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Objectives Bisphenol A (BPA) is the most used colour developer in thermal paper for cashiers receipts, labels, and tickets. BPA can migrate onto the skin and be absorbed when handling these papers. BPA is a known endocrine disruptor and is therefore being replaced in thermal paper by some alternatives such as Bisphenol S (BPS), D-8, and Pergafast 201® (PF201). To our knowledge, no studies have characterized skin permeation of these BPA alternatives. Methods We measured/characterized skin absorption for BPA, BPS, D-8, and PF201 through ex vivo human skin using flow-through diffusion cells according to OECD guideline 428. Skin samples were 7–12 per test substance from three different skin donors. Skin metabolism was studied for BPA. Dermal absorption was expressed as the amount of the BPA alternatives in the receptor fluid over applied dose in percent (%). Results The absorbed dose after 24 h of exposure was 25% for BPA, 17% for D-8, 0.4% for BPS, and Conclusions Skin absorption was in decreasing order: BPA > D-8 >> BPS > PF201. These results are in agreement with their log Kow and molecular weights. We provided here the necessary data to estimate the extent of skin absorption of BPA analogues, which is a necessary step in risk assessment, and ultimately evaluate public health risks posed by D-8, BPS, and PF201.

SIGNIFICANCE Active implants require batteries as power supply. Their lifetime is limited and may require a second surgical intervention for replacement. Intracorporal energy harvesting techniques generate power within the body and supply the implant. Solar cells below the skin can be used to harvest energy from light. AIM To investigate the potential of subdermal solar energy harvesting. APPROACH We evaluated global radiation data for defined time slots and calculated the output power of a subdermal solar module based on skin and solar cell characteristics. We assumed solar exposure profiles based on daily habits for an implanted solar cell. The output power was calculated for skin types VI and I/II. RESULTS We show that the yearly mean power in most locations on Earth is sufficient to power modern cardiac pacemakers if 10 min midday solar irradiation is assumed. All skin types are suitable for solar harvesting. Moreover, we provide a software tool to predict patient-specific output power. CONCLUSIONS Subdermal solar energy harvesting is a viable alternative to primary batteries. The comparison to a human case study showed a good agreement of the results. The developed code is available open source to enable researchers to investigate further applications of subdermal solar harvesting.

Biomarkers in sweat are a largely untapped source of health information. Most of the currently available sweat harvesting and testing devices are incapable of operating under low-sweat rates such as those experienced by humans at rest. Here we analyze the in vitro and in vivo sampling of sweat through osmosis via the use of a hydrogel interfaced with the skin, without need for active perspiration. The hydrogel also interfaces with paper-based microfluidics to transport the fluid via capillary forces toward a testing zone and then evaporation pad. We show that the hydrogel solute content and area of the evaporation pad regulate the long-term extraction of sweat and its associated biomarkers. The results indicate that the platform can sample biomarkers from a model skin system continuously for approximately 12 h. On-skin testing of the platform on both resting and exercising human subjects confirms that it can sample sweat lactate directly from the surface of skin. The results highlight that lactate in sweat increases with exercise and as a direct result of muscle activity. Implementation of such new principles for sweat fluid harvesting and management via wearable patch devices can contribute toward the advancement of next generation wearables.

Significance: Spatial frequency domain imaging (SFDI), a noncontact wide-field imaging technique using patterned illumination with multiple wavelengths, has been used to quantitatively measure structural and functional parameters of in vivo tissue. Using SFDI in a porcine model, we previously found that scattering changes in skin could potentially be used to noninvasively assess burn severity and monitor wound healing. Translating these findings to human subjects necessitates a better understanding of the variation in “baseline” human skin scattering properties across skin types and anatomical locations. Aim: Using SFDI, we aim to characterize the variation in the reduced scattering coefficient (μs′) for skin across a range of pigmentation and anatomic sites (including common burn locations) for normal human subjects. These measurements are expected to characterize baseline human skin properties to inform our use of SFDI for clinical burn severity and wound healing assessments. Approach: SFDI was used to measure μs′ in the visible- and near-infrared regime (471 to 851 nm) in 15 subjects at 10 anatomical locations. Subjects varied in age, gender, and Fitzpatrick skin type. Results: For all anatomical locations, the coefficient of variation in measured μs′ decreased with increasing wavelength. High intersubject variation in μs′ at visible wavelengths coincided with large values of the melanin extinction coefficient at those wavelengths. At 851 nm, where intersubject variation in μs′ was smallest for all anatomical locations and absorption from melanin is minimal, significant intrasubject differences in μs′ were observed at the different anatomical locations. Conclusions: Our study is the first report of wide-field mapping of human skin scattering properties across multiple skin types and anatomical locations using SFDI. Measured μs′ values varied notably between skin types at wavelengths where absorption from melanin was prominent. Additionally, μs′ varied considerably across different anatomical locations at 851 nm, where the confounding effects from melanin absorption are minimized.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, erlotinib, and afatinib, are widely used in clinical practice and remarkably effective in treatment of advanced non-small cell lung cancer. However, there are some adverse effects while taking EGFR-TKIs, among which skin adverse reactions (SAR) are the most common events. At present, the poor outcome of SAR and insufficient research on SAR models need to be addressed. In this study we focused on the SAR models to lay a foundation for mechanism researches. Gefitinib, one of the EGFR-TKIs, was used as SAR inducing agents. We chose C57BL/6 and FVB/N mice as experimental model and they were divided into four groups. The weight and skin moisture of mice were detected every 7 days, itching behavior and abnormal eyelids were tested at 35th day after gavage, and survival rate was also recorded. The weight of unit area hair, length of whiskers and inflammatory cells were evaluated after mice sacrificed. C57BL/6 animals treated with gefitinib showed significant differences in survival rate, weight of unit area hair, skin moisture changes, skin dryness, itching behavior, whisker irregular growth, abnormal eyelids, and inflammatory cells; FVB/N animals treated with gefitinib only showed significant differences in survival rate, whisker irregular growth and abnormal eyelids, compared with the control group, respectively. In this study, we compared the similarities and differences of gefitinib-induced SAR between C57BL/6 and FVB/N mice, which illustrated different patients probably showing different symptoms clinically and provided experimental basis for researching mechanism of EGFR-TKIs induced SAR.

