Guidelines for clinical trials of frontal fibrosing alopecia: consensus recommendations from the International FFA Cooperative Group (IFFACG).

BACKGROUND: Frontal fibrosing alopecia (FFA) has become one of the most common causes of cicatricial alopecia worldwide. However, there is a lack of clear aetiology and robust clinical trial evidence for the efficacy and safety of agents currently used for treatment. OBJECTIVES: To enable data to be collected worldwide on FFA using common criteria and assessment methods. METHODS: A multicentre, international group of experts in hair loss was convened by email to create consensus recommendations for clinical trials. Consensus was defined at > 90% agreement on each recommended part of these guidelines. RESULTS: Standardized diagnostic criteria, severity rating, staging, and investigator and patient assessment of scalp hair loss and other clinical features of FFA were created. CONCLUSIONS: These guidelines should allow the collection of reliable aggregate data on FFA and advance efforts in both clinical and basic research to close knowledge gaps in this condition.

Effect of minoxidil topical foam on frontotemporal and vertex androgenetic alopecia in men: a 104-week open-label clinical trial.

BACKGROUND: Topical minoxidil formulations have been shown to be effective in treating androgenetic alopecia (AGA) for 12 months. Efficacy and safety in both frontotemporal and vertex regions over longer application periods have not been studied so far. OBJECTIVES: To evaluate the effect of 5% minoxidil topical foam (5% MTF) in the frontotemporal and vertex areas in patients with moderate AGA over 104 weeks. METHODS: An 80-week, open-label extension phase was performed, following a 24-week randomized, double-blind, placebo-controlled study in men with AGA grade IIIvertex to VI. Group 1 (n = 22) received ongoing 5% MTF for 104 weeks, Group 2 (n = 23) received placebo topical foam (plaTF) until week 24, followed by 5% MTF until week 104 during the extension phase. Frontotemporal and vertex target area non-vellus hair counts (f-TAHC, v-TAHC) and cumulative hair width (f-TAHW, v-TAHW) were assessed at baseline and at weeks 24, 52, 76 and 104. RESULTS: In Group 1, f-TAHW and f-TAHC showed a statistically significant increase from baseline to week 52 and week 76, respectively, returning to values comparable to baseline at week 104. No significant differences were found between baseline and week 104 in v-TAHC in Group 1 as well as f-TAHC, v-TAHC, f-TAHW and v-TAHW values in Group 2. CONCLUSIONS: 5% MTF is effective in stabilizing hair density, hair width and scalp coverage in both frontotemporal and vertex areas over an application period of 104 weeks, while showing a good safety and tolerability profile with a low rate of irritant contact dermatitis.

Quantifying dyspigmentation in facial skin ageing: an explorative study.

OBJECTIVE: The skin melanin system is affected by ageing, resulting in dyspigmentation with associated clinical and psychosocial consequences. In dark skinned phenotypes, broad evidence is available, whereas little is known about pigmentary changes in fair-skinned Caucasians. The objective of this study was to investigate age-related changes in facial pigmentation and dyspigmentation in subjects of skin phototypes II-III and to develop and test parameters for quantifying dyspigmentation. METHODS: Twenty-four skin healthy female subjects were recruited in three distinct age groups (30-40, 50-60, 70-80 years). Skin colour was measured by Mexameter and Chromameter. Skin dyspigmentation was measured by clinical evaluation and newly developed image-processing parameters on the cheeks and the forehead. The reliability of the clinical evaluation was investigated by intraclass correlation coefficients between three raters, and the validity of the dyspigmentation parameters was analysed by bivariate correlations with related measures. RESULTS: Skin lightness decreased with increasing age. Clinical dyspigmentation scores showed positive associations with chronological age ranging between 0.452 and 0.606. RBX(®) -Brown transformation-based hyperpigmentation and hypopigmentation indices increased with age, whereas the overall pigmentation intensity decreased with age at the cheeks. The image analysis-based parameters showed strong associations with the clinical scores and related measurements. CONCLUSION: We demonstrated age-related changes in the facial colour and dyspigmentation of fair-skinned Caucasian females. An increase in dyspigmentation was found by clinical scoring and the RBX(®) -Brown transformation-based pigmentation indices. The validity of hyper- and hypopigmentation indices and overall pigmentation intensity was supported. The RBX(®) transformation-based pigmentation indices might be applied in future studies to complement or substitute clinical evaluation.

