Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.

Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.

Analysis of genetic biomarkers, polymorphisms in ADME-related genes and their impact on pharmacotherapy for prostate cancer.

Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer death. Its etiology may have been linked to genetic polymorphisms, which are not only dominating cause of malignancy casualties but also exerts significant effects on pharmacotherapy outcomes. Although many therapeutic options are available, but suitable candidates identified by useful biomarkers can exhibit maximum therapeutic efficacy. The single-nucleotide polymorphisms (SNPs) reported in androgen receptor signaling genes influence the effectiveness of androgen receptor pathway inhibitors and androgen deprivation therapy. Furthermore, SNPs located in genes involved in transport, drug metabolism, and efflux pumps also influence the efficacy of pharmacotherapy. Hence, SNPs biomarkers provide the basis for individualized pharmacotherapy. The pharmacotherapeutic options for PCa include hormonal therapy, chemotherapy (Docetaxel, Mitoxantrone, Cabazitaxel, and Estramustine, etc.), and radiotherapy. Here, we overview the impact of SNPs reported in various genes on the pharmacotherapy for PCa and evaluate current genetic biomarkers with an emphasis on early diagnosis and individualized treatment strategy in PCa.

Expression analysis of tumour necrosis factor alpha (TNF-α) and alkaline phosphatase in occupational workers exposed to low dose of X-radiation: A case-control study.

OBJECTIVES: To evaluate liver and inflammatory biomarkers in occupationally exposed radiology workers. METHODS: The descriptive study was conducted at Mufti Mehmood Memorial Teaching Hospital and Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan, from September 2017 to May 2018, and comprised X-ray technicians working 48-72 hours per week, and a group of age- and gender-matched unexposed healthy controls. The exposed group was divided into three sub-groups based on their radiation work duration. Liver health status involved estimation of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase GGT and bilirubin through automated chemistry analyser, while serum tumour necrosis factor-alpha and interleukin- 6 levels through enzyme-linked immunosorbent assay technique. Relative gene expression analysis of tumour necrosis factor-alpha and alkaline phosphatase was performed through reverse transcription-polymerase chain reaction. Data was analysed using SPSS 20. RESULTS: Of the 70 subjects, 50(71.4%) were cases with a mean age of 36.98±8.07 years and 20(28.6%) were controls with a mean age of 36.80±7.78 years. Serum alanine aminotransferase and alkaline phosphatase levels showed significant elevation in the cases compared to the controls (p<0.0001), although alanine aminotransferase levels were within the normal range. The difference in aspartate aminotransferase, gamma-glutamyl transferase and bilirubin levels was not significant (p>0.05). Tumour necrosis factor-alpha concentration was significantly high in the cases compared to the controls (p<0.0001). In contrast with proteomic analysis, relative gene expression analysis revealed reduced level of alkaline phosphatase and tumour necrosis factor-alpha in the cases compared to the controls (p<0.05). CONCLUSIONS: Serum proteomic analysis of X-ray technicians indicated acute inflammatory conditions, while genomic analysis exhibited down-regulation of alkaline phosphatase and tumour necrosis factor-alpha genes.

Influence of omega fatty acids on skin permeation of a coenzyme Q10 nanoemulsion cream formulation: characterization, in silico and ex vivo determination.