Significance: Recent generation of bioengineered human skin allowed the efficient treatment of patients with severe skin defects. However, the optical and biomechanical properties of these models are not known. Aim: Three models of bioengineered human skin based on fibrin-agarose biomaterials (acellular, dermal skin substitutes, and complete dermoepidermal skin substitutes) were generated and analyzed. Approach: Optical and biomechanical properties of these artificial human skin substitutes were investigated using the inverse adding-doubling method and tensile tests, respectively. Results: The analysis of the optical properties revealed that the model that most resembled the optical behavior of the native human skin in terms of absorption and scattering properties was the dermoepidermal human skin substitutes after 7 to 14 days in culture. The time-course evaluation of the biomechanical parameters showed that the dermoepidermal substitutes displayed significant higher values than acellular and dermal skin substitutes for all parameters analyzed and did not differ from the control skin for traction deformation, stress, and strain at fracture break. Conclusions: We demonstrate the crucial role of the cells from a physical point of view, confirming that a bioengineered dermoepidermal human skin substitute based on fibrin-agarose biomaterials is able to fulfill the minimal requirements for skin transplants for future clinical use at early stages of in vitro development., Ministry of Science, Innovation and Universities of Spain PGC2018-101904-A-I0, Instituto de Salud Carlos III (ISCIII), Ministry of Science, Innovation and Universities, through AES 2017 AC17/00013, Instituto de Salud Carlos III (ISCIII), Ministry of Science, Innovation and Universities within EuroNanoMed framework, EU AC17/00013, University of Granada A.TEP.280.UGR18, Junta de Andalucía PE-0395-2019, Fundación Benéfica Anticancer San Francisco Javier y Santa Cándida, Granada, Spain, OTRI.35A-07

When analyzing multidiameter single-fiber reflectance (MDSFR) spectra, the inhomogeneous distribution of melanin pigments in skin tissue is usually not accounted for. Especially in heavily pigmented skins, this can result in bad fits and biased estimation of tissue optical properties. A model is introduced to account for the inhomogeneous distribution of melanin pigments in skin tissue. In vivo visible MDSFR measurements were performed on heavily pigmented skin of type IV to VI. Skin tissue optical properties and related physiological properties were extracted from the measured spectra using the introduced model. The absorption of melanin pigments described by the introduced model demonstrates a good correlation with the co-localized measurement of the well-known melanin index. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License.

Melanin is known to provide strong third-harmonic generation (THG) contrast in human skin. With a high concentration in basal cell cytoplasm, THG contrast provided by melanin overshadows other THG sources in human skin studies. For better understanding of the THG signals in keratinocytes without the influence of melanin, an in vivo THG microscopy (THGM) study was first conducted on vitiliginous skin. As a result, the THG-brightness ratio between the melanin-lacking cytoplasm of basal cells and collagen fibers is about 1.106 at the dermal–epidermal junctions of vitiliginous skin, indicating high sensitivity of THGM for the presence of melanin. We further applied the in vivo THGM to assist evaluating the therapeutic outcome from the histopathological point of view for those showed no improvement under narrowband ultraviolet B therapy based on the seven-point Physician Global Assessment score. Our clinical study indicates the high potential of THGM to assist the histopathological assessment of the therapeutic efficacy of vitiligo treatments.

pTwo-photon microscopes have been successfully translated into clinical imaging tools to obtain high-resolution optical biopsies foritalicin vivo/italichistology. We report on clinical multiphoton coherent anti-Stokes Raman spectroscopy (CARS) tomography based on two tunable ultrashort near-infrared laser beams for label-freeitalicin vivo/italicmultimodal skin imaging. The multiphoton biopsies were obtained with the compact tomograph "MPTflex-CARS" using a photonic crystal fiber, an optomechanical articulated arm, and a four-detector-360 deg measurement head. The multiphoton tomograph has been employed to patients in a hospital with diseased skin. The clinical study involved 16 subjects, 8 patients with atopic dermatitis, 4 patients with psoriasis vulgaris, and 4 volunteers served as control. Two-photon cellular autofluorescence lifetime, second harmonic generation (SHG) of collagen, and CARS of intratissue lipids/proteins have been detected with single-photon sensitivity, submicron spatial resolution, and picosecond temporal resolution. The most important signal was the autofluorescence from nicotinamide adenine dinucleotide [NAD(P)H]. The SHG signal from collagen was mainly used to detect the epidermal-dermal junction and to calculate the ratio elastin/collagen. The CARS/Raman signal provided add-on information. Based on this view on the disease-affected skin on a subcellular level, skin areas affected by dermatitis and by psoriasis could be clearly identified. Multimodal multiphoton tomographs may become important label-free clinical high-resolution imaging tools foritalicin vivo/italicskin histology to realize rapid early diagnosis as well as treatment control./p.

Inexpensive near-infrared microscopy (NIRM) was developed as a convenient technique to detect the medulla loss of scalp hair while reducing analytical time with easy sample preparation, leading to a field screening tool for breast cancer. NIRM has been evaluated as an alternative to synchrotron-based nanoscopy and to the relatively expensive method of conventional infrared microscopy to determine the degree and pattern of medulla loss of scalp hairs of patients with breast cancer and benign diseases, as well as normal healthy individuals. NIR imaging showed a strong, scattering-based hyperintense contrast of the medulla compared to the fully attenuated cortex in medullated healthy hair. Complete medulla loss (CML) per hair strand was more extensively (60.9 ± 10.2 %) (p

There is a need for noninvasive, quantitative methods to characterize wound healing in the context of longitudinal investigations related to regenerative medicine. Such tools have the potential to inform the assessment of wound status and healing progression and aid the development of new treatments. We employed spatial frequency domain imaging (SFDI) to characterize the changes in optical properties of tissue during wound healing progression in a porcine model of split-thickness skin grafts and also in a model of burn wound healing with no graft intervention. Changes in the reduced scattering coefficient measured using SFDI correlated with structural changes reported by histology of biopsies taken concurrently. SFDI was able to measure spatial inhomogeneity in the wounds and predicted heterogeneous healing. In addition, we were able to visualize differences in healing rate, depending on whether a wound was debrided and grafted, versus not debrided and left to heal without intervention apart from topical burn wound care. Changes in the concentration of oxy- and deoxyhemoglobin were also quantified, giving insight into hemodynamic changes during healing.

In a pilot study of 11 healthy adults (24 to 39 years, all male), we characterize the influence of external probe pressure on optical diffuse correlation spectroscopy (DCS) measurements of pulsatile blood flow obtained on the forearm and forehead. For external probe pressure control, a hand inflatable air balloon is inserted between the tissue and an elastic strap. The air balloon is sequentially inflated to achieve a wide range of external probe pressures between 20 and 250 mmHg on the forearm and forehead, which are measured with a flexible pressure sensor underneath the probe. At each probe pressure, the pulsatility index (PI) of arteriole blood flow on the forehead and forearm is measured with DCS (2.1-cm source-detector separation). We observe a strong correlation between probe pressure and PI on the forearm (R=0.66, p

Objective. There is renewed interest in epidural and transcutaneous spinal cord stimulation (SCS) as a therapy following spinal cord injury, both to reanimate paralyzed muscles as well as to potentiate weakened volitional control of movements. However, most work to date has focussed on lumbar SCS for restoration of locomotor function. Therefore, we examined upper-limb muscle responses and modulation of supraspinal-evoked movements by different frequencies of cervical SCS delivered to various epidural and transcutaneous sites in anaesthetized, neurologically intact monkeys. Approach. Epidural SCS was delivered via a novel multielectrode cuff placed around both dorsal and ventral surfaces of the cervical spinal cord, while transcutaneous SCS was delivered using a high carrier frequency through surface electrodes. Main results. Ventral epidural SCS elicited robust movements at lower current intensities than dorsal sites, with evoked motor unit potentials that reliably followed even high-frequency trains. By contrast, the muscle responses to dorsal SCS required higher current intensities and were attenuated throughout the train. However, dorsal epidural SCS and, to a lesser extent, transcutaneous SCS were effective at facilitating supraspinal-evoked responses, especially at intermediate stimulation frequencies. The time- and frequency-dependence of dorsal SCS effects could be explained by a simple model in which transynaptic excitation of motoneurons was gated by prior stimuli through presynaptic mechanisms. Significance. Our results suggest that multicontact electrodes allowing access to both dorsal and ventral epidural sites may be beneficial for combined therapeutic purposes, and that the interaction of direct, synaptic and presynaptic effects should be considered when optimising SCS-assisted rehabilitation.