The production of 34S-depleted sulfide during bacterial disproportionation of elemental sulfur.

Bacteria that disproportionate elemental sulfur fractionate sulfur isotopes such that sulfate is enriched in sulfur-34 by 12.6 to 15.3 per mil and sulfide is depleted in sulfur-34 by 7.3 to 8.6 per mil. Through a repeated cycle of sulfide oxidation to S0 and subsequent disproportionation, these bacteria can deplete sedimentary sulfides in sulfur-34. A prediction, borne out by observation, is that more extensive sulfide oxidation will lead to sulfides that are more depleted in sulfur-34. Thus, the oxidative part of the sulfur cycle creates circumstances by which sulfides become more depleted in sulfur-34 than would be possible with sulfate-reducing bacteria alone.

Aerobic sulfate reduction in microbial mats.

Measurements of bacterial sulfate reduction and dissolved oxygen (O2) in hypersaline bacterial mats from Baja California, Mexico, revealed that sulfate reduction occurred consistently within the well-oxygenated photosynthetic zone of the mats. This evidence that dissimilatory sulfate reduction can occur in the presence of O2 challenges the conventional view that sulfate reduction is a strictly anaerobic process. At constant temperature, the rates of sulfate reduction in oxygenated mats during daytime were similar to rates in anoxic mats at night: thus, during a 24-hour cycle, variations in light and O2 have little effect on rates of sulfate reduction in these mats.

The Archean sulfur cycle and the early history of atmospheric oxygen.

The isotope record of sedimentary sulfides can help resolve the history of oxygen accumulation into the atmosphere. We measured sulfur isotopic fractionation during microbial sulfate reduction up to 88 degrees C and show how sulfate reduction rate influences the preservation of biological fractionations in sediments. The sedimentary sulfur isotope record suggests low concentrations of seawater sulfate and atmospheric oxygen in the early Archean (3.4 to 2.8 billion years ago). The accumulation of oxygen and sulfate began later, in the early Proterozoic (2.5 to 0.54 billion years ago).

Comparative Earth history and Late Permian mass extinction.

The repeated association during the late Neoproterozoic Era of large carbon-isotopic excursions, continental glaciation, and stratigraphically anomalous carbonate precipitation provides a framework for interpreting the reprise of these conditions on the Late Permian Earth. A paleoceanographic model that was developed to explain these stratigraphically linked phenomena suggests that the overturn of anoxic deep oceans during the Late Permian introduced high concentrations of carbon dioxide into surficial environments. The predicted physiological and climatic consequences for marine and terrestrial organisms are in good accord with the observed timing and selectivity of Late Permian mass extinction.

The global carbon cycle: a test of our knowledge of earth as a system.

Motivated by the rapid increase in atmospheric CO2 due to human activities since the Industrial Revolution, several international scientific research programs have analyzed the role of individual components of the Earth system in the global carbon cycle. Our knowledge of the carbon cycle within the oceans, terrestrial ecosystems, and the atmosphere is sufficiently extensive to permit us to conclude that although natural processes can potentially slow the rate of increase in atmospheric CO2, there is no natural "savior" waiting to assimilate all the anthropogenically produced CO2 in the coming century. Our knowledge is insufficient to describe the interactions between the components of the Earth system and the relationship between the carbon cycle and other biogeochemical and climatological processes. Overcoming this limitation requires a systems approach.

Mesophilic microorganisms build terrestrial mats analogous to Precambrian microbial jungles.

Development of Archean paleosols and patterns of Precambrian rock weathering suggest colonization of continents by subaerial microbial mats long before evolution of land plants in the Phanerozoic Eon. Modern analogues for such mats, however, have not been reported, and possible biogeochemical roles of these mats in the past remain largely conceptual. We show that photosynthetic, subaerial microbial mats from Indonesia grow on mafic bedrocks at ambient temperatures and form distinct layers with features similar to Precambrian mats and paleosols. Such subaerial mats could have supported a substantial aerobic biosphere, including nitrification and methanotrophy, and promoted methane emissions and oxidative weathering under ostensibly anoxic Precambrian atmospheres. High C-turnover rates and cell abundances would have made these mats prime locations for early microbial diversification. Growth of landmass in the late Archean to early Proterozoic Eons could have reorganized biogeochemical cycles between land and sea impacting atmospheric chemistry and climate.

