New Diagnostic Tools to Evaluate Hair Loss.

The precise and reliable diagnosis of hair loss disorders is essential for developing a successful management plan. It is, thus, the responsibility of the dermatologist to select the appropriate diagnostic tools to effectively evaluate patients presenting with hair loss concerns. Fortunately, there is a growing body of noninvasive and invasive diagnostic resources, each with advantages and disadvantages. For the practicing dermatologist, tactile assessments and direct visualization are enhanced with scoring instruments, questionnaires, handheld trichoscopy, and scalp biopsy. For research and clinical study purposes, the more precise, high-resolution tools such as videodermoscopy, optical coherence tomography, and phototrichograms, may be useful.

Evaluation of platelet-rich plasma as a treatment for androgenetic alopecia: A randomized controlled trial.

BACKGROUND: Platelet-rich plasma (PRP) shows promise as an androgenetic alopecia (AGA) treatment. OBJECTIVE: To conduct a randomized placebo-controlled split-scalp study to investigate the effects of PRP on hair regrowth and thickness. METHODS: Two 7.6-cm × 7.6-cm squares were tattooed on the scalps of 35 study participants with AGA. Areas were randomly assigned to intradermal injection with PRP or saline. Participants received 3 monthly treatment sessions with evaluation 3 months after the final treatment. RESULTS: Hair density in the PRP-treated area was significantly increased compared with baseline at all visits. At the final assessment, hair density in PRP-treated areas increased from 151 ± 39.82 hairs/cm2 at baseline to 170.96 ± 37.14 hairs/cm2, a mean increase of approximately 20 hairs/cm2 (P < .05). However, hair density in placebo-treated areas also increased from 151.04 ± 41.99 hairs/cm2 to 166.72 ± 37.13 hairs/cm2 (P < .05). There was no significant difference in hair density change between the 2 groups (P > .05). No serious adverse events were reported. LIMITATIONS: Possible PRP diffusion due to split-scalp study design as well as microinjections causing microinjury to both sides. CONCLUSION: PRP may have benefit in increasing hair density.

Hair Loss in Lichen Planopilaris and Frontal Fibrosing Alopecia: Not Always Irreversible.

INTRODUCTION: We present 2 cases in which typically irreversible lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) showed signs of reversal. CASE PRESENTATION: A 27-year-old Caucasian man presented with hair loss and intense pruritus on the vertex scalp for 4 years with biopsy-proven LPP and having failed multiple pharmacologic modalities. Six months after adding oral tofacitinib and later dapsone, he demonstrated reduced scalp visibility, evidence of crown and vertex hair regrowth, and elimination of itch. A 45-year-old premenopausal Hispanic woman presented with eyebrow loss for 3.75 years and hair loss for 9 months with biopsy-proven FFA. After beginning oral finasteride and hydroxychloroquine, triamcinolone injections, and topical minoxidil, she initially worsened over 11 months but subsequently improved over 6 months, demonstrating hair and eyebrow regrowth, reduction in glabella-hairline distance, and new absence of frontal hair line hyperkeratosis and inflammation. DISCUSSION/CONCLUSION: Cicatricial alopecia involves inflammation with JAK-STAT upregulation. We report a positive clinical response in LPP to tofacitinib, a JAK1/3 inhibitor, and dapsone, an anti-neutrophilic agent. FFA is believed to involve autoimmune and/or hormonal processes. Here we report a positive clinical response to androgenic and immune modulators.

Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice.

Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.

Papular mucinosis, or localized lichen myxedematosis (LM) (discrete papular type).

Lichen myxedematosus is condition characterized by localized areas of dermal deposition of mucin, presenting with firm papules localized to few areas of the body. The condition needs to be excluded from scleromyxedema, which, in addition to the firm papular eruption, has areas of induration and is usually associated with a monoclonal gammopathyand systemic symptoms. We present a 62-year-old woman with a several-year history of asymptomatic, firm papules over the face and arms with no evidence of thyroid disease or a monoclonal gammopathy,which is consistent with a diagnosis of localized lichen myxedematosus, the discrete papular variant. The patient is being treated with a topical calcineurininhibitor.