Objective: The aim of this study was to develop a coenzyme Q10 nanoemulsion cream, characterize and to determine the influence of omega fatty acids on the delivery of coenzyme Q10 across model skin membrane via ex vivo and in silico techniques. Methods: Coenzyme Q10 nanoemulsion creams were prepared using natural edible oils such as linseed, evening primrose, and olive oil. Their mechanical features and ability to deliver CoQ10 across rat skin were characterized. Computational docking analysis was performed for in silico evaluation of CoQ10 and omega fatty acid interactions. Results: Linseed, evening primrose, and olive oils each produced nano-sized emulsion creams (343.93-409.86 nm) and exhibited excellent rheological features. The computerized docking studies showed favorable interactions between CoQ10 and omega fatty acids that could improve skin permeation. The three edible-oil nanoemulsion creams displayed higher ex vivo skin permeation and drug flux compared to the liquid-paraffin control cream. The linseed oil formulation displayed the highest skin permeation (3.97 ± 0.91 mg/cm2) and drug flux (0.19 ± 0.05 mg/cm2/h). Conclusion: CoQ10 loaded-linseed oil nanoemulsion cream displayed the highest skin permeation. The highest permeation showed by linseed oil nanoemulsion cream may be due to the presence of omega-3, -6, and -9 fatty acids which might serve as permeation enhancers. This indicated that the edible oil nanoemulsion creams have potential as drug vehicles that enhance CoQ10 delivery across skin.

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids.

Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug-excipient relationships at the molecular level.

Evaluation of antibiotic resistant bacteria in underground drinking water and transfer of their resistant character to normal flora of the body.

The untreated surface water for drinking and domestic use is an alarming situation to public health especially in prevalence of antibiotics resistant bacteria. This investigation aimed to isolate and identify the antibiotic resistance bacteria in underground water samples in district Dera Ismail Khan, Pakistan. The underground water samples were collected from four different places using hand pumps (Khyber town, riverside, Gomal University and united town). Cultured on nutrient agar media, identified by Gam staining and biochemical tests. There after antibiotic resistance assay were performed by measuring zone of inhibition of different antibiotics by disc diffusion method. Six different bacterial colonies were isolated and identified as Enterobacteriaceae, Serriata specie, Proteues, Pseudomonas, all these bacterial colonies were 33% resistant to chloramphenicol with and 100% resistant to amoxicillin. Some colonies were also considered as resistant, according to the criteria of National Committee for Clinical Records (NCCL) that less than 10mm zone of inhibition are considered as resistant. Subsequently, the chloramphenicol resistance bacteria were analyzed for their ability to transfer resistant gene to sensitive bacteria. In in-vitro method, an isolate M1b (resistant) was found capable to transfer resistance gene to M1a isolate (sensitive) in nutrient rich environment. It was concluded that antibiotics resistance bacteria found in underground water, moreover capable of transferring the antibiotic resistant character to suitable recipient i.e. normal flora of the body or to other pathogens by conjugation.

Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on Immunomodulatory Activity of Imiquimod Against Skin Cancer.

PURPOSE: To characterize bigel system as a topical drug delivery vehicle and to establish the immunomodulatory role of imiquimod-fish oil combination against skin cancer and inflammation resulting from chemical carcinogenesis. METHODS: Imiquimod-loaded fish oil bigel colloidal system was prepared using a blend of carbopol hydrogel and fish oil oleogel. Bigels were first characterized for their mechanical properties and compared to conventional gel systems. Ex vivo permeation studies were performed on murine skin to analyze the ability of the bigels to transport drug across skin and to predict the release mechanism via mathematical modelling. Furthermore, to analyze pharmacological effectiveness in skin cancer and controlling imiquimod-induced inflammatory side effects, imiquimod-fish oil combination was tested in vitro on epidermoid carcinoma cells and in vivo in Swiss albino mice cancer model. RESULTS: Imiquimod-loaded fish oil bigels exhibited higher drug availability inside the skin as compared to individual imiquimod hydrogel and oleogel controls through quasi-Fickian diffusion mechanism. Imiquimod-fish oil combination in bigel enhanced the antitumor effects and significantly reduced serum pro-inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin-6, and reducing tumor progression via inhibition of vascular endothelial growth factor. Imiquimod-fish oil combination also resulted in increased expression of interleukin-10, an anti-inflammatory cytokine, which could also aid anti-tumor activity against skin cancer. CONCLUSION: Imiquimod administration through a bigel vehicle along with fish oil could be beneficial for controlling imiquimod-induced inflammatory side effects and in the treatment of skin cancer.