Bioturbation and directionality in Earth's carbon isotope record across the Neoproterozoic-Cambrian transition.

Mixing of sediments by moving animals becomes apparent in the trace fossil record from about 550 million years ago (Ma), loosely overlapping with the tail end of the extreme carbonate carbon isotope δ13 Ccarbonate fluctuations that qualitatively distinguish the Proterozoic geochemical record from that of the Phanerozoic. These Precambrian-scale fluctuations in δ13 Ccarbonate (PSF-δ13 Ccarbonate ) remain enigmatic, due to their high amplitude and inclusion of global-scale negative δ13 Ccarbonate values, below anything attributable to mantle input. Here, we note that different biogeochemical-model scenarios plausibly explaining globally synchronous PSF-δ13 Ccarbonate converge: via mechanistic requirements for extensive anoxia in marine sediments to support sedimentary build-up of 13 C-depleted carbon. We hypothesize that bioturbation qualitatively reduced marine sediment anoxia by exposing sediments to oxygenated overlying waters, which ultimately contributed to decreasing the carbon cycle's subsequent susceptibility to PSF- δ13 Ccarbonate . Bioturbation may also have reduced the quantity of (isotopically light) organic-derived carbon available to contribute to PSF- δ13 Ccarbonate via ocean crust carbonatization at depth. We conduct a comparative modelling exercise in which we introduce bioturbation to existing model scenarios for PSF- δ13 Ccarbonate : expressing both the anoxic proportion of marine sediments, and the global organic carbon burial efficiency, as a decreasing function of bioturbation. We find that bioturbation's oxygenating impact on sediments has the capacity to prevent PSF- δ13 Ccarbonate caused by authigenic carbonate precipitation or methanogenesis. Bioturbation's impact on the f-ratio via remineralization is partially offset by liberation of organic phosphate, some of which feeds back into new production. We emphasize that this study is semiquantitative, exploratory and intended merely to provide a qualitative theoretical framework within which bioturbation's impact on long-term, first-order δ13 Ccarbonate can be assessed (and it is hoped quantified in more detail by future work). With this proviso, we conclude that it is entirely plausible that bioturbation made a decisive contribution to the enigmatic directionality in the δ13 Ccarbonate record, from the Neoproterozoic-Cambrian boundary onwards.

Evidence of oxygenic phototrophy in ancient phosphatic stromatolites from the Paleoproterozoic Vindhyan and Aravalli Supergroups, India.

Fossil microbiotas are rare in the early rock record, limiting the type of ecological information extractable from ancient microbialites. In the absence of body fossils, emphasis may instead be given to microbially derived features, such as microbialite growth patterns, microbial mat morphologies, and the presence of fossilized gas bubbles in lithified mats. The metabolic affinity of micro-organisms associated with phosphatization may reveal important clues to the nature and accretion of apatite-rich microbialites. Stromatolites from the 1.6 Ga Chitrakoot Formation (Semri Group, Vindhyan Supergroup) in central India contain abundant fossilized bubbles interspersed within fine-grained in situ-precipitated apatite mats with average δ13 Corg indicative of carbon fixation by the Calvin cycle. In addition, the mats hold a synsedimentary fossil biota characteristic of cyanobacterial and rhodophyte morphotypes. Phosphatic oncoid cone-like stromatolites from the Paleoproterozoic Aravalli Supergroup (Jhamarkotra Formation) comprise abundant mineralized bubbles enmeshed within tufted filamentous mat fabrics. Construction of these tufts is considered to be the result of filamentous bacteria gliding within microbial mats, and as fossilized bubbles within pristine mat laminae can be used as a proxy for oxygenic phototrophy, this provides a strong indication for cyanobacterial activity in the Aravalli mounds. We suggest that the activity of oxygenic phototrophs may have been significant for the formation of apatite in both Vindhyan and Aravalli stromatolites, mainly by concentrating phosphate and creating steep diurnal redox gradients within mat pore spaces, promoting apatite precipitation. The presence in the Indian stromatolites of alternating apatite-carbonate lamina may result from local variations in pH and oxygen levels caused by photosynthesis-respiration in the mats. Altogether, this study presents new insights into the ecology of ancient phosphatic stromatolites and warrants further exploration into the role of oxygen-producing biotas in the formation of Paleoproterozoic shallow-basin phosphorites.

