Clinical and phototrichogrammatic evaluation of estradiol replacement therapy on hair growth in postmenopausal Japanese women with female pattern hair loss: a pilot study.

Background: Female pattern hair loss (FPHL) is known to present with characteristic pathological conditions, including reduced overall hair density. Female hormones affect hair condition; however, the detailed mechanism is unknown. Furthermore, research on the topic is complicated by the fact that senescent alopecia often occurs concurrently with FPHL. Therefore, we investigated the effect of estradiol, a female hormone, on hair growth by eliminating aging factors and objectively evaluating hair changes caused by female hormone replacement therapy (HRT). Objective: This study was conducted to elucidate the mechanism through which female hormones exert their effects on hair. Methods: The study included 11 female patients undergoing HRT who were evaluated before initiating HRT, 3 months after initiating HRT, and 6 months after initiating HRT. The thinning hair score, hair density, telogen hair rate, telogen plucking strength, hair growth rate, and hair thickness were measured and evaluated. Furthermore, hematological tests were performed to assess the general physical condition of the participants. Results: HRT increased the telogen hair rate (P = .010, paired t test) at 3 months, improved frontal hairline thinning score (P = .008, Wilcoxon test), and increased the plucking strength (P = .013, paired t test) at 6 months. Limitations: The limitation of this study included the relatively small sample size, inability to conduct further long-term tests because of participant burden, and lack of a control group. Conclusion: The results suggested that HRT improved the appearance of the frontal hairline. As few studies have analyzed the effects of female hormones on human hair, a novel finding of this study was the effects of estradiol on the plucking strength after excluding age as a factor. We believe that these findings will contribute to understanding FPHL and developing female hormone-related treatments.

Postoperative delirium in patients undergoing tumor resection with reconstructive surgery for oral cancer.

Many attempts have been made to identify the risk factors for postoperative delirium, but this has proved difficult due to its complex morbidity. Furthermore, there is little information on postoperative delirium in patients undergoing tumor resection and reconstructive surgery for oral cancer. The aim of the current study was to investigate the incidence of and risk factors for postoperative delirium in patients undergoing resection and reconstructive surgery for oral cancer. The present study included 104 patients with pedicle or free flap reconstruction. Postoperative delirium developed in 22 (21.2%) of these patients. The mean time to onset of postoperative delirium was 2.5±1.0 days and the duration of delirium was 1.9±1.2 days. Univariate analysis demonstrated that the occurrence of postoperative delirium was significantly correlated with operating time (P=0.033), duration of anesthesia (P=0.039), amount of blood loss (P=0.027), method of reconstruction (P=0.008), type of flap used (P=0.009) and time until postoperative ambulation (P=0.0008). Low postoperative red blood cell count (P=0.004), hemoglobin (P=0.004) and hematocrit (P=0.004) were significantly associated with delirium, but preoperative blood test results were not. The multiple logistic regression analysis of these risk factors revealed that the only significant correlation that remained was between postoperative delirium and the time to ambulation after surgery (P=0.005). Since 2009, the Department of Oral and Maxillofacial Surgery, Kumamoto University Hospital has promoted ambulation after the first two postoperative days for patients with oral cancer undergoing tumor resection with reconstruction, and the occurrence of postoperative delirium has decreased from 29.2 to 14.0%. The results of the current study suggest that early postoperative ambulation in patients who undergo reconstructive surgery for oral cancer is effective for preventing postoperative delirium.

Role of serum amylase and salivary cytokines in oral complications during chemoradiotherapy.

OBJECTIVES: To investigate whether serum amylase can predict the recovery of salivary volume and determine the correlation of the level of cytokines, including epidermal growth factor, hepatocyte growth factor and keratinocyte growth factor, with oral mucositis during chemoradiotherapy for oral cancer. SUBJECTS AND METHODS: This study included 84 patients treated with preoperative chemoradiotherapy followed by curative surgery, following a phase II study protocol. We measured and analysed the correlation of the stimulated saliva volume, serum amylase and cytokines in resting saliva at baseline and 1 month after chemoradiotherapy with oral mucositis levels. RESULTS: We observed a negative correlation between the serum amylase level at the beginning of chemoradiotherapy and the stimulated saliva volume at 1 month after chemoradiotherapy (p = .03). Epidermal growth factor in resting saliva was significantly reduced after chemoradiotherapy (p < .01). The incidence of severe oral mucositis during chemoradiotherapy was significantly higher and negatively associated with the epidermal growth factor and keratinocyte growth factor levels (p = .04, p = .05). CONCLUSIONS: The serum amylase level at the beginning of chemoradiotherapy may be a predictor of the recovery of the saliva volume. Furthermore, cytokines such as epidermal growth factor and keratinocyte growth factor in resting saliva affect the development of oral mucositis during chemoradiotherapy.