Recent advances in gel technologies for topical and transdermal drug delivery.

Transdermal drug delivery systems are a constant source of interest because of the benefits that they afford in overcoming many drawbacks associated with other modes of drug delivery (i.e. oral, intravenous). Because of the impermeable nature of the skin, designing a suitable drug delivery vehicle that penetrates the skin barrier is challenging. Gels are semisolid formulations, which have an external solvent phase, may be hydrophobic or hydrophilic in nature, and are immobilized within the spaces of a three-dimensional network structure. Gels have a broad range of applications in food, cosmetics, biotechnology, pharmatechnology, etc. Typically, gels can be distinguished according to the nature of the liquid phase, for example, organogels (oleogels) contain an organic solvent, and hydrogels contain water. Recent studies have reported other types of gels for dermal drug application, such as proniosomal gels, emulgels, bigels and aerogels. This review aims to introduce the latest trends in transdermal drug delivery via traditional hydrogels and organogels and to provide insight into the latest gel types (proniosomal gels, emulgels, bigels and aerogels) as well as recent technologies for topical and transdermal drug delivery.

SUV max as Predictor of Metastatic Disease on 18 F-FDG PET-CT in Hepatocellular Carcinoma.

OBJECTIVE: To ascertain the utility of maximum standardised uptake value (SUVmax) in 18F-FDG PET-CT in predicting metastatic disease burden in hepatocellular carcinoma (HCC) patients. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Nuclear Medicine and PET-CT Imaging, Institute of Nuclear Medicine and Oncology (INMOL), Lahore, Pakistan, from April to October 2022. METHODOLOGY: 18F-FDG PET-CT data of 87 patients were analysed prospectively. Patients were considered regardless of resection status. The SUVmax measurements were performed, and their association with metastases was determined. Molecular docking studies were conducted to determine a mechanism behind the higher SUVmax at the metastatic sites. RESULTS: A higher number of patients (49) was found to have metastasis (1 to 5 in numbers) and demonstrated higher SUVmax, especially in cases of pre-surgery and post-transplant state. A positive correlation existed between SUVmax of pre-surgery (r = 0.419, p = 0.001) and post-transplant patients (r = 0.779, p = 0.001). Molecular docking studies revealed a strong binding affinity (-5.18± 0.25 kcal/mol) between the hexokinase (HK-II) and 18F-FDG. CONCLUSION: SUVmax positively correlated with metastatic tumour burden. The strong binding affinity between the HK-II and 18F-FDG may be the reason. 18F-FDG PET-CT appeared beneficial in providing prognostic information for HCC in a selected group. KEY WORDS: Hepatocellular carcinoma, 18F-FDG, Positron emission tomography, Maximum standardised uptake value, SUVmax, HK-II binding, PET-CT, Metastases.

Oral Dispersible Films from Product Development to End-User Acceptability: A Review.

Orodispersible films (ODFs) have served as an emerging platform for the delivery of drugs in a convenient way. They have numerous advantages, the significant one is simplicity of administration for special populations such as pediatric and geriatric as well as patients with swallowing difficulty. Besides, the advantages include accurate dosing and fast action. The ODFs are efficiently designed with detailed knowledge of drug and polymers as well as a suitable selection of method. Many conventional and advance formulation strategies have been used for the development of ODFs. The biopharmaceutical concerns of active pharmaceutical ingredients (APIs) are given in this review in light of the fact that ODFs can be utilized to increase the bioavailability of APIs. The basic critical issues such as good mechanical properties, water solubility of the API and taste masking are very important to be considered during the development of ODFs. The knowledge of critical quality concerns of ODFs will be helpful in the future development of ODF. As ODFs remain in the mouth until complete degradation, taste, texture and mouth-feel are the qualities that in all respects liable for acceptability of the patient. An assortment of packaging choices is also accessible for ODFs. This review focuses on the different critical concerns of ODF related to composition, bio-pharmaceutical, manufacturing, quality tests, packaging and acceptability. Additionally, potential barriers in the ODFs development are discussed in details. Therefore, this review is an informative bundle of ODFs concerns from the product development stage to the end-user acceptability.

Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H.

Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., ATL1, FA2H, GJC2, AP4E1, ALDH18A1 and ATP13A2 have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase (FA2H) gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for FA2H will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families.

Clinical Biomarkers for Diagnosis of Damages in Individuals with Long-Term Exposure to X-Rays.

OBJECTIVE: To determine altered manifestation of plasma proteins in X-rays technicians who are regularly exposed to low doses of radiations over a long period during their job. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: District Headquarters Hospital and Mufti Mahmood Memorial Teaching Hospital; from January 2017 to January 2018. METHODOLOGY: The study enrolled 70 individuals consisting of 50 X-ray technicians working 8 to 12 hours/day for five days per week and 20 unexposed healthy controls. The serum protein expression pattern (concentrations of various serum proteins) was evaluated through cellulose acetate electrophoresis and serum antioxidant status was measured through ferric reducing ability of plasma (FRAP) assay. RESULTS: The antioxidant assay showed significantly low trolox-equivalent antioxidant capacity (TEAC) status and FRAP value in X-ray technicians as compared to controls (p<0.001). Analysis of serum protein demonstrated a significantly reduced concentrations of albumin (p<0.001) and elevated level of the Ɣ-globulins (p<0.001), while other globulins fractions like α1 and ß remain unchanged. There was a strong negative correlation (p<0.001) according to Pearson coefficient (r=87%⁽⁻⁾) between albumin and Ɣ-globulins fraction. Whereas, a positive correlation (p<0.001) (r=46%⁽⁺⁾) between alpha 1 globulin and albumin fraction was observed. A correlation between other globulin fractions and albumin was found statistically significant (p<0.001). CONCLUSION: Elevated serum gamma globulins may be a potential protein biomarker for triage and detection of X-radiation induced damages.

Simulation Studies and Dynamic Interaction of Venom Peptides with Ion Channels.

BACKGROUND: Arthropods such as scorpion, snake, insects, and spider as well as the marine animals like sea anemone and cone snails are venomous animals producing venoms with a complex mixture of peptide, poly peptides and small proteins. The disulfide rich peptides isolated from these animals are potent substances which specifically and selectively modulate different ion channels. The significant characteristics of these distinctive pharmacologically potent compounds highlights the molecular details of their peptide-ion channels interactions as well as provides the opportunities for the development of novel and natural therapeutic agents to treat various diseases including neurological disorders also. A good deal is going into the understanding of their therapeutic applications by unrevealing their mode of action. CONCLUSION: In this review, an attempt is made to summarizes the molecular behavior of these venom peptides, their pattern of interactions that how molecular simulation studies are used to investigate the dynamic interaction between these peptides and ion channels, structural prediction of peptide channel complex and calculation of binding free energy.

Immunomodulatory Effectiveness of Fish Oil and omega-3 Fatty Acids in Human Non-melanoma Skin Carcinoma Cells.

Fish oil is composed of various fatty acids among which omega-3 fatty acids are considered as most beneficial. The effects of fish oil on the activity of a topical anticancer drug, imiquimod, and the immunomodulatory activity of omega-3 fatty acids was investigated in human basal and squamous cell carcinoma cell lines. Imiquimod-fish oil mixture exhibited higher carcinoma cell growth inhibition and immunomodulatory activity than imiquimod alone, especially against squamous cell carcinoma cells. Omega-3 fatty acids exhibited growth inhibition of both basal cell and squamous cell carcinoma cell lines and modulated the immune response. Omega-3 fatty acids of fish oil serve as inducers of interleukin-10, an anti-inflammatory cytokine, and as suppressors of interleukin-6 and tumor necrosis factor-alpha, which not only depress tumor growth but also adequately control the inflammatory side effects of imiquimod. Thus, imiquimod administration with fish oil could be beneficial for inhibition of non-melanoma skin carcinoma cells but further in vivo studies are needed to understand their role in skin cancer.