Several noninvasive imaging techniques have been developed to monitor the health of skin and enhance the diagnosis of skin diseases. Among them, skin elastography is a popular technique used to measure the elasticity of the skin. A change in the elasticity of the skin can influence its natural frequencies and mode shapes. We propose a technique to use the resonant frequencies and mode shapes of the skin to monitor its health. Our study demonstrates how the resonant frequencies and mode shapes of skin can be obtained using numerical and experimental analysis. In our study, natural frequencies and mode shapes are obtained via two methods: (1) finite element analysis: an eigensolution is performed on a finite element model of normal skin, including stratum corneum, epidermis, dermis, and subcutaneous layers and (2) digital image correlation (DIC): several in-vivo measurements have been performed using DIC. The experimental results show a correlation between the DIC and FE results suggesting a noninvasive method to obtain vibration properties of the skin. This method can be further examined to be eventually used as a method to differentiate healthy skin from diseased skin. Prevention, early diagnosis, and treatment are critical in helping to reduce the incidence, morbidity, and mortality associated with skin cancer; thus, making the current study significant and important in the field of skin biomechanics.

The severity and cost of wound infections strongly demands for simple and fast methods for wound infection determination. Point-of-care testing devices play a crucial role in order to achieve a fast diagnosis and early treatment. Myeloperoxidase (MPO) enzyme, detected in fluids of infected wounds has been postulated as a suitable biomarker for wound diagnostics. Here we present a new system for MPO detection, based on enzyme-catalysed oxidative synthesis of a dye that can be incorporated into paper-based point of care devices. Visual MPO detection has been achieved through the use of phenylenediamine, a common colourless hair dye precursor. MPO oxidation of these compounds yielded bright coloured products distinguishable from the colour of the wound environment. Immobilisation of the MPO substrates on paper strips was achieved through in situ interaction of the oxidised coloured product with branched polyethyleneimine. The colour reaction of the immobilized substrates, detectable by naked eye, responds to the MPO levels present in infected wound fluids revealing an easy system for incorporation of MPO detection in paper based diagnostic devices.

Next-generation sequencing has produced a large quantity of DNA or RNA sequences related to the processes occurring within tumors and their microenvironment in a reasonable time and cost. These data have been used to guide the identification of neoantigens and to determine their specific T-cell receptors. Furthermore, adoptive T-cell therapy targeting neoantigens is under development for cancer treatment. In this review, we first provide an overview of sequencing technologies and the updated findings concerning neoantigens related to adoptive T-cell therapy and then summarize the methods and principles underlying the development of next-generation sequencing-based neoantigen-reactive T-cell therapy for cancer.

A water-soluble glucopyranosyl conjugate, L, has been synthesized and characterized by different analytical and spectral techniques. The L has been demonstrated to have switch-on fluorescence enhancement of ∼75 fold in the presence of La(3+) among the nine lanthanide ions studied in the HEPES buffer at pH 7.4. A minimum detection limit of 140 nM (16 ± 2 ppb) was shown by L for La(3+) in the buffer at physiological pH. The utility of L has been demonstrated by showing its sensitivity toward La(3+) on Whatman filter paper strips. The reversible and reusable action of L has been demonstrated by monitoring the fluorescence changes as a function of the addition of La(3+) followed by F(-) and HPO4(2-) ions. The complexation of L by La(3+) was shown by absorption spectra wherein isosbestic behavior was observed. The Job's plot suggests a 2:1 complex between L and La(3+), and the same was supported by ESI-MS. The control molecular study revealed the necessity of hydroxy quinoline and the amine group for La(3+) ion binding and the glyco-moiety to bring water solubility and biocompatibility. The structural features of the [2L+La(3+)] complex were established by DFT computational calculations. The chemo-ensemble, [2L+La(3+)], is shown responsible for providing intracellular fluorescence imaging in HepG2 cells.

Normal skin can resist mechanical insults to a certain degree. If not counteracted by protective measures, excessive friction or superficial skin injuries may develop into cutaneous disease. Post-traumatic eczema can persist or recur for long periods of time, while preexisting dermatoses can be aggravated by mechanical trauma. If a dynamic relationship between trauma and development of eczema is made probable, it has important medical implications when job related. Only a minor fraction of individuals exposed to repetitive mechanical stimuli such as friction develop physical irritant contact dermatitis, indicating a probable role of genetic predisposition in addition to environmental factors such as temperature and sweat production. Hyperkeratoses, calluses, and lichenification are common clinical manifestations of a frictional eczema which most often involves the hands. Frictional hand dermatitis can be caused by working in various occupations, from office workers to craftsmen such as carpet installers and shoe makers. Time from onset of exposure to development of frictional dermatitis can vary from weeks to years. Post-traumatic eczema following mechanical injury usually occurs within weeks. It may occur in association with an underlying endogenous dermatosis (isomorphic reaction of Koebner’s phenomenon) or occur as an isolated idiopathic reaction. The clinical features of posttraumatic eczema are indistinguishable from other types of hand eczema.

Bisphenol A (BPA) is an endocrine disrupting chemical used in a wide range of consumer products including photoactive dyes used in thermal paper. Recent studies have shown that dermal absorption of BPA can occur when handling these papers. Yet, regulatory agencies have largely dismissed thermal paper as a major source of BPA exposure. Exposure estimates provided by agencies such as the European Food Safety Authority (EFSA) are based on assumptions about how humans interact with this material, stating that ‘typical’ exposures for adults involve only one handling per day for short periods of time (30% of individuals hold thermal paper with more than three fingertips, and >60% allow the paper to touch their palm. Only 11% of the participants we observed were consistent with the EFSA model for time of contact and dermal surface area. Mathematical modeling based on handling times we measured and previously published transfer coefficients, concentrations of BPA in paper, and absorption factors indicate the most conservative estimated intake from handling thermal paper in this population is 51.1 ng/kg/day, similar to EFSA’s estimates of 59 ng/kg/day from dermal exposures. Less conservative estimates, using published data on concentrations in thermal paper and transfer rates to skin, indicate that exposures are likely significantly higher. Based on our observational data, we propose that the current models for estimating dermal BPA exposures are not consistent with normal human behavior and should be reevaluated.

