Immuno-regenerative biomaterials for in situ cardiovascular tissue engineering - Do patient characteristics warrant precision engineering?

In situ tissue engineering using bioresorbable material implants - or scaffolds - that harness the patient's immune response while guiding neotissue formation at the site of implantation is emerging as a novel therapy to regenerate human tissues. For the cardiovascular system, the use of such implants, like blood vessels and heart valves, is gradually entering the stage of clinical translation. This opens up the question if and to what extent patient characteristics influence tissue outcomes, necessitating the precision engineering of scaffolds to guide patient-specific neo-tissue formation. Because of the current scarcity of human in vivo data, herein we review and evaluate in vitro and preclinical investigations to predict the potential role of patient-specific parameters like sex, age, ethnicity, hemodynamics, and a multifactorial disease profile, with special emphasis on their contribution to the inflammation-driven processes of in situ tissue engineering. We conclude that patient-specific conditions have a strong impact on key aspects of in situ cardiovascular tissue engineering, including inflammation, hemodynamic conditions, scaffold resorption, and tissue remodeling capacity, suggesting that a tailored approach may be required to engineer immuno-regenerative biomaterials for safe and predictive clinical applicability.

Architecture of Ca(2+) channel pore-lining segments revealed by covalent modification of substituted cysteines.

The cysteine accessibility method was used to explore calcium channel pore topology. Cysteine mutations were introduced into the SS1-SS2 segments of Motifs I-IV of the human cardiac L-type calcium channel, expressed in Xenopus oocytes and the current block by methanethiosulfonate compounds was measured. Our studies revealed that several consecutive mutants of motifs II and III are accessible to methanethiosulfonates, suggesting that these segments exist as random coils. Motif I cysteine mutants exhibited an intermittent sensitivity to these compounds, providing evidence for a beta-sheet secondary structure. Motif IV showed a periodic sensitivity, suggesting the presence of an alpha-helix. These studies reveal that the SS1-SS2 segment repeat in each motif have non-uniform secondary structures. Thus, the channel architecture evolves as a highly distorted 4-fold pore symmetry.

Amelanotic melanoma: the great masquerader.

BACKGROUND: Cutaneous melanoma is often recognized by its dark color, but some tumors have little or no pigmentation. OBJECTIVE: We present the clinical findings of 4 cases of primary cutaneous amelanotic melanoma in which the clinical diagnosis was unsuspected and one case of amelanotic metastatic melanoma. METHODS: Five cases of melanoma are reviewed. The clinical morphology of the lesions is presented and discussed. We surveyed the literature regarding conditions that mimic amelanotic melanoma, and we discuss the treatment and prognosis for amelanotic melanoma. RESULTS: Amelanotic melanoma may masquerade as a variety of other conditions leading to a delay in the diagnosis or an inappropriate biopsy technique. The prognosis of amelanotic primary tumors is no different from that for its pigmented counterpart. CONCLUSION: The clinician should be familiar with the presentation of amelanotic melanoma to facilitate prompt diagnosis.

Is physician detection associated with thinner melanomas?

CONTEXT: In cutaneous melanoma, tumor depth remains the best biologic predictor of patient survival. Detection of prognostically favorable lesions may be associated with improved survival in patients with melanoma. OBJECTIVE: To determine melanoma detection patterns and relate them to tumor thickness. DESIGN: Interview survey. SETTING AND PATIENTS: All patients with newly detected primary cutaneous melanoma at the Melanoma Center, Johns Hopkins Medical Institutions, between June 1995 and June 1997. MAIN OUTCOME MEASURE: Tumor thickness grouped according to detection source. RESULTS: Of the 102 patients (47 men, 55 women) in the study, the majority of melanomas were self-detected (55%), followed by detection by physician (24%), spouse (12%), and others (10%). Physicians were more likely to detect thinner lesions than were patients who detected their own melanomas (median thickness, 0.23 mm vs 0.9 mm; P<.001). When grouped according to thickness, 11 (46%) of 24 physician-detected melanomas were in situ, vs only 8 (14%) of 56 patient-detected melanomas. Physician detection was associated with an increase in the probability of detecting thinner (< or =0.75 mm) melanomas (relative risk, 4.2; 95% confidence interval, 1.4-11.1; P=.01). CONCLUSIONS: Thinner melanomas are more likely to have been detected by physicians. Increased awareness by all physicians may result in greater detection of early melanomas.

Hereditary epidermolytic palmoplantar keratoderma (Vörner type) in a family with Ehlers-Danlos syndrome.

We describe a kindred in whom epidermolytic palmoplantar keratoderma occurred in association with Ehlers-Danlos syndrome type III (benign hypermobility syndrome). This kindred consisted of 27 members of four generations, 14 of whom had palmoplantar keratoderma (PPK). Of those who had palmoplantar keratoderma, 6 had Ehlers-Danlos type III (EDS II). The proband presented with diffuse, symmetrical hyperkeratotic plaques that were yellow and sharply demarcated, covering the entire palms and soles, in addition to marked large and small joint flexibility and skin hyperextensibility. A biopsy specimen from the palm revealed features of epidermolytic hyperkeratosis with acanthosis. To our knowledge, this is the first report of PPK in a family with Ehlers-Danlos syndrome. Linkage analysis of these two clinical traits showed that the genes responsible for PPK and EDS III are not closely linked, and therefore are not immediately adjacent. However, linkage at greater genetic distances could not be excluded.

Atypical mole syndrome: a brief overview for the primary care physician.

Early detection of melanoma and identification of potential markers or precursor lesions can substantially improve survival. Several risk factors have been identified in the pathogenesis of this potentially lethal cancer. Numerous reports in the literature have confirmed a subset of persons with an increased risk of developing melanoma. These patients are identified by a distinctive clinical phenotype depicted by unusually appearing melanocytic nevi (moles) in association with an increased number of total body nevi. They may have a family history of atypical moles or melanoma. In order to facilitate the recognition of such individuals by the non-dermatologist, a brief overview and salient features of the atypical mole syndrome are presented.

Dermatitis in treated maple syrup urine disease.

Two children who had classic maple syrup urine disease developed an eruptive dermatitis when plasma isoleucine levels, leucine levels, or both fell below normal during periods of protein restriction. The dermatitis was resistant to topical corticosteroid therapy. Rapid resolution occurred after treatment with isoleucine and leucine dietary supplements.

Mycosis fungoides beginning in childhood and adolescence.

Mycosis fungoides is a form of cutaneous T cell lymphoma usually occurring in mid to late adulthood. We report 12 patients with mycosis fungoides whose eruption began before age 20 years, including one patient with histologic documentation at 5 years of age. The onset of mycosis fungoides during the first two decades may be more common than is generally recognized and should be included in the differential diagnosis of chronic dermatoses in children and adolescents.

Laugier-Hunziker syndrome.

The Laugier-Hunziker syndrome represents a rare acquired pigmentary disorder of the lips, oral mucosa, and nails. We report the first case of this syndrome to be recognized in the United States and review other causes of hyperpigmentation in these locations.

Acquired cutis laxa: case report and review of disorders of elastolysis.

A 10-year-old boy developed cutis laxa while receiving isoniazid therapy; no systemic manifestations occurred. There are several well-documented cases of acquired cutis laxa. We propose a classification of the elastolysis syndromes, including inherited, neonatal, and acquired forms of cutis laxa.