Photoaging and topical tretinoin: therapy, pathogenesis, and prevention

Repeated exposure to UV radiation from the sun causes premature skin aging. This photoaging is characterized by wrinkles, mottled pigmentations, dry and rough skin, and loss of skin tone. Since the clinical demonstration that the use of topical tretinoin can improve photoaged skin, a great deal of knowledge that may explain wrinkle effacement has been acquired. Central to this pursuit has been dermal collagen. In this article, we summarize evidence (mainly from humans) that implicates a deficiency of superficial dermal collagen as the cause of the dermal aspects of photoaging. In addition, a mechanism through which UV radiation can lead to reduced collagen is presented. Through our understanding of the pathophysiological mechanism of photoaging, our ability to treat and possibly prevent this skin condition is enhanced.     

Open questions in photobiology. IV. Photoaging of the skin

Two isoforms of troponin C (TnC) are encoded by distinct single copy genes. Expression of fast TnC is restricted to the skeletal muscle, whereas the slow isoform is expressed in both skeletal and cardiac muscle. Chicken slow TnC (cTnC) gene is also expressed in some non-muscle tissues like the liver and the brain. Expression of cTnC gene is regulated by two distinct enhancers in cardiac and skeletal muscles. The cardiac specific enhancer is located in the immediate 5' flanking region (bp-124 to -79) of the murine cTnC gene whereas the skeletal enhancer is located within the first intron (bp 997 to 1141). In the present study we have examined how cTnC gene expression is regulated in the chicken liver. Transient transfection of liver cells with CTnC-CAT reporter constructs containing various regions of the murine cTnC gene showed that its expression in chicken liver is regulated by the cardiac specific enhancer. Furthermore, electrophoretic mobility shift assays using synthetic oligonucleotides corresponding to both CEF-1 and CEF-2 regions of the murine cardiac enhancer revealed formation of specific DNA-protein complexes. Ultraviolet light induced covalent linking of nuclear proteins to CEF-1 and CEF-2 oligomers were used to examine the nature of the cardiac enhancer binding polypeptides; one polypeptide of 48 kDa appeared to bind to both CEF-1 and CEF-2 sequences.     

Effect of topical tretinoin under occlusion on atypical naevi

Atypical naevi are potential precursors of melanoma and markers of increased melanoma risk. To examine the possibility of chemoprevention of melanoma by retinoids, we studied the effect of topical tretinoin 0.1% (all-transretinoic acid; vitamin A acid) and tretinoin 0.1% with hydrocortisone on atypical naevi. Thirty patients with atypical naevi were enrolled in a prospective randomized double blind study. For each patient three comparable naevi were selected and randomized to receive tretinoin 0.1% (T), tretinoin 0.1% with hydrocortisone 1% (C) or a placebo cream (P) once a week under Actiderm occlusion for 4 months. Baseline views of the naevi, taken with a videomicroscope (magnification 20 x), were assessed for morphological changes compared with views taken 2 months after the beginning of treatment, 1 week after completion of treatment and 6 months later. After completion of the study all naevi in the T and C groups and six naevi in the P group were removed and evaluated histologically for the presence of atypia. The number of naevi that had changed in colour or size was significantly higher in the T and C groups compared with the placebo group. A size reduction took place in 42.9% (T) and 40.0% (C) of the naevi and the colour changed in 75.0% (T) and 66.7% (C). The effect of treatment, in general subtle, did not differ significantly between groups T and C, but naevi treated with C became significantly less irritated. Histologically, 75.0% of the naevi treated with T and 69.6% of the naevi treated with C were atypical. Therefore, no major change was seen in the clinical aspect of atypical naevi after treatment with tretinoin 0.1% or tretinoin with hydrocortisone 1%, and most of the treated naevi still met the histological criteria for atypia after the treatment period. The current management of follow-up of atypical naevi and excision when change to melanoma is suspected is therefore still recommended. Nevertheless, some response was seen, which may justify a further exploration of tretinoin and hydrocortisone 1% therapy for a longer treatment period in combination with research to clarify its mechanism.     

Pyogenic granuloma-like lesions in a patient using topical tretinoin

A 16-year-old male developed numerous pyogenic granuloma like-lesions across his neck, chest and back after 6 weeks isotretinoin therapy for cystic acne. The isotretinoin was ceased and he was commenced on oral steroids. After 6 weeks, the lesions were almost completely healed. However, due to worsening comedonal acne, the patient was commenced on topical tretinoin cream 0.05% twice daily to his chest. He was reviewed 2 weeks later and, surprisingly, 2 new pyogenic granuloma-like lesions had developed on his chest. These lesions persisted until the topical tretinoin was ceased 3 months later.     

