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Biomedical subjects

J J DiGiovanna

Publications and source records attributed to J J DiGiovanna.

At least 19 recordsLinked to original sources
PubMed2006

Conformational differences in protein disulfide linkages between normal hair and hair from subjects with trichothiodystrophy: a quantitative analysis by Raman microspectroscopy.

Raman spectra of normal hair shafts and hair shafts from patients exhibiting trichothiodystrophy (TTD) were obtained using line focus laser illumination. Because hair from TTD patients has a significant decrease in the content of the sulfur-containing amino acids in comparison to normal hair, the 550-500 cm(-1) disulfide stretching mode region of the Raman spectrum was examined in detail. A quantitative spectral analysis demonstrates significant increases in the two energetically less favored gauche-gauche-trans (g-g-t) and trans-gauche-trans (t-g-t) forms. These observations suggest that the increased amounts of these less stable disulfide conformers are contributing factors to or associated with the hair brittleness observed for this congenital disorder. Structure-spectra correlations for the three dominant disulfide conformers are confirmed by quantum chemical calculations using modern density functional theory (DFT).

Biopolymers↗
PubMed2001

Retinoid chemoprevention in patients at high risk for skin cancer.

Patients who develop large numbers of skin cancers suffer increased morbidity and mortality. A high skin cancer risk can result from inherited disorders such as xeroderma pigmentosum (abnormal repair of UV-induced DNA damage) or the nevoid basal cell carcinoma syndrome (tumor suppressor gene abnormality). The efficacy of systemic retinoid skin cancer chemoprevention was first demonstrated in these disorders. Since the mechanism of cancer prevention was not thought to involve correction of the underlying defect causing the disorder, individuals at high risk for new skin cancers from other causes may also benefit from this approach. With the success of organ transplantation, there is a growing population of transplant recipients living long, active lives who also have sustained chronic UV damage. This population is at high risk for developing aggressive squamous cell carcinomas. In this population, extensive skin involvement with human papilloma virus induced warts and actinic keratoses results in difficulty with diagnosis and monitoring for these dangerous malignancies. Patients who have received treatment with agents that cause DNA damage, such as X-radiation, may also have a high skin cancer risk. Retinoid chemoprevention may also be of benefit in the management of selected patients with these iatrogenic conditions. This evolving therapeutic role has heightened the need for the development of new retinoids, with more efficacy and less toxicity, for cancer chemoprevention.

Genetic Predisposition to Disease↗
PubMed2001

Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials.

Changes in body weight and the incidence of estrogen-related side effects with low-dose oral contraceptives (OCs) containing 20 microg ethinyl estradiol (EE) have not been demonstrated in placebo-controlled trials. Two placebo-controlled, randomized trials demonstrated the efficacy of a low-dose OC for the treatment of acne in healthy females (n = 704; >or=14 years old) with regular menstrual cycles and moderate facial acne. Patients were randomized to receive 20 microg EE/100 microg levonorgestrel (LNG) or placebo for six cycles. Body weight was measured at baseline and during Cycles 1, 3, and 6. The occurrence of adverse events was recorded at each visit. Mean changes in weight from baseline were similar with 20 microg EE/100 microg LNG [0.72 kg +/- 2.64 (SD; n = 349)] and placebo [0.56 kg +/- 2.64 (SD; n = 355; p > 0.05)] for the last measured weight of each patient. Rates of headache, nausea, weight gain, and breast pain, side effects commonly attributed to OCs, were also similar between groups (p > 0.05). No serious, unexpected, drug-related adverse events occurred during the study. The low-dose OC containing 20 microg EE/100 microg LNG is safe, well tolerated, and does not cause weight gain.

Adolescent↗
PubMed2001

Systemic retinoid therapy.

Systemic retinoids represent a growing armamentarium in the treatment of a wide range of skin disorders and malignancies. Although these drugs can have substantial toxicities, their wise use can result in safe and efficacious therapy that can alter dramatically the lives of individuals with severe skin disorders.

