Treatment of palmar hyperhidrosis with botulinum toxin type A: results of a pilot study based on a novel injective approach.

Botulinum toxin type A (BoNT/A) improves symptoms of palmar hyperhidrosis, but some drawbacks related to its injection in the hands still persist (e.g., muscle weakness caused by drug diffusion, pain during injections, or delayed functional recovery of the hand when using wrist block). In this open, controlled, non-randomized, intra-individual clinical trial, 50 patients with severe palmar hyperhidrosis received in the same session intradermal injections of BoNT/A through a new injection technique (NA/BoNT/A) based on the use of a specific adapter for needles (PCT/IT2011/000299) in one hand, and BoNT/A injection following the anaesthetic block of the wrist (WB/BoNT/A) in the other. Several measures of efficacy and safety were evaluated both before (T0) and four weeks after the treatment (T4): disease severity improvement, sweat reduction, handgrip strength decrease, pain/discomfort during the treatment, and patient's global satisfaction. All patients were also re-evaluated through the gravimetric assessment of sweat production in both hands at T12 and T24 to compare the long-term efficacy of the two treatments. All patients were responsive to the treatments, and disease severity was significantly decreased at T4 compared to baseline (p < 0.0001). Both procedures were equally effective in reducing sweat production in the short term (p = 0.08 at T4), but WB/BoNT/A caused a higher decrease of handgrip strength compared with WB/BoNT/A at T4 (p < 0.0001). Finally, patients reported that NA/BoNT/A and WB/BoNT/A procedures were comparable for pain/discomfort (p = 0.204); however, they were globally more satisfied with the NA/BoNT/A rather than WB/BoNT/A method (p < 0.0001). No significant difference in percentage of clinical relapse at T12 and T24 was detected between hands treated via WB/BoNT/A or NA/BoNT/A (p = 0.70). The use of the described adapter to inject BoNT/A in the hands seems to lead the clinicians to obtain same therapeutic results of conventional method based on the use of anaesthetic block of the wrist. Moreover, this new injective approach seems to increase the safety of the treatment by reducing the extent of muscle weakness and is preferred by patients mostly because it makes the functional recovery of the hand faster.

Treatment of focal idiopathic hyperhidrosis with Botulinum Toxin Type A: clinical predictive factors of relapse-free survival.

BACKGROUND: No material about the identification of predictive clinical factors of therapeutic response to Botulinum Toxin Type A (BTX-A) in focal idiopathic hyperhidrosis has been found. OBJECTIVE: To evaluate if age, sex, extension rate of hyperhidrotic area, localization, disease-related impairment of life quality, number of previous local, non-invasive treatments different from BTX-A, and duration of disease, may affect the relapse-free survival (RFS) after a BTX-A treatment in palmar and axillary focal idiopathic hyperhidrosis. METHODS: Forty-one patients suffering from palmar hyperhidrosis, and 38 patients suffering from axillary hyperhidrosis received intradermal injections of BTX-A. All patients were clinically screened before and after treatment; they were followed for 15 months after it, according to Hyperhidrosis Disease Severity Scale (HDSS), Minor's test, and DLQI test, to state disease severity, and disease-related impairment of quality of life. RESULTS: The duration of therapeutic effect of BTX-A is not significantly influenced by age (P = 0.783), sex (P = 0.762), extension of hyperhidrotic area (P = 0.770), site of involvement (P = 0.402), disease-induced impairment of life quality (P = 0.745), number of previous therapies (P = 0.730), or site of involvement (P = 0.402). In palmar idiopathic hyperhidrosis, patients with a longer disease history show a shorter duration of RFS after a treatment with BTX-A (P = 0.01). CONCLUSIONS: Patients suffering from palmar hyperhidrosis have a longer lasting disease, and a length of disease more than 20 years in these patients influences the RFS after BTX-A treatment.

In vitro activity of Tachyplesin III alone and in combination with terbinafine against clinical isolates of dermatophytes.