Corticotropin-releasing hormone directly stimulates cortisol and the cortisol biosynthetic pathway in human fetal adrenal cells.

Near term the human fetal adrenals (HFAs) initiate production of cortisol, which promotes organ maturation and acts to increase placental CRH biosynthesis. The objective of the present study was to determine whether CRH directly stimulates both cortisol production and expression of the steroidogenic enzymes in HFA-definitive zone cells. CRH stimulated the production of cortisol in a time- and dose-dependent manner, with an effective concentration of as low as 0.01 nm. In real-time RT-PCR experiments, CRH treatment increased the mRNA levels of steroidogenic acute regulatory protein and each of the enzymes needed to produce cortisol. CRH induced 3beta-hydroxysteroid dehydrogenase type II (HSD3B2) by 34-fold, 21-hydroxylase (CYP21) by 55-fold, and 11beta-hydroxylase by 41-fold. Induction of steroidogenic acute regulatory protein, cholesterol side chain cleavage (CYP11A), and 17alpha-hydroxylase (CYP17) mRNA by CRH was 6-, 4-, and 6-fold, respectively. We also demonstrated that submaximal concentrations of CRH (30 pm) and ACTH (30 pm) that are seen in fetal circulation were additive on cortisol biosynthesis and 3beta-hydroxysteroid dehydrogenase type II mRNA induction. We suggest that CRH may play an important role in the late gestational rise in cortisol secretion from the HFAs, which may serve to augment placental CRH production and therefore participate in the endocrine cascade that is involved in fetal organ maturation and potentially in the timing of human parturition.

Expression profiles for steroidogenic enzymes in adrenocortical disease.

CONTEXT: Excess production of aldosterone or cortisol has profound effects on cardiovascular function and impacts other major organ systems. The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in aldosterone-producing adenoma (APA) or cortisol-producing adenoma (CPA) are unknown. OBJECTIVE: The objective of this study was to compare the expression profiles of several steroid-metabolizing enzymes and transcription factors from normal adrenal (NA), APAs, and CPAs. DESIGN: RNA from NAs, APAs, and CPAs were analyzed by microarray and real-time RT-PCR. SETTING: This study was performed at academic research laboratories. PATIENTS: At least nine normal controls and 12 patients with APA or CPA were studied. INTERVENTION: There was no intervention procedure. MAIN OUTCOME MEASURE: The main outcome measure was the expression of steroidogenic enzymes in adrenocortical disease. RESULTS: A microarray indicated a greater than 3-fold increase in the expression of CYP11B2 (aldosterone synthase) in APA, whereas 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) and HSD17B1 had greater than 3-fold increases in expression in CPA compared with NA. Real-time RT-PCR showed that APAs produced higher levels of HSD3B2, CYP21 (21-hydroxylase), and CYP11B2 mRNA, whereas CPAs produced higher levels of CYP11A (cholesterol side-chain cleavage), CYP17 (17alpha-hydroxylase/17-20 lyase), HSD3B2, and CYP11B1 (11beta-hydroxylase) mRNA compared with normal adrenal. Steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome gene 1), and GATA-6 were expressed at higher levels in APAs and CPAs, whereas NURR1 was expressed at higher levels in APAs than in CPAs or NAs. CONCLUSION: Elevated production of aldosterone in APAs and of cortisol in CPAs is associated with increased expression of enzymes needed for corticosteroid production along with alterations in transcription factors that enhance the expression of steroid-metabolizing enzymes.

Probing the effects of fish oil on the delivery and inflammation-inducing potential of imiquimod.