Background The ideal gentle cleansing product is one that effectively removes soils while minimizing damage to the skin. Thus, measuring physical abrasion caused by cleansing tissues is critical to the continued development of gentle cleansing products. Current analysis of cleansing materials for skin gentleness is time consuming and requires expensive human subject testing. This report describes the development of a rapid and inexpensive bench assay for the assessment of skin abrasion caused by wiping. Methods Coefficient of friction (COF) evaluations using bench methods were compared with results from clinical studies of repeated wiping and with confocal visualizations of excised skin. A Monitor/Slip and Friction™ instrument (model 32-06; TMI, Amityville, NY, USA) was used to measure tissue friction on simulated skin (Vitro-Skin®, N19-5X; IMS, Milford, CT, USA). Clinical data from a 4-day repetitive forearm wiping study measuring transepidermal water loss (TEWL) in 30 subjects was compared with results from the bench top assay. In addition, excised skin samples were also treated using the COF bench assay and examined using confocal microscopy to visualize stratum corneum damage caused by wiping. Results Using the bench COF assay, we were able to distinguish between bath tissue codes by comparing average static friction value (ASFV) for the test codes, where lower ASFV indicated less abrasive tissue. The ASFV followed the same gentleness trend observed in the clinical study. Confocal microscopy of excised skin wiped with the same materials indicated stratum corneum damage consistent with the bench COF and clinical TEWL observations. Conclusion We observed significant correlation between bench and clinical methods for measuring skin damage caused by wiping of skin with tissue. The bench method will facilitate rapid and inexpensive skin gentleness assessment of cleansing materials.

Hand washing is a primary means of infection control. The Centers for Disease Control and Prevention (CDC), the Association for Professionals in Infection Control and Epidemiology, and the World Health Organization all cite handwashing with soap and water as important in preventing the spread of infectious diseases.1-3 The CDC states that “keeping hands clean is one of the most important steps we can take to avoid getting sick and spreading germs to others.”3 Numerous studies have demonstrated that handwashing in the school setting reduces infectious diseases, particularly respiratory and gastrointestinal infections.4-7 Handwashing reduces absenteeism among students and staff.4,7 However, many barriers to handwashing in the school environment have been described that can reduce compliance with handwashing. These barriers include insufficient time for students to wash, lack of education and promotion around hand hygiene, and insufficient handwashing facilities.4,8 Maintaining adequate handwashing supplies in student bathrooms is made difficult by lack of money, limited staff time, student vandalism, and misguided efforts by school staff to prevent messes in bathrooms. One large school district in New Mexico began environmental inspections in the fall of 2006 to address issues of hygiene and safety and to make improvements when indicated in their schools. They reported initial inspection findings from 91 schools in September 2006. Within those schools inspected, 25% of student bathrooms lacked soap and 38% lacked paper towels or hand dryers.9 A pilot study was conducted to measure the availability of handwashing supplies for students in public schools in New Mexico. The study further aimed to determine whether scheduled school nurse inspections of handwashing supplies in school bathrooms, with reporting of findings to appropriate school officials, would result in improved availability of handwashing supplies for students.

Background/purpose: Cold and allergy sufferers often develop irritation around the nostrils as a result of repeated and frequent rubbing of the skin site with facial tissues. This irritation is a combination of the inherent irritant properties of the tissue components (chemical irritation), and mechanical irritation from friction. Lotion-coated facial tissues are being developed to provide soothing, skin benefits, and to promote healing of this type of irritation. The objective of these studies was to evaluate the efficacy of different lotion formulations on facial tissues in preventing irritation, or aiding in the healing of irritation. Methods: The modified forearm-controlled application test (Modified FCAT) was adapted as a means of quickly evaluating the relative skin benefits of various lotion formulations used to coat facial tissues. The test was conducted on the volar surface of the forearms of volunteer subjects. Test sites were pretreated with 24 h occlusive patches of sodium lauryl sulfate (SLS) to induce mild or moderate skin irritation. This was followed by repeated wiping of the lotion-coated tissues. Irritation was evaluated using visual scoring for erythema and dryness. Lotion formulation options were compared in the model. Comparisons included assessments of the type of fatty alcohol in the formulation (stearyl and cetearyl alcohol), the presence of silicone and the base formulation (mineral oil, petrolatum of a proprietary formula). Results: Differences in the degree of erythema and dryness were detected among various formulation options. No differences were found between formulations containing stearyl or cetearyl alcohol. Low levels of silicone produced benefits in one of two experiments. The proprietary base formula produced greater reductions in erythema following treatment of SLS-irritated skin compared with mineral oil and petrolatum bases. Conclusions: The results indicated that this modification of the FCAT can be used to compare various lotion formulations for skin benefits and healing properties, and to rank qualitatively the benefits of various formulation options.

Background Lack of a second sample often precludes the ability to perform repeat lead measurements on filter paper bloodspot samples. We investigated whether annular specimens remaining from once-punched filter paper bloodspot specimens could provide accurate Pb measurements when measurements were scaled for the remainder area relative to the original punch area. Methods 50 μl bloodspot specimens were prepared using Pb-spiked EDTA whole blood. After removal of 6 mm punches, bitmap images of the remainder specimens were obtained using a scanner. Image analysis was used to determine the bloodspot area of the remainder sample relative to the area of the original punch. Measurement of Pb for punches and for remainder specimens was performed by ICP-MS. Results Area-corrected Pb measurements for remainder samples were significantly higher than for the punches, by an average factor of 1.52 ± 0.12 ( p n = 28). The difference was due to a discontinuity (an increase) in the per-area Pb at the bloodspot perimeter. Area-corrected results for annular specimens that excluded the perimeter were identical to those of the punch. Conclusion Area-corrected Pb measurement using annular once-punched bloodspot remainder specimens can accurately reproduce lead measurements obtained from the original punch when the bloodspot perimeter area is excluded.

A short, practical, and validated quality of life (QoL) scale for hemifacial spasm (HFS) is not currently available.To examine the reliability and validity of a short self-rating scale (HFS-7) by comparing HFS patients with healthy controls. We also evaluated the correlation of HFS-7 with the physical and mental domains of SF-36, a generic QoL scale.Seven self-rating items (HFS-7) were administered to HFS patients and healthy controls. In addition, HFS patients answered the SF-36 questionnaire. The validity and reliability of HFS-7 were analysed and correlation between HFS-7 and SF-36 examined.A total of 178 subjects were enrolled in the study, including 85 HFS patients with mean age of 54.8 (SD 11.0) years, of whom 52 (61.2%) were women, and 93 controls with mean age of 51.4 (SD 10.0) years, of whom 59 (63.4%) were women. The test-retest intraclass correlation coefficient for the seven items was between 0.75 and 0.90 and Cronbach's coefficient of reliability for the HFS-7 scale was 0.88. Every item in HFS-7 discriminated between disease and controls (p0.0001). The HFS-7 summary index correlated with the SF-36 summary score (Spearman's correlation r = -0.28, p = 0.009), in particular the mental health summary score (r = -0.416, p0.0001) and the emotional domain (r = -0.466, p0.00001).HFS-7 could prove useful as a simple clinical tool to assess and monitor QoL measures in HFS patients.