Aim of our study was to investigate the in vitro effects of Tachyplesin III (TP), a potent disulfide-linked peptide, in dermatophytes infections, with respect to or in combination with terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to four species. A broth microdilution method following the CLSI recommendations (M38-A) was used for testing drugs alone and in combination. TERB MICs were significantly lower than those observed for TP (p<0.001). Testing for antifungal agents in combination was performed for TERB with TP for all the 20 isolates. TERB activity in combination with TP showed indifferent activity for 14 of the 20 isolates (70%); synergic activity for 6 of the 20 isolates (30%); no antagonistic activity was observed. Further experiments were conducted with Microsporum canis 133, Trichophyton rubrum 62 and Trichophyton mentagrophytes 91 for fungal biomass. TP and TERB did not show a significant growth reduction compared to the control against T. mentagrophytes and T. rubrum. A significant difference of growth reduction both for TP and TERB compared to controls was observed for M. canis (p<0.01). In conclusion our study demonstrated that Tachyplesin III has potential activity against dermatophytes. In addition, we observed that the in vitro activity of Tachyplesin III can be enhanced upon combination with terbinafine. Synergy could permit lower doses of the individual antifungal agents to be used more effectively and/or safely.

Callosal connections of dorso-lateral premotor cortex.

This study investigated the organization of the callosal connections of the two subdivisions of the monkey dorsal premotor cortex (PMd), dorso-rostral (F7) and dorso-caudal (F2). In one animal, Fast blue and Diamidino yellow were injected in F7 and F2, respectively; in a second animal, the pattern of injections was reversed. F7 and F2 receive a major callosal input from their homotopic counterpart. The heterotopic connections of F7 originate mainly from F2, with smaller contingent from pre-supplementary motor area (pre-SMA, F6), area 8 (frontal eye fields), and prefrontal cortex (area 46), while those of F2 originate from F7, with smaller contributions from ventral premotor areas (F5, F4), SMA-proper (F3), and primary motor cortex (M1). Callosal cells projecting homotopically are mostly located in layers II-III, those projecting heterotopically occupy layers II-III and V-VI. A spectral analysis was used to characterize the spatial fluctuations of the distribution of callosal neurons, in both F7 and F2, as well as in adjacent cortical areas. The results revealed two main periodic components. The first, in the domain of the low spatial frequencies, corresponds to periodicities of cell density with peak-to-peak distances of approximately 10 mm, and suggests an arrangement of callosal cells in the form of 5-mm wide bands. The second corresponds to periodicities of approximately 2 mm, and probably reflects a 1-mm columnar-like arrangement. Coherency and phase analyses showed that, although similar in their spatial arrangements, callosal cells projecting to dorsal premotor areas are segregated in the tangential cortical domain.

Plasma and skin concentration of 5-methoxypsoralen in psoriatic patients after oral administration.

The aim of this work was to investigate the distribution of 5-methoxypsoralen in the skin after oral administration of the drug and to examine the correlation between skin and plasma concentrations. 5-Methoxypsoralen skin concentration was measured in both healthy and psoriatic sites of 10 psoriatic patients after single and multiple oral doses. The results obtained show that 5-methoxypsoralen accumulates at higher levels in the more external layers of the skin after oral administration. The high affinity of drug for the stratum corneum was confirmed by in vitro skin affinity measurements. The concentration of 5-methoxypsoralen in the skin was similar in both psoriatic and healthy sites, indicating that the pathology does not influence drug distribution in the skin. After single dose administration, a linear correlation was found between skin and plasma drug concentration. After multiple dose administration, drug concentration in the skin was fairly constant despite the variable plasma concentrations in different subjects.

Eye-hand coordination during reaching. I. Anatomical relationships between parietal and frontal cortex.

