug cm(-2) h(-1) was achieved. The study demonstrates that the stratum corneum is the main barrier to tetrapeptide skin penetration and must be overcome if therapeutically relevant amounts of tetrapeptide are to be delivered to the skin.

Type 1 nitrergic (ND1) cells of the rabbit retina: Comparison with other axon-bearing amacrine cells

NADPH diaphorase (NADPHd) histochemistry labels two types of nitrergic amacrine cells in the rabbit retina. Both the large ND1 cells and the small ND2 cells stratify in the middle of the inner plexiform layer, and their overlapping processes produce a dense plexus, which makes it difficult to trace the morphology of single cells. The complete morphology of the ND1 amacrine cells has been revealed by injecting Neurobiotin into large round somata in the inner nuclear layer, which resulted in the labelling of amacrine cells whose proximal morphology and stratification matched those of the ND1 cells stained by NADPHd histochemistry. The Neurobiotin-injected ND1 cells showed strong homologous tracer coupling to surrounding ND1 cells, and double-labelling experiments confirmed that these coupled cells showed NADPHd reactivity. The ND1 amacrine cells branch in stratum 3 of the inner plexiform layer, where they produce a sparsely branched dendritic tree of 400-600 mum diameter in ventral peripheral retina. In addition, each cell gives rise to several fine beaded processes, which arise either from a side branch of the dendritic tree or from the tapering of a distal dendrite. These axon-like processes branch successively within the vicinity of the dendritic field before extending, with little or no further branching, for 3-5 mm from the soma in ventral peripheral retina. Consequently, these cells may span one-third of the visual field of each eye, and their spatial extent appears to be greater than that of most other types of axon-bearing amacrine cells injected with Neurobiotin in this study. The morphology and tracer-coupling pattern of the ND1 cells are compared with those of confirmed type 1 catecholaminergic cells, a presumptive type 2 catecholaminergic cell, the type 1 polyaxonal. cells, the long-range amacrine cells, a novel type of axon-bearing cell that also branches in stratum 3, and a type of displaced amacrine cell that may correspond to the type 2 polyaxonal cell. (C) 2004 Wiley-Liss, Inc.

Influence of socioeconomic deprivation on the primary care burden and treatment of patients with a diagnosis of heart failure in general practice in Scotland: population based study

Objectives To examine whether there are socioeconomic gradients in die incidence, prevalence, treatment, and follow up of patients with heart failure in primary care. Design Population based study. Setting 53 general practices (307741 patients) participating in the Scottish continuous morbidity recording project between 1 April 1999 and 31 March 2000. Participants 2186 adults with heart failure. Main outcome measures Comorbid diagnoses, frequency of visits to general practitioner, and prescribed drugs. Results 2186 patients with heart failure were seen (prevalence 7.1 per 1000 population, incidence 2.0 per 1000 population). The age and sex standardised incidence of heart failure increased with greater socioeconomic deprivation, from 1.8 per 1000 population in the most affluent stratum to 2.6 per 1000 population in the most deprived stratum (odds ratio 1.44, P=0.0003). On average, patients were seen 2.4 times yearly, but follow up rates were less frequent with increasing socioeconomic deprivation (from 2.6 yearly in the most affluent subgroup to 2.0 yearly in the most deprived subgroup, P=0.00009). Overall, 812 (80.6%) patients were prescribed diuretics, 396 (39.3%) angiotensin converting enzyme inhibitors, 216 (21.4%) beta blockers, 208 (20.7%) digoxin, and 86 (8.5%) spironolactone. The wide discrepancies in prescribing between different general practices disappeared after adjustment for patient age and sex. Prescribing patterns did not vary by deprivation categories on univariate or multivariate analyses. Conclusions Compared with affluent patients, socioeconomically deprived patients were 44% more likely to develop heart failure but 23% less likely to see their general practitioner on an ongoing basis. Prescribed treatment did not differ across socioeconomic gradients.

The jigsaw sign. A reliable indicator of congenital aetiology in os odontoideum

There is evidence in the literature for both a congenital and a post-traumatic aetiology for os odontoideum. In no series published to date has CT been used to aid in the diagnosis. This is a prospective study of the history of trauma and presence of diagnostic features on CT of 18 consecutive cases with os odontoideum. Our objective was to derive clinically useful radiological features enabling accurate differentiation between congenital and post-traumatic aetiologies. A mid-sagittal CT reconstruction of the atlanto-dens joint was obtained. Hypertrophy of the anterior arch of the atlas was quantified by measurement of the arch-peg-area ratio. The presence of dysplastic features (a positive jigsaw sign) of the atlanto-axial joint were noted. These included narrowing of the cartilage space and interdigitation of the two joint surfaces. A history of a potential traumatic aetiology was only obtained in one of the 18 (6%) in our series. A significant elevation of the arch-peg ratio was found when comparing this series to 85 controls. And a positive jigsaw sign was observed in 75% of cases. These features were not seen in paediatric cases of atlanto-axial instability, including odontoid non-union. In conclusion, an elevated arch-peg ratio and the presence of a jigsaw sign are sensitive and specific diagnostic criteria for os odontoideum. This series supports a congenital aetiology for this condition.