The nuclear factor-kappaB (NF-kappaB) signalling pathway regulates immune responses and is implicated in the pathogenesis of many inflammatory diseases. Given the well established pro-inflammatory functions of NF-kappaB, inhibition of this pathway would be expected to have anti-inflammatory effects. However, recent studies in mouse models have led to surprising and provocative results, as NF-kappaB inhibition in epithelial cells resulted in the spontaneous development of severe chronic inflammatory conditions. These findings indicate that NF-kappaB signalling acts in non-immune cells to control the maintenance of tissue immune homeostasis. This Review discusses the mechanisms by which NF-kappaB activity in non-immune cells regulates tissue immune homeostasis and prevents the pathogenesis of inflammatory diseases.

Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases

The nuclear factor-kappa B (NF-kappaB) signaling pathway is a multi-component pathway that regulates the expression of hundreds of genes that are involved in diverse and key cellular and organismal processes, including cell proliferation, cell survival, the cellular stress response, innate immunity and inflammation. Not surprisingly, mis-regulation of the NF-kappaB pathway, either by mutation or epigenetic mechanisms, is involved in many human and animal diseases, especially ones associated with chronic inflammation, immunodeficiency or cancer. This review describes human diseases in which mutations in the components of the core NF-kappaB signaling pathway have been implicated and discusses the molecular mechanisms by which these alterations in NF-kappaB signaling are likely to contribute to the disease pathology. These mutations can be germline or somatic and include gene amplification (e.g., REL), point mutations and deletions (REL, NFKB2, IKBA, CYLD, NEMO) and chromosomal translocations (BCL-3). In addition, human genetic diseases are briefly described wherein mutations affect protein modifiers or transducers of NF-kappaB signaling or disrupt NF-kappaB-binding sites in promoters/enhancers.

Mutations in the NF-kappaB signaling pathway: implications for human disease.

The drive to attain cosmetic facial enhancement with minimal risk and rapid recovery has inspired the field of nonsurgical skin rejuvenation. Laser resurfacing was introduced in the 1980s with continuous wave carbon dioxide (CO 2 ) lasers; however, because of a high rate of side effects, including scarring, short-pulse, high-peak power, and rapidly scanned, focused-beam CO 2 lasers and normal-mode erbium-doped yttrium aluminium garnet lasers were developed, which remove skin in a precisely controlled manner. The prolonged 2-week recovery time and small but significant complication risk prompted the development of non-ablative and, more recently, fractional resurfacing in order to minimize risk and shorten recovery times. Nonablative resurfacing produces dermal thermal injury to improve rhytides and photodamage while preserving the epidermis. Fractional resurfacing thermally ablates microscopic columns of epidermal and dermal tissue in regularly spaced arrays over a fraction of the skin surface. This intermediate approach increases efficacy as compared to nonablative resurfacing, but with faster recovery as compared to ablative resurfacing. Neither nonablative nor fractional resurfacing produces results comparable to ablative laser skin resurfacing, but both have become much more popular than the latter because the risks of treatment are limited in the face of acceptable improvement. Learning objectives At the completion of this learning activity, participants should be familiar with the spectrum of lasers and light technologies available for skin resurfacing, published studies of safety and efficacy, indications, methodologies, side effects, complications, and management.

The spectrum of laser skin resurfacing: Nonablative, fractional, and ablative laser resurfacing

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients; 6% of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The "ash leaf" macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a "Fitzpatrick patch." Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. Learning objective After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.

Tuberous sclerosis complex: advances in diagnosis, genetics, and management.

Advances in laser technology have progressed so rapidly during the past decade that successful treatment of many cutaneous concerns and congenital defects, including vascular and pigmented lesions, tattoos, scars, and unwanted hair-can be achieved. The demand for laser surgery has increased substantially by patients and dermatologists alike as a result of the relative ease with which many of these lesions can be removed, combined with a low incidence of adverse postoperative sequelae. Refinements in laser technology and technique have provided patients and practitioners with more therapeutic choices and improved clinical results. In this review, the currently available laser systems with cutaneous applications are outlined, with primary focus placed on recent advancements and modifications in laser technology that have greatly expanded the cutaneous laser surgeon's armamentarium and improved overall treatment efficacy and safety.

Lasers in dermatology: four decades of progress.

Incontinentia pigmenti is an uncommon X-linked dominant disorder, lethal in the majority of affected males in utero and variably expressed in females. Cutaneous manifestations are classically subdivided into 4 stages: vesicular, verrucous, hyperpigmented, and atrophic. Various hair and nail abnormalities, dental anomalies, and ophthalmologic and neurologic deficits are associated with the disorder. The gene for incontinentia pigmenti has been mapped to Xq28. Recently, mutations in the NEMO/IKK γ gene located at Xq28 have been found to cause expression of the disease. Knockout mice heterozygous for NEMO/IKK γ gene deficiency develop a clinical phenotype very similar to that of incontinentia pigmenti. NEMO/IKKγ is an essential component of the newly discovered nuclear factor κB (NF-κB) signaling pathway. When activated, NF-κB controls the expression of multiple genes, including cytokines and chemokines, and protects cells against apoptosis. The mechanism by which NEMO/IKKγ deficiency causes, via the NF-κB pathway, the phenotypical expression of the disease has recently been elucidated. In addition, the newest research findings on eosinophil recruitment through eotaxin release by activated keratinocytes are described in the review. Finally, anhidrotic ectodermal dysplasia with immunodeficiency, a disorder allelic to incontinentia pigmenti, is discussed together with implications on the current understanding of NF-κB function. (J Am Acad Dermatol 2002;47:169-87.) Learning objective: At the completion of this learning activity, participants will have a comprehensive and current understanding of incontinentia pigmenti, including its typical and uncommon clinical and histopathologic characteristics, diagnostic assessment, and current management strategies. Additionally, participants will gain the most current knowledge of the genetic and molecular basis of cutaneous pathomechanism.

