Selective induction of apoptosis in the hamster flank sebaceous gland organ by a topical liposome 5-α-reductase inhibitor: A treatment strategy for acne

Acne is a very widespread cosmesis problem. Isotretinoin, a synthetic oral retinoid is used to treat acne, which is androgen dependent. Numerous side-effects occur from this treatment. 5-α-Reductase plays a critical role in normal and pathological androgen-dependent processes. We have taken the approach to develop a selective, effective, topically-applied 5-α-reductase inhibitor to modify unwanted or pathological processes in the pilosebaceous unit such as acne. Toward this goal, we have previously developed a selective liposome hair follicle targeting system. We demonstrate in this report that the 5-α-reductase inhibitor N , N -diethyl-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide (4-MA) incorporated into liposomes induces apoptosis and inhibits growth of the dihydrotestosterone (DHT)-dependent hamster flank organ sebaceous gland. We have compared topical application of liposome 4-MA and solvent-formulated 4-MA and observed selective efficacy of topical application of liposome 4-MA by the reduction of size and induction of apoptosis only in the treated hamster flank organ. Apoptosis induced by liposome 4-MA in the treated flank organ sebaceous gland cells was observed both by assays for DNA fragments (transferase deoxytidyl uridine end labeling) and by observation of condensed and fragmented nuclei. When 4-MA was topically applied formulated in ethanol and glycerol without liposomes, the selective efficacy was lost. Liposome 4-MA did not significantly affect prostate weight, testosterone/DHT ratios or bodyweight gain compared to controls indicating safety as well as efficacy of topical application of liposome 4-MA for pathological processes such as acne.     

Physical exercise-associated gene expression signatures in peripheral blood.

OBJECTIVE: To assess response to physical stress, gene expression profiles in peripheral blood cells were analyzed using an original microarray carrying 1467 stress-responsive complementary DNA probes. DESIGN: Gene expression was analyzed at 4, 24, and 48 hours after exercising on a cycle ergometer at 60% VO2 max for 1 hour (aerobic exercise) or until exhausted (exhaustive exercise). SETTING: Institute of Health Biosciences, University of Tokushima Graduate School. PARTICIPANTS: Twelve healthy male students of the postgraduate or undergraduate school. INTERVENTIONS: The volunteers performed the aerobic or exhaustive exercise on a cycle ergometer. MAIN OUTCOME MEASUREMENTS: Detection of aerobic exercise-responsive or exhaustive exercise-responsive genes in peripheral blood cells. RESULTS: Aerobic and exhaustive exercise transiently changed the expression of 21 and 16 genes, respectively, with the peak at 4 hours. Only 2 genes significantly responded to both types of exercise. Exhaustive but not aerobic exercise produced a secondary response with significantly altered expression of 14 genes at 24 hours. Five of those genes encode receptors for neurotransmitters (HTR1A, CHRNB2, GABRB3, GABRG3, and LOC51289). CONCLUSIONS: The behavior of the individual genes shown here may be informative to objectively assess acute physical stress and exhaustion-associated responses.     

A review of the researches focusing on the heterogeneity of obsessive-compulsive disorder and its potential subtypes]