Hematopoietic stem cells with high proliferative potential. Assay of their concentration in marrow by the frequency and duration of cure of W/Wv mice.

THIS STUDY WAS DESIGNED TO APPROACH TWO PRIMARY QUESTIONS CONCERNING HEMATOPOIETIC STEM CELLS (HSC) IN MICE: what is the concentration of HSC with extensive proliferative potential in marrow, and how long can an HSC continue to function in an intact animal? The assay system was the W/W(v) mouse, a mouse with an inherited HSC defect, reflected in a reduction in all myeloid tissue and most particularly in a macrocytic anemia.A single chromosomally marked HSC will reconstitute the defective hematopoietic system of the W/W(v). The concentration of HSC in normal littermate (+/+) marrow was assayed by limiting dilution calculation using cure of W/W(v) as an end point (correction of anemia and erythrocytes' macrocytosis) and found to be approximately 10/10(5). This is significantly less than spleen colony forming cell (CFU-S) concentration: approximately 220/10(5) in +/+ and ranging from 50 to 270/10(5) in various other studies. Blood values were studied at selected intervals for as long as 26 mo. Of 24 initially cured mice, which were observed for at least 2 yr, 75% remained cured. However, of all cured mice, 17 lost the cure, returning to a macrocytic anemic state. Cured mice had normal numbers of nucleated and granulocytic cells per humerus and a normal concentration of CFU-S. However, cure of secondary W/W(v) recipients by this marrow was inefficient compared with the original +/+ marrow. These studies suggest the CFU-S assay over-estimates extensively proliferating HSC or perhaps does not assay such a cell. A single such HSC can not only cure a W/W(v), but can sustain the cure for 2 yr or more, despite a relative deficit of cells capable of curing other W/W(v). However, the duration of sustained cure may be finite.

A trophic framework for animal origins.

Metazoans emerged in a microbial world and play a unique role in the biosphere as the only complex multicellular eukaryotes capable of phagocytosis. While the bodyplan and feeding mode of the last common metazoan ancestor remain unresolved, the earliest multicellular stem-metazoans likely subsisted on picoplankton (planktonic microbes 0.2-2 µm in diameter) and dissolved organic matter (DOM), similarly to modern sponges. Once multicellular stem-metazoans emerged, they conceivably modulated both the local availability of picoplankton, which they preferentially removed from the water column for feeding, and detrital particles 2-100 µm in diameter, which they expelled and deposited into the benthos as waste products. By influencing the availability of these heterotrophic food sources, the earliest multicellular stem-metazoans would have acted as ecosystem engineers, helping create the ecological conditions under which other metazoans, namely detritivores and non-sponge suspension feeders incapable of subsisting on picoplankton and DOM, could emerge and diversify. This early style of metazoan feeding, specifically the phagocytosis of small eukaryotic prey, could have also encouraged the evolution of larger, even multicellular, eukaryotic forms less prone to metazoan consumption. Therefore, the first multicellular stem-metazoans, through their feeding, arguably helped bridge the strictly microbial food webs of the Proterozoic Eon (2.5-0.541 billion years ago) to the more macroscopic, metazoan-sustaining food webs of the Phanerozoic Eon (0.541-0 billion years ago).

Evidence of molybdenum association with particulate organic matter under sulfidic conditions.

The geochemical behavior of molybdenum (Mo) in the oceans is closely linked to the presence of sulfide species in anoxic environments, where Fe availability may play a key role in the Mo scavenging. Here, we show that Mo(VI) is reduced in the presence of particulate organic matter (represented by sulfate-reducing bacteria). Molybdenum was immobilized at the surface of both living cells and dead/lysed cells, but not in cell-free control experiments. Experiments were carried out at four different Mo concentrations (0.1 to 2 mm) to yield cell-associated Mo precipitates with little or no Fe, consisting of mainly Mo(IV)-sulfide compounds with molecular structures similar to Mo enzymes and to those found in natural euxinic sediments. Therefore, we propose that Mo removal in natural sulfidic waters can proceed via a non-Fe-assisted pathway that requires particulate organic matter (dead or living sulfate-reducing bacteria). This pathway has implications for global marine Mo cycling and the current use of Mo-based proxies for paleo-environmental investigations.