Objective: To report our experience with repeat microvascular decompression (MVD) for hemifacial spasm (HFS) in patients who have failed their first operation. Methods: The authors describe 41 redo MVDs for HFS in 36 patients performed over a 3 year period. Seven patients underwent early re-operation after an aborted seventh nerve decompression. Eight patients underwent early re-operation for clinical failure. Eighteen patients underwent late re-operation for spasm recurrence long after their original MVD. Eight MVDs were performed on patients who had already undergone at least two prior operations. Results: Twenty four patients experienced complete spasm resolution (70.6%), eight patients had near total resolution (23.5%), and two patients failed re-operation (5.9%). Two patients were lost to follow up (5.6%). A favourable outcome was reported by 82.4% of patients at a mean follow up interval of 18 months. A total of 91.7% of patients 50 years of age or younger were cured at follow up versus 59.1% of patients older than 50 (p = 0.04). Patients undergoing early re-operation were significantly more likely to be cured or improved than patients undergoing late re-operation (p = 0.03). Conclusions: Repeat MVD for HFS is effective in experienced hands. Younger patients respond better to repeat MVD. Late repeat MVD for HFS is a reasonable treatment option, although results are less favourable than for early re-operation.

Aims: The dural and arachnoid hole caused by lumbar puncture needles is a determining factor in triggering headaches. The aim of this study is to assess the dimensions and morphological features of the dura mater and arachnoids when they are punctured by a 22 gauge Quincke needle having its bevel either in the parallel or in the transverse position. Methods: Fifty punctures were made with 22 gauge Quincke needles in the dural sac of four fresh cadavers using an “in vitro” model especially designed for this purpose. The punctures were performed by needles with bevels parallel or perpendicular to the spinal axis and studied under scanning electron microscopy. Results: Thirty five of the 50 punctures done by Quincke needles (19 in the external surface and 16 in the internal) were used for evaluation. When the needle was inserted with its bevel parallel to the axis of the dural sac (17 of 35), the size of the dura-arachnoid lesion was 0.032 mm 2 in the epidural surface and 0.037 mm 2 in the subarachnoid surface of the dural sac. When the needle’s bevel was perpendicular to the axis (18 of 35) the measurement of the lesion size was 0.042 mm 2 for the external surface and 0.033 mm 2 for the internal. There were no statistical significant differences between these results. Conclusions: It is believed that the reported lower frequency of postdural puncture headache when the needle is inserted parallel to the cord axis should be explained by some other factors besides the size of the dura-arachnoid injury.

Objective: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. Methods: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. Results: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. Conclusions: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postpoperative decline in verbal fluency.

Objectives: To use the technique of dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in patients with familial dysautonomia (FD) and in healthy controls. Methods: In 14 patients with FD and 12 healthy controls, plasma extravasation, local laser Doppler blood flow, and skin blanching were observed before, during, and after application of 10-6 M NA through a microdialysis membrane, located intradermally in the skin of the lower leg. Results: Maximum local vasoconstriction measured by laser Doppler blood flow did not differ between patients with FD and controls. In contrast, patients with FD had an earlier onset of vasoconstriction (p = 0.02). Moreover, reaction to NA was more prominent and prolonged in FD, shown by a larger zone of skin blanching around the microdialysis membrane (p < 0.001) and delayed reduction of the protein content in the dialysate after termination of NA application (p = 0.03). Conclusion: These data support the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines. This may be one mechanism contributing to the major hypertension that frequently occurs during "dysautonomic crises" in FD.

Aims - To analyse the similarities between the Twisted gastrulation (TSG) proteins known to date; in addition, to determine phylogenetic relations among the TSG proteins, and between the TSGs and other protein families - the CCN (for example, CCN2 (CTGF), CCN1 (CYR61), and CCN3 (NOV)) and IGFBP (insulin-like growth factor binding protein) families. Methods - TBLASTN and FASTA3 were used to identify new tsg genes and relatives of the TSG family. The sequences were aligned with Clusta1W. The predictions of sites for signal peptide cleavage, post-translational modifications, and putative protein domains were carried out with software available at various databases. Unrooted phylogenetic trees were calculated using the UPGMA method. Results - Several tsg genes from vertebrates and invertebrates were compared. Alignment of protein sequences revealed a highly conserved family of TSG proteins present in both vertebrates and invertebrates, whereas the slightly less well conserved IGFBP and CCN proteins are apparently present only in vertebrates. The TSG proteins display strong homology among themselves and they are composed of a putative signal peptide at the N-terminus followed by a cysteine rich (CR) region, a conserved domain devoid of cysteines, a variable midregion, and a C-terminal CR region. The most striking similarity between the TSGs and the IGFBP and CCN proteins occurs in the N-terminal conserved cysteine rich domain and the characteristic 5′ cysteine rich domain(s), spacer region, and 3′ cysteine rich domain structure. Conclusion - The family of highly conserved TSG proteins, together with the IGFBP and CCN families, constitute an emerging multigene superfamily of secreted cysteine rich factors. The TSG branch of the superfamily appears to predate the others because it is present in all species examined, whereas the CCN and IGFBP genes are found only in vertebrates.

Although the role of transforming growth factor beta (TGFbeta) in initiating fibrosis is well established, the role that TGFbeta plays in maintaining fibrosis is unclear. The gene encoding connective tissue growth factor (ccn2; ctgf), which promotes fibrosis, is not normally expressed in dermal fibroblasts unless TGFbeta is present. However, in dermal fibroblasts cultured from lesional areas of scleroderma, ccn2 (ctgf) is expressed constitutively. The contribution of several elements in the ccn2 (ctgf) promoter to basal and TGFbeta induced ccn2 (ctgf) expression in normal and scleroderma fibroblasts has been investigated. A functional SMAD binding site in the ccn2 (ctgf) promoter that is necessary for the TGFbeta mediated induction of this gene has been identified. The previously termed TGFbeta responsive enhancer (TGFbetaRE) in the ccn2 (ctgf) promoter has been found to be necessary for basal promoter activity in normal fibroblasts. The SMAD element is not necessary for the high ccn2 (ctgf) promoter activity seen in scleroderma fibroblasts. However, mutation of the previously termed TGFbetaRE reduces ccn2 (ctgf) promoter activity in scleroderma fibroblasts to that seen in normal fibroblasts. Thus, the maintenance of the scleroderma phenotype, as assessed by a high degree of ccn2 (ctgf) promoter activity, appears to be relatively independent of SMAD action and seems to reflect increased basal promoter activity.

Background—Connective tissue growth factor (CCN2; CTGF) is a newly identified growth factor, which is involved in the regulation of wound repair and fibrosis. Because there is variation among individuals with respect to tissue response to injury, genetic factors might be involved in the final outcome of tissue repair or scarring. For example, polymorphisms in the promoter region of genes, such as those encoding transforming growth factor β1 (TGF-β1), interleukin 10 (IL-10), and tumour necrosis factor α (TNF-α), influence transcriptional responses and are thought to contribute to the dysregulation of these genes in pathological conditions. Aim—To investigate whether the promoter region of the ccn2 (ctgf) gene contains polymorphic sequences that might account for differential expression. Materials/Methods—Seventy seven human DNA samples were sequenced—45 were from healthy controls and 32 were from patients with ischaemic heart disease (IHD)—using M13 tailed sequence specific ccn2 (ctgf) primers for amplification of a 600 bp fragment upstream of the transcription start site. Amplicons were bidirectionally sequenced with a dye primer M13 forward and reverse sequencing kit. Results—A C to G substitution was identified at position −132 in one of the patients with IHD. Moreover, in five of the 32 patients with IHD and in six of the 45 healthy controls, a G to C polymorphism was found at position −447. These substitutions at −132 and −447 are thought to lie within predicted binding domains for the transcription factors Pbx-1 and MZF1, respectively. In addition, insertions at position −43 (G), −47 (C), −71 (G) and a C to T substitution at position −198 were found in all DNA samples compared with the published ccn2 (ctgf) promoter sequence. These corrections do not involve sequences predicted to function as transcription factor binding sites. Conclusion—Sequence analysis of the ccn2 (ctgf) promoter of 77 human DNA samples has revealed corrections and polymorphic sites. The latter lie within putative regulatory elements.