Acne Vulgaris↗
PubMed2001

Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation.

Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.

Calcium-Transporting ATPases↗
PubMed2001

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Adolescent↗
PubMed2001

Isotretinoin effects on bone.

Isotretinoin has demonstrated efficacy in a wide range of disorders. The beneficial effects of the drug, however, are limited by its adverse effects on the bone. Children exposed to high doses are at risk for premature epiphyseal closure, while adults on long-term therapy have an increased tendency to develop hyperstosis and other changes of the bone. The knowledge of these effects, in conjunction with continued surveillance, are necessary for expert management and can ensure many years of efficacious treatment with minimal toxicity.

Acne Vulgaris↗
PubMed2001

From vitamin to Vesanoid: systemic retinoids for the new millennium.

Retinoids are a fascinating class of compounds that exert control over cellular function from the time of conception to death. They play a critical role in such vital processes as fetal morphogenesis, cellular differentiation and apoptosis. Over the years synthetic retinoids have provided dermatologists with a spectrum of medications that have profound therapeutic effects on a variety of recalcitrant skin disorders. Moreover, retinoids are an expanding component of the treatment arsenal against hematologic and solid malignancies. Retinoids are poised to offer exciting new therapeutic options in the field of endocrinology for the treatment of diabetes and lipid disorders. Researchers and clinicians are only beginning to unveil the therapeutic potential of this class of medications. The development of new retinoid compounds targeting specific receptors promises a wealth of new therapies for the new millennium.

Acne Vulgaris↗
PubMed2001

Reliability of counting actinic keratoses before and after brief consensus discussion: the VA topical tretinoin chemoprevention (VATTC) trial.

OBJECTIVE: To assess the reliability of counts of actinic keratoses (AKs) and the effect of a brief joint discussion of discrepancies on that reliability. DESIGN AND INTERVENTION: Seven dermatologists independently counted AKs on the face and ears before and after a brief joint discussion of discrepancies. SETTING AND PATIENTS: A volunteer sample of 9 patients from the ongoing VA (Department of Veterans Affairs) Topical Tretinoin Chemoprevention (VATTC) Trial. All participating individuals are veterans and have had 2 or more keratinocyte carcinomas (basal or squamous cell carcinoma) in the 5 years before enrollment in the study. MAIN OUTCOME MEASURE: Standard deviation of estimates of the Poisson regression parameter for the dermatologists. RESULTS: Substantial variation was found among the dermatologists in their AK counts. The SD of the parameter estimates for the dermatologists decreased from 0.45 to 0.24 after the brief joint discussion, a 47% decrease (P =.076). The variation attributable to the dermatologists also decreased substantially (chi(2)(6) decrease, 94 to 12). CONCLUSIONS: Actinic keratoses are common, and there is a continuous spectrum of lesions that ranges from sun-damaged skin to squamous cell carcinoma in situ. Clinical distinguishing features may be difficult to delineate precisely. Counts of AK are commonly performed, but appear to be unreliable, even when performed by experienced dermatologists. Joint discussion of discrepancies may enhance the reliability of these counts, although substantial variation remains. Research that relied on these counts must be reevaluated in light of the marked variation among expert observers. Future studies should consider measures to assess and enhance reliability.

Aged↗
PubMed2000

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies.

Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.

Adolescent↗
PubMed2000

Cutaneous manifestations of end-stage renal disease.

Examination of the skin and nails can reveal many abnormalities in patients with end-stage renal disease that precede or follow initiation of dialysis treatment or kidney transplantation. This article focuses on specific and nonspecific cutaneous signs of end-stage renal disease, reviewing both banal and life-threatening conditions, including pruritus, perforating disorders, calcifying disorders, and bullous dermatoses. The pathogenesis, clinical findings, histologic findings, differential diagnosis, and treatment of these diseases are discussed. Cutaneous manifestations unique to kidney transplantation will not be covered. (J Am Acad Dermatol 2000;43:975-86.)