Measuring acne using Coproporphyrin III, Protoporphyrin IX, and lesion-specific inflammation: an exploratory study.

Propionibacterium acnes: (P. acnes) produce Porphyrins; however, fluorescence measurement of Porphyrins from Ultraviolet-A (UVA) images has failed to establish a correlation. Acne clinical research and imaging has ignored the spectral excitation-emission characteristics and the exact pattern of the Porphyrins synthesized by P. acnes. In this exploratory study, for the first time, the possible relationships of Coproporphyrin III (CpIII) and Protoporphyrin IX (PpIX) fluorescence as well as acne lesion-specific inflammation measurements with clinical signs of acne are investigated. Furthermore, the sensitivity of these measurements in tracking and differentiating the known treatment effects of Benzoyl Peroxide (BPO) 5%, and combination of Clindamycin + BPO are also evaluated. Comedonal and papulopustular lesions identified by investigators during a live assessment of 24 mild-to-severe acne subjects were compared with fluorescence and inflammation measurements obtained from analysis of VISIA®-CR images. CpIII fluorescence spots showed a strong correlation (r = 0.69-0.83), while PpIX fluorescence spots showed a weak correlation (r = 0.19-0.27) with the investigators' comedonal lesion counts. A strong correlation was also observed between the investigators' papulopustular lesion counts and acne lesion-specific inflammation (r = 0.76). Our results suggest that CpIII fluorescence and acne lesion-specific-inflammation measurement can provide objective indication of comedonal and papulopustular acne severity, respectively. Furthermore, these measurements may be more sensitive and specific in evaluating treatment effects and early signs of acne lesion progression compared to investigators' lesion counts.

Carbon isotope fractionation by anoxygenic phototrophic bacteria in euxinic Lake Cadagno.

Anoxygenic phototrophic bacteria utilize ancient metabolic pathways to link sulfur and iron metabolism to the reduction of CO2 . In meromictic Lake Cadagno, Switzerland, both purple sulfur (PSB) and green sulfur anoxygenic phototrophic bacteria (GSB) dominate the chemocline community and drive the sulfur cycle. PSB and GSB fix carbon utilizing different enzymatic pathways and these fractionate C-isotopes to different extents. Here, these differences in C-isotope fractionation are used to constrain the relative input of various anoxygenic phototrophs to the bulk community C-isotope signal in the chemocline. We sought to determine whether a distinct isotopic signature of GSB and PSB in the chemocline persists in the settling fraction and in the sediment. To answer these questions, we also sought investigated C-isotope fractionation in the water column, settling material, and sediment of Lake Cadagno, compared these values to C-isotope fractionation of isolated anoxygenic phototroph cultures, and took a mass balance approach to investigate relative contributions to the bulk fractionation signature. We found a large C-isotope fractionation between dissolved inorganic carbon (DIC) and particulate organic carbon (POC) in the Lake Cadagno chemocline. This large fractionation between the DIC and POC was also found in culture experiments carried out with anoxygenic phototrophic bacteria isolated from the lake. In the Lake Cadagno chemocline, anoxygenic phototrophic bacteria controlled the bulk C-isotope fractionation, but the influence of GSB and PSB differed with season. Furthermore, the contribution of PSB and GSB to bulk C-isotope fractionation in the chemocline could be traced in the settling fraction and in the sediment. Taken together with other studies, such as lipid biomarker analyzes and investigations of other stratified lakes, these results offer a firmer understanding of diagenetic influences on bacterial biomass.

Mass spectrometric data characteristics of commonly abused amphetamines with sequential derivatization at two active sites.