Quantitative determination of Ca, Mg, and Zn in fingernails was performed with laser-induced breakdown spectroscopy. Two different methods of producing solid standards for calibration were explored – preparation of keratin pellets and deposition of aqueous solutions to filter papers. Measurements of the temperature and electron density of the plasma produced on keratin pellets, filter paper, and nails were performed, and it was determined that the standards prepared on filter paper gave plasma temperatures and electron densities closer to those observed on the nails. The ablation rate of the filter paper was also more similar to that of the nails. Using calibration curves produced using these filter paper standards, Ca, Mg, and Zn were determined in fingernails of 11 subjects. For comparison, the same samples were digested and atomic absorption was used to determine the same three elements. The differences in results are discussed in light of sample homogeneity and instrumental precision; the best agreement was obtained for determination of Zn. The work suggests that the filter paper method of standard preparation may be appropriate for LIBS analysis of other samples that give relatively low temperature, low electron density plasmas (i.e., polymers).

The mechanism of the increase in the hydrolysis rate and yield by the addition of Tween 80 to the hydrolysis reaction of filter paper was investigated under static and agitated conditions. The increase in the hydrolysis rate by addition of Tween 80 was observed under the agitated condition only. The effects of Tween 80 on the changes in the protein concentration of individual cellulase components were investigated in the absence of substrates. Agitation of the enzyme solution resulted in the drastic decrease of SDS-PAGE bands intensity of CBH2 (cellobiohydrolase 2). The addition of Tween 80 prevented this. Thus, the Tween 80 functions to stabilize instable cellulase components under the agitated condition. Moreover, addition of Tween 80 completely suppressed the decrease of CBH2 intensity by agitation at 30°C. Results suggest that Tween 80 stabilizes instable cellulase components not only during hydrolysis, but during enzyme production also.

Background. Alopecia areata is a common disease and may be associated with autoimmune disease, atopy, Down syndrome, emotional stress, and foci of sepsis. Methods. Seven cases of alopecia areata were diagnosed among workers in the Water and Effluent Treatment Sector (WETS) of a paper factory, representing a 0.6% incidence, when the value for the population at large is 0.1%. Three of these workers are assigned to the WETS on a permanent basis and four provide maintenance services. One of the latter patients had alopecia areata that fully regressed. Because biologic treatment of water and effluents involves saprophytic bacteria and fungi as well as chemical substances such as acrylamide, a clinical examination and laboratory tests were performed on all workers assigned permanently to the WETS (N = 9) and on 25% of the workers, selected at random providing services to the sector (N = 14). Results. There was no association between alopecia areata and atopy, dermatophytosis, or bacteria isolated. Toxicologic evaluation revealed an acrylamide-like substance in 7 workers with alopecia areata, with a statistically significant correlation. Measures were taken at the workplace to decrease worker contact with the mists (probably containing acrylamide) in the pulp-pressing room; no other cases of alopecia areata had been detected 1 year after the study. Conclusions. A survey of the literature did not show reports of alopecia areata as an occupational dermatosis, but our conclusion is, that this dermatosis could be due to the professional activities of the workers at the paper factory studied.

Quantifying sweat gland activation provides important information when explaining differences in sweat rate between populations and physiological conditions. However, no standard technique has been proposed to measure sweat gland activation, while the reliability of sweat gland activation measurements is unknown. We examined the interrater and internal reliability of the modified-iodine paper technique, as well as compared computer-aided analysis to manual counts of sweat gland activation. Iodine-impregnated paper was pressed against the skin of 35 participants in whom sweating was elicited by exercise in the heat or infusion of methylcholine. The number of active glands was subsequently determined by computer-aided analysis. In total, 382 measurements were used to evaluate: 1) agreement between computer analysis and manual counts; 2) the interrater reliability of computer analysis between independent investigators; and 3) the internal reliability of sweat gland activation measurements between duplicate samples. The number of glands identified with computer analysis did not differ from manual counts (68 ± 29 vs. 72 ± 24 glands/cm2; P = 0.27). These measures were highly correlated ( r = 0.77) with a mean bias ± limits of agreement of −4 ± 38 glands/cm2. When comparing computer analysis measures between investigators, values were highly correlated ( r = 0.95; P < 0.001) and the mean bias ± limits of agreement was 4 ± 18 glands/cm2. Finally, duplicate measures of sweat gland activation were highly correlated ( r = 0.88; P < 0.001) with a mean bias ± limits of agreement of 3 ± 29 glands/cm2. These results favor the use of the modified-iodine paper technique with computer-aided analysis as a standard technique to reliably evaluate the number of active sweat glands.

Process and office workers at a Swedish paper mill (n + 274) and dairy workers (n + 45) were investigated with questionnaires regarding skin symptoms. In the second part of the study, subjects reporting skin symptoms and a random sample of subjects without symptoms were examined and investigated with patch testing. Pruritus and skin irritation probably related to exposure to dust were found. The results do not indicate an increased prevalence of contact allergy. In two cases, positive patch test reactions to paper size (rosin) and a slimicide, mercaptobenzothiazole (MBT), were noted. © 1993 Wiley-Liss, Inc.

Of 13 thermal printing papers analyzed, 11 contained 8-17 g/kg bisphenol A (BPA). When taking hold of a receipt consisting of thermal printing paper for 5 s, roughly 1 microg BPA (0.2-6 microg) was transferred to the forefinger and the middle finger if the skin was rather dry and about ten times more if these fingers were wet or very greasy. This amount transferred to dry skin was neither significantly increased when taking hold of the paper at up to 10 sites, nor reduced when BPA-free paper was contacted afterwards. After 60-90 min, BPA applied to the skin as a solution in ethanol was only partially or no longer at all extractable with ethanol, whereas BPA transferred to the skin by holding thermal printer paper remained largely extractable after 2 h. This suggests that penetration of the skin depends on the conditions. Extractability experiments did not enable us to conclude whether BPA passes through the skin, but indicated that it can enter the skin to such a depth that it can no longer be washed off. If this BPA ends up in the human metabolism, exposure of a person repeatedly touching thermal printer paper for 10 h/day, such as at a cash register, could reach 71 microg/day, which is 42 times less than the present tolerable daily intake (TDI). However, if more than just the finger pads contact the BPA-containing paper or a hand cream enhances permeability of the skin, this margin might be smaller.