https://www.jaad.org/article/S0190-9622(02)00046-4/pdf

Incontinentia pigmenti: A review and update on the molecular basis of pathophysiology

BACKGROUND Soft-tissue augmentation using calcium hydroxylapatite (CaHA) filler has been shown to be a safe and effective filler agent. A previous study utilizing electron microscopy demonstrated deposition of collagen around filler microspheres with minimal inflammatory response. OBJECTIVE The purpose of this study was to further characterize the expression of collagen in response to injected CaHA filler material using conventional, special, and immunohistochemical (IHC) staining. MATERIALS AND METHODS Five subjects with mild to moderate nasolabial rhytids underwent a single treatment with CaHA filler. Additionally, 0.1 to 0.2 mL of the filler material was injected subdermally into the postauricular area. Six months following the treatment, all subjects underwent biopsy of the treated postauricular area. Biopsies were analyzed using hematoxylin and eosin staining, special staining with picrosirius red (PSR), and IHC staining for collagen Types I and III. RESULTS All subjects completed the study with no complications. Biopsy specimens revealed increased deposition of collagen around the filler material, which was confirmed and further characterized using PSR and IHC staining. CONCLUSION Soft tissue augmentation with CaHA filler leads to long-term deposition of new collagen surrounding filler microspheres, which may contribute to the overall improvement in the appearance of treated rhytids.

Calcium hydroxylapatite filler for facial rejuvenation: a histologic and immunohistochemical analysis.

Background and Objective
Fractional photothermolysis is a popular treatment option for photodamaged skin and other cutaneous conditions. Recently, successful improvement in melasma has been achieved with this laser system. We undertook this study to evaluate the ultrastructural changes associated with fractional laser treatment of melasma.

Study Design/Materials and Methods
Ten subjects with skin types III and IV and a clinical diagnosis of epidermal melasma were treated with a 1,550-nm erbium:glass laser delivering light in a fractional manner (Fraxel SR 750, Reliant Technologies, Inc., Mountain View, CA) every 2 weeks for a total of four sessions. Biopsies were obtained from all subjects both before treatment and at 3 months following the final treatment. All biopsies were analyzed by light and electron microscopy for treatment-induced changes. In addition, a secondary endpoint of the study was to assess for clinical improvement in melasma following fractional resurfacing. This assessment was performed by the investigator using pre- and post-treatment photographs.

Results
Light microscopy on post-treatment specimens showed a relative decrease in melanocytes compared to the pre-treatment ones. Post-treatment electron microscopy revealed fewer melanocytes and a relative absence of melanin in the surrounding keratinocytes compared to pre-treatment specimens. In addition, six subjects with skin type III were determined to have good improvement, whereas four subjects with skin type IV had fair improvement, as assessed by the investigator.

Conclusion
Post-treatment ultrastructural changes are consistent with an elimination process and may help to explain clinical improvement following laser treatment. Lesers Surg. Med. 40:134–138, 2008. © 2008 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/lsm.20591

Histologic and ultrastructural analysis of melasma after fractional resurfacing.

BACKGROUNDAlthough unparalleled in its efficacy, carbon dioxide (CO2) laser resurfacing has a high risk:benefit ratio. A modified device uses a novel handpiece and software to deliver nonsequential fractional ablative CO2 laser exposures.OBJECTIVETo evaluate the safety and efficacy of this fractiona

A prospective study of fractional scanned nonsequential carbon dioxide laser resurfacing: a clinical and histopathologic evaluation.

BACKGROUND Cellulite is seen in more than 85% of postpubertal women. Recent studies show that bipolar radiofrequency and low-level laser devices can produce mild skin tightening of cellulite.



OBJECTIVE The primary objective was to determine if a novel unipolar, more deeply penetrating, radiofrequency device can promote better skin tightening with fewer treatments than is seen with previously described devices. The secondary objective was to determine if such a deeply penetrating device produced undesired effects on lipid metabolism.



METHODS Thirty subjects, with Nurnberger-Muller Scale III–IV upper thigh cellulite, were entered into the study. All were treated, every other week, with a unipolar radiofrequency device for a total of six treatments. Subjects were evaluated before and 6 months after treatment with clinical photographs, clinical measurements, biopsies, MRIs, and blood lipid evaluations.



RESULTS Twenty-seven subjects showed evidence of clinical improvement. The mean decrease in leg circumference was 2.45 cm. Histologic changes showed dermal fibrosis of the upper dermis. No MRI or lipid abnormalities were noted.



CONCLUSION Upper thigh skin cellulite can be improved with a new unipolar radiofrequency device. Histologic changes suggest skin tightening as the method of improvement. No undesired complications of the skin or lipid metabolism were noted.

Alexander L. Berlin

Papers

Incontinentia pigmenti: A review and update on the molecular basis of pathophysiology

Calcium hydroxylapatite filler for facial rejuvenation: a histologic and immunohistochemical analysis.

Histologic and ultrastructural analysis of melasma after fractional resurfacing.

A prospective study of fractional scanned nonsequential carbon dioxide laser resurfacing: a clinical and histopathologic evaluation.

Clinical, laboratory, and MRI analysis of cellulite treatment with a unipolar radiofrequency device.