Topical retinoic acid (tretinoin) for photoaging: conceptions and misperceptions

Sinusoidal rotation and rotational stimulation tests were used to examine vestibular function in guinea pigs. The results showed that there was no statistically significant difference in the mean number of nystagmus of semi-cycle sinusoidal rotation test and the duration of nystagmus of rotational stimulation test for both the control and test groups before treatment in albinos and pigmented guinea pigs. Meantime, daily subcutaneous injection of gentamicin 125 mg/kg body weight for 12 days in albinos and pigmented guinea pigs showed no significant change in vestibular function until the 7th day of treatment. Significant impairment of vestibular function was noticed on the 10th treatment day. At 5 days after treatment vestibular impairment reached its maximum and minimal recovery was seen at 14 days after treatment. No Further improvement of vestibular function was noticed three months after treatment. The methods are feasible and reliable.     

Treatment of photodamaged skin with topical tretinoin: an update

The utility of topical tretinoin in combination with sun protection has now been formally established as a useful approach to the treatment of sun-damaged skin. The early observations of our group have been confirmed in numerous well controlled clinical trials. Moreover, a great deal is known about structural and even molecular changes induced by topical tretinoin, which account for the clinical benefits achieved by this agent. A great deal has been learned in a very short period of time, and these findings represent another major use of retinoid therapy in dermatologic disease.     

CD95 predicts responsiveness to tretinoin in acute promyelocytic leukemia

We describe a predictive marker (CD95) for the responsiveness to tretinoin (RA) in acute promyelocytic leukemia (APL). Functional CD95 expression during RA treatment have been observed only in those patients who responded to RA. Expression of CD95 (Fas antigen), which plays a major role in apoptosis, was determined by fluorescence activated cell sorter (FACS) analysis. APL cases in which no enhancement of CD95 expression was observed showed no response to RA and did not obtain complete remission. We propose that CD95 can predict the clinical response to RA probably due to differentiation.     

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.     

Efficacy and safety of azelaic acid and glycolic acid combination therapy compared with tretinoin therapy for acne

We conducted a 12-week, multicenter, randomized, double-masked, parallel-group study of the efficacy, safety, and tolerability of azelaic acid 20% cream and glycolic acid lotion compared with tretinoin 0.025% cream and a vehicle lotion to treat mild-to-moderate facial acne vulgaris. Patients treated with azelaic/glycolic acid experienced a significantly greater reduction in the number of papules, as well as a greater reduction in the number of inflammatory lesions, than those treated with tretinoin. Overall global improvement was approximately 25% in both groups. In the physician evaluations, treatment with azelaic/glycolic acid was found to cause significantly less dryness, scaling, and erythema than tretinoin. Patients also reported significantly less dryness, redness, and peeling with azelaic/glycolic acid. Significantly more patients in the azelaic/glycolic acid group than the tretinoin group reported that they felt attractive. The combination of azelaic acid and glycolic acid is a useful alternative to tretinoin, being at least as efficacious as the latter, while offering a superior tolerability and patient approval profile.     

Pretreatment of photoaged forearm skin with topical tretinoin accelerates healing of full-thickness wounds

Pretreatment of skin with all-trans retinoic acid (tretinoin) has been shown to enhance wound healing. Previous studies have mainly used animal models to demonstrate this effect. We wanted to determine whether pretreatment could promote wound healing in severely photoaged dorsal forearm skin. Four elderly men with severely actinically damaged forearms were treated daily for 16 weeks. One arm was treated with 0.05-0.1% tretinoin cream (Retin A, Ortho), and the other with Purpose cream (Ortho) as a vehicle control. Four-millimetre punch biopsies were taken from both dorsal forearms prior to treatment. After 16 weeks, full-thickness 2-mm punch biopsies were taken from both sides. Serial photographs were taken, and healing of the wounds quantitatively assessed by image analysis. On the 11th day, the wounds were excised using a 4-mm biopsy punch. Biopsies were processed for light microscopy. After 16 weeks, the tretinoin-treated forearms showed moderate erythema and scaling. Polarized light photographs revealed multiple, red, vascularized foci and/or a diffuse network of small vessels. The histological effects were typical for tretinoin, i.e. compaction of the stratum corneum, epidermal acanthosis with correction of atypia, an increase in small vessels, and increased cellularity in the upper dermis. Purpose cream had no effect, either clinically or histologically. On the tretinoin-treated side, the wound areas were 35-37% smaller on days 1 and 4, and 47-50% smaller on days 6, 8, 11, compared with the controls. Clinically and histologically, reepithelialization occurred more rapidly. Thus tretinoin dramatically accelerated wound healing in photodamaged skin.     