This study was conducted to evaluate the pretreatment effects of different in vivo moxibustion on the permeation of a model high molecular compound, FITC-dextran, with a mean molecular weight of 4 kDa (FD-4), through excised hairless rat skin. Direct or indirect moxibustion (0.10 g moxa) was pretreated consecutively 4 times every 5 min on the abdomen of hairless rats, and the permeation of FD-4 was determined through the excised skin over 8h from 30 min after starting the first moxibustion. This consecutive moxibustion pretreatment showed a significant increase in the skin temperature as well as skin permeation of FD-4 compared with the control group (no moxibustion pretreatment). Quantitative parameters showed an increase in skin temperature and skin permeation: the area under the skin temperature over control temperature-time curve during one burning cycle (5.0 min) (AUCtemp) or the maximum skin temperature during moxibustion (Tmax) and the cumulative amount of FD-4 permeated through skin over 8h (Q8) or steady-state flux were increased by moxibustion pretreatment. Then, the effect of pedestal thickness (distance from the moxa cylinder and skin surface), shape of the moxa cylinder (5mm diameter, 13 mm height or 9 mm diameter, 7 mm height), burning materials (moxa or aromatic incense), pedestal component (paper, potato or ginger) and moxibustion pretreatment method (direct or indirect moxibustion) was evaluated on the AUCtemp or Tmax and Q8 or flux. The amount of protein leached from the skin surface was also determined as an inflammatory index by this moxibustion pretreatment. When the skin temperature was increased to 60 degrees C, the Q8 or flux as well as the amount of protein leached were markedly increased. When the skin temperature was controlled to 42 to 45 degrees C by an adequate selection of pedestal thickness, shape of the moxa cylinder, burning materials, pedestal component and moxibustion pretreatment method, on the other hand, protein leaching remained unaltered, but the Q8 or flux significantly increased with the Tmax. This study thus provides credible evidence that moxibustion pretreatment increases the skin permeation of high molecular compounds.

Objective: To determine the statistical characteristics of blood pressure (BP) readings from a large number of head-injured patients. Methods: The BrainIT group has collected high time-resolution physiological and clinical data from head-injured patients who require intracranial pressure (ICP) monitoring. The statistical features of this dataset of BP measurements with time resolution of 1 min from 200 patients is examined. The distributions of BP measurements and their relationship with simultaneous ICP measurements are described. Results: The distributions of mean, systolic and diastolic readings are close to normal with modest skewing towards higher values. There is a trend towards an increase in blood pressure with advancing age, but this is not significant. Simultaneous blood pressure and ICP values suggest a triphasic relationship with a BP rising at 0.28 mm Hg/mm Hg of ICP, for ICP up to 32 mm Hg, and 0.9 mm Hg/mm Hg of ICP for ICP from 33 to 55 mm Hg, and falling sharply with rising ICP for ICP >55 mm Hg. Conclusions: Patients with head injury appear to have a near normal distribution of blood pressure readings that are skewed towards higher values. The relationship between BP and ICP may be triphasic.

Most arsenic bearing solid residuals (ABSR) from water treatment will be disposed in nonhazardous landfills. The lack of an appropriate leaching test to predict arsenic mobilization from ABSR creates a need to evaluate the magnitude and mechanisms of arsenic release under landfill conditions. This work studies the leaching of arsenic and iron from a common ABSR, granular ferric hydroxide, in a laboratory-scale column that simulates the biological and physicochemical conditions of a mature, mixed solid waste landfill. The column operated for approximately 900 days and the mode of transport as well as chemical speciation of iron and arsenic changed with column age. Both iron and arsenic were readily mobilized under the anaerobic, reducing conditions. During the early stages of operation, most arsenic and iron leaching (80% and 65%, respectively) was associated with suspended particulate matter, and iron was lost proportionately faster than arsenic. In later stages, while the rate of iron leaching declined, the arsenic leaching rate increased greater than 7-fold. The final phase was characterized by dissolved species leaching. Future work on the development of standard batch leaching tests should take into account the dominant mobilization mechanisms identified in this work: solid associated transport, reductive sorbent dissolution, and microbially mediated arsenic reduction.

We report a case of Alternaria infection of the nail and cornea in an immunocompromised patient working in the paper-manufacturing industry. This unusual clinical presentation could represent an occupational disorder. The importance of histologic examination of the altered nails is emphasized. The proof of a real nondermatophytic onychomycosis is established only when hyphae of culture-proven molds are shown inside the nail plate.

Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity.In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function.Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function.The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.

to study the underlying cognitive deficits influencing a stroke patient's ability to relearn to dress. The aim was to investigate how recovery had occurred and whether the nature of cognitive impairment was the reason for persistent dressing problems.the dressing performance of 30 stroke patients was compared at the sub-acute stage and three months later. Standardised cognitive and physical tests were carried out, together with a video analysis of patients putting on a polo shirt.thirteen patients with preserved power in the upper limb used both arms to put on the shirt. Despite visuospatial impairment or apraxia in some cases, all were successful given sufficient time. Out of 17 patients with arm paresis, 12 were dependent putting on the shirt. Amongst the five who were independent, significantly fewer cases of cognitive impairment were seen on tests for apraxia (p0.05) and visuospatial perception (p0.05). Video analysis confirmed the importance of cognitive problems such as neglect or apraxia. Three patients who failed shirt dressing showed neglect or apraxia at follow up and had persistent arm paresis. Test failures also occurred amongst those who were independent.cognitive impairment affected patients attempting to relearn to dress with one hand, but did not affect patients who used both hands. The three patients who remained impaired on cognitive tests at follow up were unable to adapt or learn any compensatory strategies. The influence of cognition on a person's ability to learn compensatory strategies has implications for the design of rehabilitation therapies.

Objective: To clarify the characteristics of sympathetic vasomotor function in Parkinson's disease by sympathetic neurographic analysis. Methods: Muscle sympathetic nerve activity (MSNA) was recorded using a microneurographic technique at rest and during head up tilt in 18 patients with idiopathic Parkinson's disease and 21 healthy controls. Results: Heart rate and blood pressure at rest did not differ between index and control subjects. The increase in these variables and MSNA in response to tilting was slightly blunted in the Parkinson's group. Resting MSNA showed a negative correlation with age in patients with Parkinson's disease (p

Objective: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin. Methods: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21. Results: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity. Conclusions: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy.

Objectives: To explore the outcome of management of possible shunt related symptoms using intracranial pressure (ICP) monitoring, and to identify potential methodological limitations with the current strategies of ICP assessment. Methods: The distribution of persistent symptoms related to extracranial shunt treatment was compared before and after management of shunt failure in 69 consecutive hydrocephalic cases. Management was heavily based on ICP monitoring (calculation of mean ICP and visual determination of plateau waves). After the end of patient management, all ICP curves were re-evaluated using a quantitative method and software (SensometricsTM pressure analyser). The ICP curves were presented as a matrix of numbers of ICP elevations (20 to 35 mm Hg) or depressions (-10 to -5 mm Hg) of different durations (0.5, 1, or 5 minutes). The numbers of ICP elevations/depressions standardised to 10 hours recording time were calculated to allow comparisons of ICP between individuals. Results: After ICP monitoring and management of the putative shunt related symptoms, the symptoms remained unchanged in as many as 58% of the cases, with the highest percentages in those patients with ICP considered normal or too low at the time of ICP monitoring. The quantitative analysis revealed a high frequency of ICP elevations (20 to 35 mm Hg lasting 0.5 to 1 minute) and ICP depressions (-10 to -5 mm Hg lasting 0.5, 1, or 5 minutes), particularly in patients with ICP considered normal. Conclusions: The value of continuous ICP monitoring with ICP analysis using current criteria appears doubtful in the management of possible shunt related symptoms. This may reflect limitations in the strategies of ICP analysis. Calculation of the exact numbers of ICP elevations and depressions may provide a more accurate description of the ICP profile.