Generalized hyperhidrosis secondary to presumed eccrine gland dysfunction with possible apocrine metaplasia.

We present a 57 year-old man presented with generalized hyperhidrosis and widespread, smooth, flesh colored papules on the torso and extremities.Histological examination from multiple biopsies demonstrated morphologic alteration of the eccrine glands with an apocrine phenotype, suggesting eitherapocrine metaplasia or the presence of "apoeccrine glands." The morphologic similarities between eccrine, apocrine, and apoeccrine as they relate to ourpatient's histologic findings are discussed. We consider secondary causes of generalized hyperhidrosis, which may also play a role in this patient's presentation. Treatment and further workup are discussed, whilemanagement of this patient remains in progress.

Ulcerated tophaceous gout.

Gout is an inflammatory arthritis characterised by hyperuricemia, which, if poorly controlled, can lead to the development of tophi. We report the case of a 60-year-old Caucasian man with poorly controlled polyarticular tophaceous gout with multiple comorbidities (including renal failure) who presented with tophaceous ulcers of the upper extremity. These ulcers caused extreme pain, requiring chronic opiate medications, and were associated with decreased sensation and reduced ability to move the extremity. His hospital course was complicated by acute kidney injury, haemolytic anaemia and Clostridium difficile infection. He required 1 month of antibiotics and intensive wound care for his ulcers. This case highlights the diagnosis, natural history and management of an unusual complication of hyperuricemia.

Eruptive furunculosis following the soak and smear regimen.

The 'soak and smear' regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA)-positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community.

Lgr5 Marks Post-Mitotic, Lineage Restricted Cerebellar Granule Neurons during Postnatal Development.

Wnt signaling regulates self-renewal and fate commitment of stem and progenitor cells in development and homeostasis. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is a co-receptor for Wnt signaling that marks highly proliferative stem and progenitor cells in many epithelial tissue types. Wnt signaling instructs neural developmental and homeostatic processes; however, Lgr5 expression in the developing and adult brain has not been characterized. Here we report that Lgr5 is expressed in the postnatal cerebellum during the maturation and synaptogenesis of cerebellar granule neurons (CGNs), processes controlled by Wnt signaling. Using a transgenic reporter mouse for in vivo Lgr5 expression analysis and lineage tracing, we reveal that Lgr5 specifically identified CGNs and was restricted temporally to the CGN maturation phase within the internal granule layer, but absent in the adult brain. Cells marked by Lgr5 were lineage restricted, post-mitotic and long-lived. The ligand for Lgr5, R-spondin, was secreted in a paracrine fashion that evolved during the maturation of CGNs, which coincided with the Lgr5 expression pattern. Our findings provide potential new insight into the critical regulation of Wnt signaling in the developing cerebellum and support a novel role for Lgr5 in the regulation of post-mitotic cells.

The Lgr5 transgene is expressed specifically in glycinergic amacrine cells in the mouse retina.

Retinal amacrine cells are a diverse set of interneurons within the inner nuclear layer. The canonical Wnt pathway is highly active within mature amacrine cells, but its role remains unclear. Leucine-rich repeat containing G-protein receptor 5 (Lgr5) is a newly identified component of the Wnt receptor complex that potentiates beta-catenin signaling. In multiple epithelial organs Lgr5 marks adult tissue stem cells. We investigated the expression of this gene using Lgr5-eGFP-IRES-CreER transgenic reporter mice. In the eye, Lgr5 was exclusively expressed in glycinergic amacrine cells in adult mice. Amacrine cells are post-mitotic and represent the first neuronal and non-stem cell lineage to express Lgr5. We further interrogated the spatiotemporal labeling of individual amacrine cells with controlled fluorophore expression. This "fluorofilling" technique provides a tool to study amacrine morphology and dissect neural networks.

Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.

Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.

Ionizing radiation in glioblastoma initiating cells.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12-15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.