MLH1-mediated recruitment of FAN1 to chromatin for the induction of apoptosis triggered by O6 -methylguanine.

O6 -Methylguanines (O6 -meG), which are produced in DNA by the action of alkylating agents, are mutagenic and cytotoxic, and induce apoptosis in a mismatch repair (MMR) protein-dependent manner. To understand the molecular mechanism of O6 -meG-induced apoptosis, we performed functional analyses of FANCD2 and FANCI-associated nuclease 1 (FAN1), which was identified as an interacting partner of MLH1. Immunoprecipitation analyses showed that FAN1 interacted with both MLH1 and MSH2 after treatment with N-methyl-N-nitrosourea (MNU), indicating the formation of a FAN1-MMR complex. In comparison with control cells, FAN1-knockdown cells were more resistant to MNU, and the appearances of a sub-G1 population and caspase-9 activation were suppressed. FAN1 formed nuclear foci in an MLH1-dependent manner after MNU treatment, and some were colocalized with both MLH1 foci and single-stranded DNA (ssDNA) created at damaged sites. Under the same condition, FANCD2 also formed nuclear foci, although it was dispensable for the formation of FAN1 foci and ssDNA. MNU-induced formation of ssDNA was dramatically suppressed in FAN1-knockdown cells. We therefore propose that FAN1 is loaded on chromatin through the interaction with MLH1 and produces ssDNA by its exonuclease activity, which contributes to the activation of the DNA damage response followed by the induction of apoptosis triggered by O6 -meG.

SMARCAD1-mediated recruitment of the DNA mismatch repair protein MutLα to MutSα on damaged chromatin induces apoptosis in human cells.

The mismatch repair (MMR) complex is composed of MutSα (MSH2-MSH6) and MutLα (MLH1-PMS2) and specifically recognizes mismatched bases during DNA replication. O6-Methylguanine is produced by treatment with alkylating agents, such as N-methyl-N-nitrosourea (MNU), and during DNA replication forms a DNA mismatch (i.e. an O6-methylguanine/thymine pair) and induces a G/C to A/T transition mutation. To prevent this outcome, cells carrying this DNA mismatch are eliminated by MMR-dependent apoptosis, but the underlying molecular mechanism is unclear. In this study, we provide evidence that the chromatin-regulatory and ATP-dependent nucleosome-remodeling protein SMARCAD1 is involved in the induction of MMR-dependent apoptosis in human cells. Unlike control cells, SMARCAD1-knockout cells (ΔSMARCAD1) were MNU-resistant, and the appearance of a sub-G1 population and caspase-9 activation were significantly suppressed in the ΔSMARCAD1 cells. Furthermore, the MNU-induced mutation frequencies were increased in these cells. Immunoprecipitation analyses revealed that the recruitment of MutLα to chromatin-bound MutSα, observed in SMARCAD1-proficient cells, is suppressed in ΔSMARCAD1 cells. Of note, the effect of SMARCAD1 on the recruitment of MutLα exclusively depended on the ATPase activity of the protein. On the basis of these findings, we propose that SMARCAD1 induces apoptosis via its chromatin-remodeling activity, which helps recruit MutLα to MutSα on damaged chromatin.

Reversal of the hair loss phenotype by modulating the estradiol-ANGPT2 axis in the mouse model of female pattern hair loss.

BACKGROUND: Despite high demand for a remedy, the treatment options for female pattern hair loss (FPHL) are limited. FPHL is frequent in postmenopausal women. In ovariectomized (OVX) mice, which lack ß-estradiol (E2) and manifest hair loss mimicking FPHL, E2 supplementation has been shown to increase hair density. However, the mechanism by which E2 exhibits its biological activity remains elusive. OBJECTIVE: To identify the downstream targets of E2 in the context of FPHL pathophysiology and discover a potential therapeutic agent for the E2-dependent subtype of FPHL. METHODS: Human dermal papilla cells (hDPCs) were cultured with E2, and a microarray analysis was performed to identify the genes regulated by E2. Using OVX mice, the identified gene product was intradermally administered and then quantitative image analysis of hair density was conducted. In silico analysis to link E2 and the identified gene was performed. RESULTS: Global gene expression and bioinformatics analyses revealed that the genes associated with the angiopoietin-2 (ANGPT2) pathway were upregulated by E2 in hDPCs. ANGPT2 was significantly downregulated in OVX mice than in sham-operated mice (P < 0.01). Importantly, hair density was higher in OVX mice treated with ANGPT2 than in control mice (P < 0.05). In silico analysis showed DNA sequences with high possibility of estrogen receptor binding in the promoter region of ANGPT2. CONCLUSION: The E2-ANGPT2 axis is present in hair follicles. ANGPT2 provides a strategy for the management of E2-dependent and postmenopausal subsets of FPHL.