To describe a reversible neurological condition resembling a crossed midbrain syndrome resulting from high frequency stimulation (HFS) in the midbrain.Postoperative evaluation of quadripolar electrodes implanted in the area of the subthalamic nucleus of 25 patients with Parkinson's disease (PD) successfully treated by HFS.Four of the 25 patients experienced reversible acute diplopia, with dystonic posture and tremor in the contralateral upper limb when the white matter between the red nucleus and the substantia nigra was stimulated. The motor signs resembled those caused by lesions of the red nucleus. The ipsilateral resting eye position was "in and down" (three patients) or "in" (one patient). Enophthalmos was seen. Abduction was impaired and vertical eye movements were limited, but adduction was spared. The movements of the controlateral eye were normal. The ocular signs could be best explained by sustained hyperactivity of the extrinsic oculomotor nerve. Simultaneous tonic contraction of the superior rectus, the inferior rectus, and inferior oblique may cause the enophthalmos and partial limitation of upward and downward eye movements. Antagonist tonic contraction of the ipsilateral medial rectus severely impairs abduction.This crossed midbrain syndrome, possibly resulting from simultaneous activation of oculomotor nerve and lesion-like inhibition of the red nucleus suggests that high frequency stimulation has opposite effects on grey and white matter.

Aims —To determine mechanisms regulating the production of connective tissue growth factor (CCN2; CTGF) and transforming growth factor β1 (TGF-β1) in the mouse uterus. Methods —In situ hybridisation and immunohistochemistry were used to localise CCN2 (CTGF) and TGF-β1 in uteri from sexually mature female mice that had either been (1) mated with sterile males to induce pseudopregnancy or (2) ovariectomised (OVX) and administered estradiol-17β (E 2 ) or progesterone (P 4 ), either alone or in combination. Uteri collected on days 0.5, 1.5, 2.5, 3.5, 4.5, or 5.5 of pseudopregnancy or at one, three, six, 12, or 24 hours after steroid administration were fixed, sectioned, and incubated with specific riboprobes or antibodies to permit detection and localisation of mRNA or protein for CTGF and TGF-β1. Results —On days 0.5–2.5 of pseudopregnancy, CCN2 (CTGF) and TGF-β1 were principally colocalised to uterine epithelial cells, with much smaller amounts in the stroma. On days 3.5–4.5, there was a reduction of CCN2 (CTGF) and TGF-β1 in the epithelium but an increase in stromal and endothelial cells, corresponding to a period of extracellular matrix remodelling and neovascularisation within the endometrium. In OVX mice, epithelial cells were weakly positive for both CCN2 (CTGF) and TGF-β1 in the absence of steroid hormones. Epithelial CTGF mRNA production were strongly but transiently stimulated in OVX mice cells by E 2 . These effects were antagonised by P 4 , which itself transiently stimulated epithelial CCN2 (CTGF) production, although less robustly than E 2 . CTGF and TGF-β1 protein amounts were high in epithelial cells throughout steroid treatment and were increased in the stroma, where they were relatively long lived. Stromal CCN2 (CTGF) and TGF-β1 were lower after co-administration of E 2 and P 4 than in response to each hormone individually. Although ccn2 (ctgf) is a TGF-β1 inducible gene in other systems, and both growth factors were often co-localised in uterine tissues in these studies, several treatment regimens resulted in high amounts of TGF-β1 protein in stromal cells without the concomitant production of ccn2 (ctgf) mRNA. Conclusions— Maternal factors are principal cues for CCN2 (CTGF) and TGF-β1 production in the uterus because (1) their expression during pseudopregnancy is comparable to that seen in pregnancy and (2) they are regulated by ovarian steroids. TGF-β dependent and independent mechanisms of ccn2 (ctgf) gene transcription exist in the uterus that are variably regulated by steroid hormones. Collectively, the data support a role for CCN2 (CTGF) in mediating the effects of steroid hormones and TGF-β on endometrial function.

Aims—To establish whether the ectopic expression of CCN3 (NOV) in glioma cells can interfere with their tumorigenic potential and assess its potential value in molecular medicine. Methods—Glioma cell lines were used to assess whether differences in the degree of intracellular communication induced by the expression of the gap junction protein connexin 43 (Cx43) is related to the differential expression of CCN3 (NOV). The antiproliferative activity of rat CCN3 (rCCN3; NOV) in glioma cells, has been assessed both in vitro and in vivo with glioma cell lines expressing different amounts of CCN3 (NOV). Results—Upon ectopic expression of Cx43, the growth of C6 glioma cells is decreased. An increase of CCN3 (NOV) expression matches the reduced tumorigenic potential of these transfected cells. The localisation of CCN3 (NOV) is affected by the increased expression of Cx43 in the Cx-13 transfected cells, in which it is detected at areas of cell–cell contact. In a xenograft model, CCN3 (NOV) transfected glioma cells were found to induce tumours to a lesser degree than their parental counterparts, which do not express detectable amounts of CCN3 (NOV). Conclusions—Previous observations had suggested an inverse relation between CCN3 (NOV) expression in glioma cells and their tumorigenicity. These results establish a direct association between the establishment of functional gap junctional intercellular communication and the expression of rCCN3 (NOV). In addition to a negative effect on murine and human cell growth, CCN3 (NOV) has antiproliferative activity on tumour cells in vivo. Thus, the antiproliferative activity of the CCN3 (NOV) protein might involve reorganisation of cellular contacts that play a crucial role in tumorigenesis. The antiproliferative activity of CCN3 (NOV) established in this work sets the stage for the potential use of CCN proteins in molecular oncology.

Aims—To investigate the expression of the human ccn3 (hccn3; nov) proto-oncogene, a member of the CCN family of proteins, in prostate epithelial cells and prostate tissue samples. Methods—Normal adult prostate luminal epithelial cells immortalised by SV40 large T (PNT1A and PNT1B), metastatic tumours (LNCaP, DU-145, and PC-3), and prostate tissue samples from patients with benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma were used. hccn3 (nov) mRNA was measured by the reverse transcription polymerase chain reaction (RT-PCR) and hCCN3 (NOV) protein expression was determined by immunochemistry. Results—hccn3 (nov) RNA values were higher in PC-3 cells than in the other prostate cell lines. The immortalised normal cell lines either did not express hccn3 (nov) RNA (PNT1B) or expressed very low amounts (PNT1A). BPH samples expressed variable amounts of hccn3 (nov) RNA. With the use of immunocytochemistry, all cell lines except PNT1A and PNT1B were shown to contain hCCN3 (NOV) protein. hCCN3 (NOV) was localised mainly in the epithelial compartment of BPH and adenocarcinoma samples, and there was evidence of luminal secretion. Conclusion—The overexpression of hccn3 (nov) RNA in cancer cell lines compared with other cell lines and its epithelial localisation in human prostate samples are consistent with a role for hCCN3 (NOV) in prostatic tumorigenesis.