The anatomical and physiological substrata of eye-hand coordination during reaching were studied through combined anatomical and physiological techniques. The association connections of parietal areas V6A and PEc, and those of dorso-rostral (F7) and dorso-caudal (F2) premotor cortex were studied in monkeys, after physiological characterization of the parietal regions where retrograde tracers were injected. The results show that parieto-occipital area V6A is reciprocally connected with F7, and receives a smaller projection from F2. Local parietal projections to V6A arise from areas MIP and, to a lesser extent, 7m, PEa and PEC: On the contrary, parietal area PEc is strongly and reciprocally connected with the part of F2 located close to the pre-central dimple (pre-CD). Local parietal projections to PEc come from a distributed network, including PEa, MIP, PEci and, to a lesser extent, 7m, V6A, 7a and MST. Premotor area F7 receives parietal projections mainly from 7m and V6A, and local frontal projections mainly from F2. On the contrary, premotor area F2 in the pre-CD zone receives parietal inputs from PEc and, to a lesser extent, PEci, while in the peri-arcuate zone F2 receives parietal projections from PEa and MIP. Local frontal projections to F2 pre-CD mostly stem from F4, and, to a lesser extent, from F7 and F3, and CMAd; those addressed to peri-arcuate zone of F2 arise mainly from F5 and, to a lesser extent, from F7, F4, dorsal (CMAd) and ventral (CMAv) cingulate motor areas, pre-supplementary (F6) and supplementary (F3) motor areas. The distribution of association cells in both frontal and parietal cortex was characterized through a spectral analysis that revealed an arrangement of these cells in the form of bands, composed of cell clusters, or 'columns'. The reciprocal connections linking parietal and frontal cortex might explain the presence of visually related and eye-position signals in premotor cortex, as well as the influence of information about arm position and movement direction in V6A and PEC: The association connections identified in this study might carry sensory as well motor information that presumably provides a basis for a re-entrant signaling. This might be necessary to match retinal-, eye- and hand-related information underlying eye-hand coordination during reaching.

Eye-hand coordination during reaching. II. An analysis of the relationships between visuomanual signals in parietal cortex and parieto-frontal association projections.

The relationships between the distribution of visuomanual signals in parietal cortex and that of parieto-frontal projections are the subject of the present study. Single cell recording was performed in areas PEc and V6A, where different anatomical tracers were also injected. The monkeys performed a variety of behavioral tasks, aimed at studying the visual and motor properties of parietal cells, as well as the potential combination of retinal-, eye- and hand-related signals on cell activity. The activity of most cells was related to the direction of movement and the active position of the hand. Many of these reach-related cells were influenced by eye position information. Fewer cells displayed relationships to saccadic eye movements. The activity of most neurons related to a combination of both hand and eye signals. Many cells were also modulated during preparation for hand movement. Light-dark differences of activity were common and interpreted as related to the sight and monitoring of hand motion and/or position in the visual field. Most cells studied were very sensitive to moving visual stimuli and also responded to optic flow stimulation. Visual receptive fields were generally large and extended to the periphery of the visual field. For most neurons, the orientation of the preferred directions computed across different epochs and tasks conditions clustered within a limited sector of space, the field of global tuning. This can be regarded as an ideal frame to combine spatially congruent eye- and hand-related information for different forms of visuomanual behavior. All these properties were common to both PEc and V6A. Retinal, eye- and hand-related activity types, as well as parieto-frontal association cells, were distributed in a periodic fashion across the tangential domain of areas PEc and V6A. These functional and anatomical distributions were characterized and compared through a spectral and coherency analysis, which revealed the existence of a selective 'match' between activity types and parieto-frontal connections. This match depended on where each individual efferent projection was addressed. The results of the present and of the companion study can be relevant for a re-interpretation of optic ataxia as the consequence of the breakdown of the combination of retinal-, eye- and hand-related directional signals within the global tuning fields of parietal neurons.

Early coding of visuomanual coordination during reaching in parietal area PEc.