Keratinizing dermatoses. Combined data from four centers on short-term topical treatment with tretinoin

In four medical centers, 40 patients with keratinizing dermatoses were treated with topical tretinoin (vitamin A acid) 0.1% cream and salicylic acid 2% cream in a short-term, double-blind study. Tretinoin was the more effective treatment for several of the keratinizing dermatoses with the exception of palmar-plantar hyperkeratosis, for which it was not effective in the concentration and method of application used. The most striking clinical responses occurred in patients with lamellar ichthyosis and ichthyosis vulgaris. Local adverse reactions-chiefly pruritus, erythema, burning, excoriation, and irritation-were not severe and could be controlled by modification of the treatment regimen.     

Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study

BACKGROUND: The addition of polyolprepolymer-2 in tretinoin formulations may reduce tretinoin-induced cutaneous irritation. OBJECTIVE: This study compared the efficacy and safety of a new 0.025% tretinoin gel containing polyolprepolymer-2, its vehicle, and a commercially-available 0.025% tretinoin gel in patients with mild to moderate acne vulgaris. METHODS: In this 12-week multicenter, double-blind, parallel group study, efficacy was evaluated by objective lesion counts and the investigators' global evaluations. Subjective assessment of cutaneous irritation by the investigators and patients evaluated safety. RESULTS: The efficacy of the two active treatments in this 215 patient study was comparable, and both treatments were statistically significantly more effective than vehicle. When compared with the commercially-available tretinoin gel, the formulation containing polyolprepolymer-2 demonstrated statistically significantly less peeling at days 28, 56, and 84, statistically significantly less dryness by day 84, and statistically significantly less itching at day 14. Irritation scores for the formulation containing polyolprepolymer-2 were numerically lower but not statistically different from those of the commercially-available gel for erythema and burning. The number of cutaneous and noncutaneous adverse events were similar for both active medications. CONCLUSION: The two 0.025% gels studied demonstrated comparable efficacy. However, the gel formulation containing polyolprepolymer-2 caused significantly less peeling and drying than the commercially-available formulation by day 84 of the study.     

Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris

BACKGROUND: Preclinical study and human patch tests indicate polyolprepolymer-2 may reduce cutaneous tretinoin-induced irritation. OBJECTIVE: This study compared the clinical efficacy and safety of a 0.025% tretinoin cream containing polyolprepolymer-2 and its vehicle to a commercially-available 0.025% tretinoin cream. METHODS: In this 12-week multicenter, double-blind, parallel group study in patients with mild to moderate acne, objective lesion counts and the investigators' global evaluations evaluated efficacy. Subjective evaluations of skin irritation were used to study safety. RESULTS: A total of 271 patients were enrolled. The active treatments demonstrated comparable efficacy that was statistically significantly greater than that of the vehicle. Safety evaluations of cutaneous and noncutaneous adverse events also indicated comparable results of the active treatments. CONCLUSION: The commercially-available 0.025% tretinoin cream and the 0.025% tretinoin cream containing polyolprepolymer-2 demonstrated comparable efficacy and safety.     

Voices of fear and anxiety and sadness and depression: The effects of speech rate and loudness on fear and anxiety and sadness and depression.

Two studies investigated the role of expressive vocal behavior (specifically, speech rate and loudness) in fear and anxiety and in sadness and depression. In the 1st study, participants spoke about personally experienced fear and anxiety-arousing and neutral events using 3 different voice styles: fast and loud, normal, and slow and soft. In the 2nd study, participants spoke about personally experienced sad or depressing and neutral events using the same 3 voice styles. In both studies, the participants' highest levels of subjective affective and cardiovascular (CV) arousal occurred when they spoke about the emotional events in a mood-congruent voice style: fast and loud in the case of fear and anxiety, and slow and soft in the case of sadness or depression. Mood-incongruent voice styles canceled the heightened levels of CV arousal normally associated with these negative emotions. The voice-style manipulation had no significant effect on the participants' levels of CV arousal during the neutral discussions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spondylolysis and spondylolisthesis and sports

Spondylolysis and spondylolisthesis occur predominantly in the lower lumbar spine. Besides congenital defects such as predisposition of spondylolysis the correlation between competitive sports activities and an increased incidence of spondylolysis is proved. In early stages, complete healing can be achieved by conservative treatment (abstinence from sports activities for 3 months, orthesis). Persistence of pain, neurologic symptoms and progression of vertebral slipping are indications for operative treatment (reconstruction of the isthmus, dorso-ventral spondylodesis). The exercise tolerance depends on the extent of instability, progression of vertebral slipping and clinical symptoms. The limits of exercise tolerance vary among the individual athletes and require the decision of the physician. Backstroke swimming, abdominal and back muscle strengthening exercises, and types of sport involving smooth movements are advisable. Sports education in school is possible without restriction in patients with stable spondylolysis and in those with spondylolisthesis without unfavourable concomitant factors.     