Recently, obsessive-compulsive disorder (OCD) is often conceptualized as a heterogeneous disorder. To verify and more fully understand this OCD heterogeneity, more homogeneous and potentially valid phenotypic methods are needed. If OCD subtypes can be characterized using distinct features of psychobiology, then this would account for the variance in clinical and neurobiological studies on biological markers, and would potentially impact on treatment strategies for each patient. Most of the work on OCD subtypes has taken a categorical approach. For instance, it has been suggested that some forms of OCD are etiologically related to tic disorders, and OCD with comorbid tics has been characterized by specific phenomenological, genetic, and neuro-imaging features and a differential treatment response. There have been other attempts to subdivide OCD categorically based on predominant compulsions (e.g., cleaning or checking), age at onset (e.g., early-or late-onset), gender, impulsive features, comorbidity, or insight. The dimensional approach regards OCD as being composed of sets of obsessive-compulsive symptom dimensions. In recent studies, factor analyses have provided consistent evidence that distinct obsessive-compulsive symptom dimensions exist, including obsessions/ checking, contamination/washing, symmetry/ordering, and hoarding. It has been hypothesized that each symptom dimension may be underpinned by a distinctive set of bio-behavioral mechanisms. Indeed, neuroimaging studies have suggested particular neural correlates for different symptom dimensions, and some genetic and family studies are also consistent with such a hypothesis. Further, symptom dimensions may predict treatment responses; for example, a higher hoarding dimension level has consistently been associated with a poorer treatment response to selective serotonin re-uptake inhibitors and cognitive-behavioral therapy. However, the dimensional structure of OCD symptoms is still not definitive, and the further standardization of methodological and analytic processes is also required. Thus, the relevance and limitations of each approach still remain to be discussed, and there is probably not one but several heuristic strategies that can be employed to identify more homogeneous OCD subtypes, which, when combined, may be, the most reasonable and useful method.     

Treatment of osmidrosis using the ultrasonic surgical aspirator

Numerous surgical methods have been introduced to treat osmidrosis. However, many problems with wound healing have been reported, including haematoma, seroma, skin necrosis and severe scarring. Ultrasound energy liquefies sweat glands via cavitation, but minimally affects blood vessels and nerves at the same energy level. Our patient was treated with ultrasonic surgical aspiration, which allowed the effective removal of the apocrine glands with little scarring. The ultrasonic surgical aspirator offers a safe and effective method to treat osmidrosis with few complications. This is the operation of first choice, especially for the patients who are sensitive about their surgical scars.     

Ulcerative lichen planus associated with Sjögren's syndrome

Ulcerative lichen planus is a rare variant of lichen planus that is characterized by ulcerations of the feet and toes that are accompanied by toenail loss. However, the nail, oral mucosa, genital mucosa and the scalp are also sometimes affected by ulcerative lichen planus. Several authors have drawn attention to the association of ulcerative lichen planus and autoimmune diseases. We report a patient who had ulcerative lichen planus, with ulcerative erythema on the soles and palms, nail dystrophy and oral lesions, as well as Sjögren's syndrome; she was successfully treated with etretinate.     

Recombinant Mycobacterium leprae protein associated with entry into mammalian cells of respiratory and skin components

BACKGROUNDS: The transmission of Mycobacterium leprae, the causative pathogen of leprosy, has been postulated to occur mainly through upper respiratory route rather than skin-to-skin contact via minor injuries. The M. leprae genome contains mce1A gene, which encodes a putative mammalian cell entry protein. However, to date, there have been no functional analyses of the M. leprae mce1A gene product. OBJECTIVE: The aim of this study was to elucidate a possible relationship between this transmission mechanism and the mce1A gene product. METHODS: We analyzed the cell uptake activity in vitro of polystyrene latex beads coated with a purified recombinant (r-) protein expressed by a 849-bp locus within the mce1A gene. RESULTS: The r-protein promoted uptake of the beads into human nasal epithelial cells derived from nasal polyps, human bronchial epithelial cell line, normal human dermal fibroblasts, normal human microvascular endothelial cells and normal human keratinocytes cultured at 0.01 mM extracellular calcium concentration [Ca]; no uptake occurred with keratinocytes cultured at 1.2mM [Ca]. CONCLUSION: These results suggest that the mce1A gene product can mediate M. leprae entry into respiratory epithelial cells as their natural target cells, which may be the main mode of transmission. Endothelial cells, on the other hand, may serve as the reservoir of the bacilli for long-term infection. The M. leprae Mce1A protein has potential important implications for mode of transmission and pathogenesis of leprosy.     

Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n  = 3) and 2 (0.12 mg/kg/day, n  = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35–65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab. ( Cancer Sci 2009; 100: 1344–1350)