The parietal mechanisms of eye-hand coordination during reaching were studied by recording neural activity in area PEc while monkeys performed different tasks, aimed at assessing the influence of retinal, hand-, and eye-related signals on neural activity. The tasks used consisted of 1) reaching to foveated and 2) to extra-foveal targets, with constant eye position; and 3) saccadic eye movement toward, and holding of eye position on peripheral targets, the same as those of the reaching tasks. In all tasks, hand and/or eye movements were made from a central position to eight peripheral targets. A conventional visual fixation paradigm was used as a control task, to assess location and extent of visual receptive field of neurons. A large proportion of cells in area PEc displayed significant relationships to hand movement direction and position. Many of them were also related to the eye's position. Relationships to saccadic eye movements were found for a smaller proportion of cells. Most neurons were tuned to different combination of hand- and eye-related signals; some of them were also influenced by visual information. This combination of signals can be an expression of the early stages of the composition of motor commands for different forms of visuomotor coordination that depend on the integration of hand- and eye-related information. These results assign to area PEc, classically considered as a somatosensory association cortex, a new visuomotor role.

Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13.

PURPOSE: To determine if Biafine compared to Best Supportive Care (BSC) is effective in minimizing or preventing radiation-induced dermatitis in women undergoing breast irradiation. METHODS AND MATERIALS: Patients were randomized between Biafine (n = 83) vs. BSC (n = 89). The institutions identified preference for BSC at the time of randomization. A no-treatment arm was allowed (16% received no treatment). Patients were instructed to apply randomized product three times a day, but not within 4 h of their daily RT session. Application began following their first radiation treatment and continued 2 weeks postradiation. Skin dermatitis was scored weekly utilizing the RTOG and ONS (Oncology Nursing Society) skin toxicity scales, a weekly patient satisfaction and quality-of-life questionnaire. RESULTS: Using the RTOG toxicity scale there was no overall difference for maximum dermatitis during RT between Biafine and BSC (p = 0.77). There was no difference in maximum toxicity by arm or breast size. There was an interaction between breast size and toxicity, with large-breasted women exhibiting more toxicity. Large-breasted women receiving Biafine were more likely to have no toxicity 6 weeks post RT. CONCLUSION: There was no overall difference between BSC and Biafine in the prevention, time to, or duration of radiation-induced dermatitis.

Early coding of reaching in the parietooccipital cortex.

Neural activity was recorded in the parietooccipital cortex while monkeys performed different tasks aimed at investigating visuomotor interactions of retinal, eye, and arm-related signals on neural activity. The tasks were arm reaching 1) to foveated targets; 2) to extrafoveal targets, with constant eye position; 3) within an instructed-delayed paradigm, under both light and darkness; 4) saccadic eye movements toward, and static eye holding on peripheral targets; and 5) visual fixation and stimulation. The activity of many cells was modulated during arm reaction (68%) and movement time (58%), and during static holding of the arm in space (64%), when eye position was kept constant. Eye position influenced the activity of many cells during hand reaction (45%) and movement time (51%) and holding of hand static position (69%). Many cells (56%) were also modulated during preparation for hand movement, in the delayed reach task. Modulation was present also in the dark in 59% of cells during this epoch, 51% during reaction and movement time, and 48% during eye/hand holding on the target. Cells (50%) displaying light-dark differences of activity were considered as related to the sight and monitoring of hand motion and/or position in the visual field. Saccadic eye movements modulated a smaller percentage (25%) of cells than eye position (68%). Visual receptive fields were mapped in 44% of the cells studied. They were generally large and extended to the periphery of the tested (30 degrees ) visual field. Sixty-six percent of cells were motion sensitive. Therefore the activity of many neurons in this area reflects the combined influence of visual, eye, and arm movement-related signals. For most neurons, the orientation of the preferred directions computed across different epochs and tasks, therefore expression of all different eye- and hand-related activity types, clustered within a limited sector of space, the field of global tuning. These spatial fields might be an ideal frame to combine eye and hand signals, thanks to the congruence of their tuning properties. The relationships between cell activity and oculomotor and visuomanual behavior were task dependent. During saccades, most cells were recruited when the eye moved to a spatial location that was also target for hand movement, whereas during hand movement most cells fired depending on whether or not the animal had prior knowledge about the location of the visual targets.

Early coding of reaching: frontal and parietal association connections of parieto-occipital cortex.