Synthesis and analysis of mixed chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans and assessment of formation and occurrence of the fluorinated and chlorinated-fluorinated dibenzo-p-dioxins and dibenzofurans

Despite the use of multimodal therapy, higher-grade glioma is still uniformly fatal in the adult population. There is a considerable difference between the length of survival in each given patient, even within the same tumor type and malignancy grade group, suggesting that there are factors that might differentially influence outcome. To identify such factors, 107 patients with anaplastic or malignant glioma were retrospectively investigated. Clinical parameters and paraclinical data on the p53, mdm2, and EGFR genes at the DNA or protein level were evaluated by univariate analysis and Cox proportional hazards regression modeling. Kaplan-Meier survival estimation demonstrated that immunohistochemical positivity for mdm2 protein in patients with anaplastic astrocytoma or with glioblastoma multiforme was associated with a shorter survival time (p = 0.02). P53 gene mutations and immunopositivity for the epidermal growth factor receptor (EGFR) protein were not significantly related to poor prognosis. The Cox proportional hazards model revealed immunohistochemical positivity for p53, mdm2, or for both of them, the presence of postoperative irradiation, and the extent of surgical resection of tumor to be variables significantly associated with prolonged survival. EGFR overexpression, age over 60 years, and Karnofsky performance score below 40 points did not significantly shorten survival time. In conclusion, the present study identified immunohistochemically detected mdm2-protein overexpression as a statistically significant negative prognostic parameter in patients bearing anaplastic or malignant glioma. Association analysis of variables revealed a possible correlation between mdm2 and p53, which is also consistent with the biological interaction mode of both proteins in vivo.     

Sexuality and aging--usual and successful

BACKGROUND: As aging research increasingly reflects an effort to dissociate true time-driven changes from those that can be improved, sexuality in later life remains largely unexplored. Several problems are evident. There is a lack of normative data, a lack of a conceptual framework relating to the biology, psychology, and sociology of sex, and an attitudinal resistance that obscures the entire topic. METHODS: We conducted a three-part instructional series on major topics involved with sexuality and aging. We surveyed our group of attendees (n 158, average age 68 for males, 65 for females) before and after the series. RESULTS: A remarkably robust sex life was evidenced by both the men and the women, even until advanced old age. Yet, a substantially decreased involvement was reported from 10 years earlier. Despite current activities, people of both sexes wished they were participating even more than they currently were. Impotency was identified as the major negative feature for the men; relationship problems were for the women. A questionnaire 6 months after the series reported improved sexual attitudes, but no change in sexual activities from the earlier survey. CONCLUSION: Sexuality is a major quality-of-life issue which persists into old age. Our study showed that the usual sexual practices reported by our group were not considered by them to be ideal. The intervention of this instructional series provided improved sexual attitudes but not performance. Additional studies are encouraged.     

Larks and owls and health, wealth, and wisdom

OBJECTIVE: To test the validity of Benjamin Franklin's maxim "early to bed and early to rise makes a man healthy, wealthy, and wise." DESIGN: Cross sectional analysis of sleeping patterns in a nationally representative group of elderly people, and longitudinal investigation of mortality. SETTING: Eight areas in Britain (five in England, two in Scotland, and one in Wales). SUBJECTS: 1229 men and women aged 65 and over who in 1973-4 had taken part in a survey funded by the Department of Health and Social Security and for whom data on sleeping patterns, health, socioeconomic circumstances, and cognitive function had been recorded. MAIN OUTCOME MEASURES: Self reported income, access to a car, standard of accommodation, performance on a test of cognitive function, state of health and mortality during 23 years of follow up. RESULTS: 356 people (29%) were defined as larks (to bed before 11 pm and up before 8 am) and 318 (26%) were defined as owls (to bed at or after 11 pm and up at or after 8 am). There was no indication that larks were richer than those with other sleeping patterns. On the contrary, owls had the largest mean income and were more likely to have access to a car. There was also no evidence that larks were superior to those with other sleeping patterns with regard to their cognitive performance or their state of health. Both larks and owls had a slightly reduced risk of death compared with the rest of the study sample, but this was accounted for by the fact that they spent less time in bed at night. In the study sample as a whole, longer periods of time in bed were associated with increased mortality. After adjustment for age, sex, the presence of illness, and other risk factors, people who spent 12 or more hours in bed had a relative risk of death of 1.7 (1.2 to 2.5) compared with those who were in bed for 9 hours. The lowest risk occurred in people who spent 8 hours in bed (adjusted relative risk 0.8; 0.7 to 1.0). CONCLUSION: These findings do not support Franklin's claim. A "late to bed and late to rise" lifestyle does not seem to lead to socioeconomic, cognitive, or health disadvantage, but a longer time spent in bed may be associated with increased mortality.