There have been reports on improved chromatographic parameters derived from the incorporation of sequential derivatization in preparing biological specimens for the analysis of opiates. This current study was designed to characterize the mass spectrometric data resulting from sequential derivatizations of commonly abused amphetamines (along with all commercially available deuterated analogs) containing two active sites, i.e., amphetamine, methylenedioxyamphetamine, phenylpropanolamine. The first derivatization groups included in this study were trifluoroacetyl, pentafluoropropionyl, and heptafluorobutyryl, while t-butyldimethylsilyl was used as the second derivatization group. Products resulting from the first step and the two-step derivatization processes were analyzed by GC-MS. Full-scan mass spectrometric data were used to select ions with potential for designating the analytes and their respective isotopically labeled analogs in quantitative analysis protocols. Selected ion monitoring data were then collected and assessed to determine the quality of these ions when one or two different derivatization groups were incorporated in the sample preparation processes. A total of 77 full-scan mass spectra and 8 ion intensity cross-contribution tables, representing various forms of derivatization and isotopic analogs of the three amphetamines, are systematically presented for reference. Evaluations of these data concluded that many, but not all, products derived from "double derivatization" (sequential derivatization with two derivatization groups), generate ions of higher quality than those derived from "single derivatization".

Safety of airway gene transfer with Ad2/CFTR2: aerosol administration in the nonhuman primate.

In this study, the safety and efficacy of aerosol delivery to non-human primates of an adenoviral vector encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) were evaluated. The technique of concurrent flow spirometry was used to determine the deposited dose of Ad2/CFTR-2, which ranged from 3 to 8 x 10(10) I.U. Transgene DNA was detected by the polymerase chain reaction (PCR) in lung tissue from all treated animals, and human CFTR mRNA was detected on days 3, 7, and 21 post-exposure. The treatment was well tolerated, with no evidence of respiratory distress. Histologic changes in the lungs from Ad2/CFTR-2-treated animals were mild and, overall, indistinguishable from animals exposed to aerosolized vehicle. One vector-treated animal demonstrated an increase in lavage lymphocyte numbers 3 days after treatment and another had an abnormal chest radiograph 14 days after treatment. A third vector-treated animal had histologic evidence of a bronchointerstitial pneumonia 7 days after aerosol treatment that resolved by day 21. This study demonstrated that Ad2/CFTR-2 can effectively be delivered to the lungs of nonhuman primates and result in minimal adverse effects.

Group teaching of auscultation. Use of a new wireless stethoscope-type headphone.

A new technique using infrared light for the transmission of heart sounds and murmurs is described. This method enables the simultaneous transmission of heart sounds and murmurs to large groups of persons without the need for hard-wire connections to the amplifying device. The method facilitates teaching of cardiac auscultation at the bedside as well as in the setting of conferences, seminars or postgraduate education programs.

Pharmacological characterization of amine receptors on embryonic chick sensory neurones.

The effects of noradrenaline, dopamine and 5-hydroxytryptamine were investigated on the duration of the action potential of embryonic chick sensory neurones in vitro. All three amines, like gamma-aminobutyric acid, decreased the duration of the action potential evoked by current injection. The onset of the noradrenaline-induced decrease in action potential duration was fast (less than 1s) and the recovery phase was dependent upon the dose of noradrenaline applied. Rapid washout of the noradrenaline revealed a minimum 30s recovery time which was independent of the initial noradrenaline concentration. Dopamine and 5-hydroxytryptamine could mimic the effects of noradrenaline on action potential duration. The ED50 for all three amines was approximately 1 microM. At a saturating concentration of 10 microM, noradrenaline was more potent than dopamine and 5-hydroxytryptamine. Saturating doses of noradrenaline and dopamine or 5-hydroxytryptamine were not additive. Responses to all three amines were affected similarly by antagonists: they were antagonized by yohimbine, phentolamine, haloperidol and mianserin but not by propranolol, prazosin, domperidone, spiperone or methysergide. Clonidine and xylazine (alpha 2-adrenoceptor agonists) were also without effect. In contrast to the amines, saturating concentrations of gamma-aminobutyric acid were additive with those of noradrenaline. Responses to GABA were not antagonized by the amine receptor antagonists. The evidence described here suggests that the amines and gamma-aminobutyric acid acid decrease sensory neurone action potential duration via pharmacologically-distinct membrane receptors. In addition, it is likely that the amines are acting via a single class of receptor whose pharmacology is different from classical adrenoceptors, dopamine receptors and 5-hydroxytryptamine receptors.