The ipsilateral association connections of the cortex of the dorsal part of the rostral bank of the parieto-occipital sulcus and of the adjoining posterior part of the superior parietal lobule were studied by using different retrograde fluorescent tracers. Fluoro-Ruby, Fast blue and Diamidino yellow were injected into visual area V6A, and dorso-caudal (PMdc, F2) and dorso-rostral (PMdr, F7) premotor cortex, respectively. The parietal area of injection had been previously characterized physiologically in behaving monkeys, through a variety of oculomotor and visuomanual tasks. Area V6A is mainly linked by reciprocal projections to parietal areas 7m, MIP (medial intraparietal) and PEa, and, to a lesser extent, to frontal areas PMdr (rostral dorsal premotor cortex, F7) and PMdc (F2). All these areas project to that part of the dorsocaudal premotor cortex that has a direct access to primary motor cortex. V6A is also connected to area F5 and, to a lesser extent, to 7a, ventral (VIP) and lateral (LIP) intraparietal areas. This pattern of association connections may explain the presence of visually-related and eye-position signals in premotor cortex, as well as the influence of information concerning arm position and movement direction on V6A neural activity. Area V6A emerges as a potential 'early' node of the distributed network underlying visually-guided reaching. In this network, reciprocal association connections probably impose, through re-entrant signalling, a recursive property to the operations leading to the composition of eye and hand motor commands.

Distribution of khellin in excised human skin following iontophoresis and passive dermal transport.

The aim of this work was to study in vitro khellin distribution into human skin after passive or iontophoretic transport. The experiments were performed on excised human skin, using vertical Franz-type diffusion cells. The effects of current application and reservoir pH were studied. At the end of the experiments the skin was sliced thinly and the drug was extracted and analyzed by HPLC. The results showed that khellin is able to penetrate through stratum corneum, to reach basal epidermis and upper dermis. The application time proved to be an important parameter. Current application (30 min; 0.5 mA/cm(2)), with a donor at pH 7.0, favored khellin accumulation even if the drug is not ionized. On the contrary, the use of a formulation at pH 3.2 inhibited drug accumulation. Leaving the drug reservoir in contact with the skin for 30 min after current application led to a dramatic increase of khellin concentration. A combination of dermal iontophoresis and passive diffusion is then a useful technique to govern khellin distribution in the skin.

Early motor influences on visuomotor transformations for reaching: a positive image of optic ataxia.

Coding of reaching in the cerebral cortex is based on the operation of distributed populations of parietal and frontal neurons, whose main functional characteristics reside in their combinatorial power, i.e., in the capacity for combining different information related to the spatial aspects of reaching. The tangential distribution of reach-related neurons endowed with different functional properties changes gradually in the cortex and defines, in the parieto-frontal network, trends of functional properties. These visual-to-somatic gradients imply the existence of cortical regions of functional overlaps, i.e., of combinatorial domains, where the integration of different reach-related signals occurs. Studies of early coding of reaching in the mesial parietal areas show how somatomotor information, such as that related to arm posture and movement, influences neuronal activity in the very early stages of the visuomotor transformation underlying the composition of the motor command and is not added "downstream" in the frontal cortex. This influence is probably due to re-entrant signals traveling through fronto-parietal-association connections. Together with the gradient architecture of the network and the reciprocity of cortico-cortical connections, this implies that coding of reaching cannot be regarded as a top-down, serial sequence of coordinate transformation, each performed by a given cortical area, but as a recursive process, where different signals are progressively matched and further elaborated locally, due to intrinsic cortical connections. This model of reaching is also supported by psychophysical studies stressing the parallel processing of the different relevant parameters and the "hybrid" nature of the reference frame where they are combined. The theoretical frame presented here can also offer a background for a new interpretation of a well-known visuomotor disorder, due to superior parietal lesions, i.e., optic ataxia. More than a disconnection syndrome, this can now be interpreted as the consequence of the breakdown of the operations occurring in the combinatorial domains of the superior parietal segment of the parieto-frontal network.