Imiquimod is a chemotherapeutic agent for many skin-associated diseases, but it has also been associated with inflammatory side effects. The aim of this study was to prevent the inflammatory effect of commercial imiquimod (Aldara(®)) by controlled release of imiquimod through a hydrogel/oleogel colloidal mixture (CA bigel) containing fish oil as an anti-inflammatory agent. Imiquimod permeability from Aldara® cream and bigel through mice skin was evaluated, and the drug content residing in the skin via the tape stripping technique was quantified. The fish oil fatty acid content in skin along with its lipophilic environment was also determined. An inflammation study was conducted using animal models, and Aldara(®) cream was found to potentially cause psoriasis-like inflammation, which could be owing to prolonged application and excessive drug permeation. Controlled release of imiquimod along with fish oil through CA bigel may have caused reduced imiquimod inflammation. NMR studies and computerized molecular modeling were also conducted to observe whether the fish oil and imiquimod formed a complex that was responsible for improving imiquimod transport and reducing its side effects. NMR spectra showed dose-dependent chemical shifts and molecular modeling revealed π-σ interaction between EPA and imiquimod, which could help reduce imiquimod inflammation.

Sex differences in adrenal androgens.

The primate adrenal cortex secretes high levels of 19 carbon (C19) steroids including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione. These steroids exhibit weak androgenic activity but serve as precursors for estrogens and active androgens such as testosterone. Thus, they are commonly known as adrenal androgens. Age-related changes in adrenal androgen production are well-described in humans and other primates. This article discusses the evidence for sex differences in adrenal androgen production in humans and both nonhuman primate and nonprimate animal models, which present varying degrees of sexual dimorphism in adrenal structure and function. Possible mechanisms underlying these gender differences and their relevance to human adrenocortical physiology will be discussed. Although animal and human studies have provided insight into the regulation of adrenal androgen production, the basis of the observed sex differences remains poorly understood. The putative modulation of adrenal androgen production by sex steroids merits further research, as does the possibility of gender-specific differences in adrenocortical zonation.

The human fetal adrenal: making adrenal androgens for placental estrogens.

During most of gestation, the fetal adrenal gland is almost solely dedicated to the production of dehydroepiandrosterone sulfate (DHEA-S). This specialized ability of the fetal adrenal is unique to primates and occurs because of a specialized fetal zone that composes the bulk of the fetal adrenal gland. Morphologically and physiologically, the human fetal adrenal (HFA) glands are remarkable organs. The glands at term are almost the size of the fetal kidney due in large part to the presence of the fetal zone, which at term produces more steroid than is normally secreted by adrenal glands of the adult. Much of the steroid released by the fetal zone is DHEA-S, which is used by the placenta to produce estrogens. Herein, we review the features of the HFA gland, including its impressive ability to synthesize large amounts of adrenal androgens for use by the placenta to produce estrogens.

Gene therapy and reproductive medicine.

OBJECTIVE: To review the literature on the principles of gene therapy and its potential application in reproductive medicine. DESIGN: Literature review. SETTING: Gene therapy involves transfer of genetic material to target cells using a delivery system, or vector. Attention has primarily focused on viral vectors. Significant problems remain to be overcome including low efficacy of gene transfer, the transient expression of some vectors, safety issues with modified adenoviruses and retroviruses, and ethical concerns. If these issues can be resolved, gene therapy will be applicable to an increasing spectrum of single and multiple gene disorders, as the Human Genome Project data are analyzed, and the genetic component of human disease becomes better understood. Gynecologic gene therapy has advanced to human clinical trials for ovarian carcinoma, and shows potential for the treatment of uterine leiomyomata. Obstetric applications of gene therapy, including fetal gene therapy, remain more distant goals. CONCLUSION(S): Concerns about the safety of human gene therapy research are being actively addressed, and remarkable progress in improving DNA transfer has been made. The first treatment success for a genetic disease (severe combined immunodeficiency disease) has been achieved, and ongoing research efforts will eventually yield clinical applications in many spheres of reproductive medicine.