Female↗
PubMed1998

Posttransplantation skin cancer: scope of the problem, management, and role for systemic retinoid chemoprevention.

Long-term immunosuppression necessary for transplantation places susceptible individuals with chronic actinic damage at increased risk for the development of aggressive skin cancers. Candidates for transplantation should be evaluated for the risk factors associated with skin cancer. Those who are at risk should be educated in the measures for and the importance of diligent UVR protection, frequent self-examination of the skin, and regular dermatologic evaluation to minimize the morbidity and morality from NMSC. Identified skin cancers (especially SCC) should be treated aggressively. Individuals who are actively developing many cancers may be candidates for retinoid chemoprevention.

Anticarcinogenic Agents↗
PubMed1998

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Amino Acid Sequence↗
PubMed1998

Xeroderma pigmentosum: spinal cord astrocytoma with 9-year survival after radiation and isotretinoin therapy.

BACKGROUND: Patients with xeroderma pigmentosum (XP) frequently develop sunlight-induced skin cancer. Infrequently, internal neoplasms may also occur. A 21-year-old patient with XP, who had many skin cancers, developed a rare internal tumour - a grade II diffuse fibrillary spinal cord astrocytoma - during a break in a therapeutic trial of isotretinoin for skin cancer prevention. Treatment of neoplasms in XP patients presents special difficulties because of their defect in DNA repair. OBJECTIVE: The study objective was to raise awareness of the cancer surveillance process in XP patients and the concerns involved in choice of therapy. METHODS: Since the spinal cord tumour was inoperable, the patient was treated with x-radiation, continued on isotretinoin treatment and was followed closely for tumour response. RESULTS: Despite sensitivity to sunlight, the patient had a normal acute response to the x-ray treatment without excessive skin reaction. Serial examinations by magnetic resonance imaging (MRI) starting 8 months after x-ray treatment was initiated, showed a marked gadolinium enhancement followed by regression. This clearing was first seen at 2 years after biopsy and persisted to at least 9 years after treatment. CONCLUSION: In contrast to the exaggerated sensitivity to UV radiation, XP patients may tolerate therapeutic doses of x-radiation. Isotretinoin treatment may have contributed to the good response of this spinal cord astrocytoma.

Adult↗
PubMed1998

Phase 1 clinical trials.

BACKGROUND: In the United States, drug development and approval is a complex process regulated by the Food and Drug Administration under the authority outlined in the Code of Federal Regulation. The goal of this multi-step process is to determine safety and efficacy of new therapeutic entities. Initially, exposure of humans to new therapeutic agents is accomplished in a graded and limited fashion. This approach seeks to minimize risks to study participants from exposure to damaging agents. During early phases, limiting exposure to a few individuals results in the accumulation of preliminary data on pharmacology, short-term toxicity, and efficacy. The inherent limitations of this process necessitate careful critique and caution in extrapolation of phase 1 data. OBJECTIVES: The purpose of this article is to provide a review of the drug approval process focusing on phase 1 trials, which are the earliest human exposure to a new drug. The purpose, variations, and significance of phase 1 trials are described, and a framework is provided to critically evaluate data published from these trials. CONCLUSIONS: Phase 1 trials are primarily designed to accumulate short-term safety (toxicity) and pharmacological data. Although preliminary efficacy may be addressed ("proof of concept" efficacy), it is a secondary endpoint. The numbers of patients are small, the numbers of patients receiving efficacious doses are very small, and controls are absent. Evaluation of efficacy and of long-term toxicity requires longer, larger, and controlled studies.

Clinical Trials, Phase I as Topic↗
PubMed1997

Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: a rare case illustrating gene-environment interaction.

We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus' mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient's at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered.

Basal Cell Nevus Syndrome↗