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Biomedical subjects

K E McKenna

Publications and source records attributed to K E McKenna.

At least 19 recordsLinked to original sources
PubMed2006

Evidence-based practice of photopheresis 1987-2001: a report of a workshop of the British Photodermatology Group and the U.K. Skin Lymphoma Group.

Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy which involves separation of the patient's leucocyte-rich plasma, followed by ex vivo administration of a photosensitizer and ultraviolet A radiation, before reinfusion. ECP has been used successfully for the treatment of cutaneous T-cell lymphoma (CTCL: Sézary syndrome), graft-versus-host disease (GVHD) and cardiac transplant rejection. ECP has a dose-sparing effect on concurrent immunosuppressive therapy. The procedure induces apoptosis of the irradiated lymphocytes, but the exact mechanism by which ECP exerts its therapeutic effect in these different conditions is uncertain. The treatment has very few adverse effects and in particular is not associated with an increased incidence of opportunistic infections. The evidence for the efficacy of ECP has been appraised by a combined British Photodermatology Group and U.K. Skin Lymphoma Group workshop on the basis of evidence published up to the end of 2001 and on the consensus of best practice. There is fair evidence for the use of ECP in erythrodermic CTCL and steroid-refractory GVHD, but randomized controlled studies are needed. There is good evidence supporting the use of ECP in preventing cardiac rejection following transplantation. Randomized controlled trials have also shown a therapeutic benefit in type 1 diabetes mellitus, but the inconvenience associated with the procedure outweighed the clinical benefit. There is fair evidence not to use ECP for the treatment of systemic sclerosis and multiple sclerosis, and good evidence not to use ECP for other forms of CTCL.

Combined Modality Therapy↗
PubMed2006

Mutation analysis in Irish families with glomuvenous malformations.

BACKGROUND: Glomuvenous malformations (GVMs) are rare bluish lesions that can affect the skin and mucosal surfaces. They represent defects in vasculogenesis. Lesions can occur sporadically or in an autosomal dominant mode of inheritance. Recent studies have shown that mutations in the glomulin gene (GLMN) on chromosome 1p21-22 are responsible for familial GVMs. OBJECTIVES: To search for mutations in GLMN in Irish families with GVMs. METHODS: We identified four Irish families with GVMs and confirmed linkage to chromosome 1p21-22 in these cases. We sequenced the glomulin gene in all affected and unaffected members of the families. Results Linkage analysis showed that affected individuals from the families shared a common haplotype. Mutation analysis revealed a delAAGAA mutation in exon 3 of the glomulin gene in all four families with GVMs. CONCLUSIONS: We confirm that mutations in the glomulin gene are responsible for GVMs and suggest a founder Irish mutation in the glomulin gene in four Irish families.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The effect of ultra violet B (TL-01) phototherapy on epidermal expression of p53 protein in psoriatic plaques.

BACKGROUND: Psoriasis is a genetically determined inflammatory skin disease. It is now recognized that narrow band TL-01 phototherapy is an effective treatment for psoriasis. However, ultraviolet (UV) exposure induces p53 mutations in keratinocytes and repeated exposure of skin to UV radiation results in clonal expansion of these initiated p53-mutant cells within the epidermis. AIM: The present study aims to examine epidermal p53 expression in the skin of psoriatic patients at different time points following TL-01 phototherapy. METHODS: Skin samples from patients suffering from plaque-type psoriasis, collected before, during and at the final stages of TL-01 phototherapy were examined for p53 expression by immunohistochemistry. RESULTS/CONCLUSION: Our results showed an increase in p53 expressing keratinocytes following TL-01 phototherapy. Some of these cells were arranged spatially, as conical clones arising from putative stem cell compartments, suggesting that the chronic TL-01 treatment might have triggered cell growth and clonal expansion, an important step in initiating skin carcinogenesis.

Adult↗
PubMed2005

Sonic hedgehog, the penis and erectile dysfunction: a review of sonic hedgehog signaling in the penis.

The sinusoid anatomy of the penis is complex and requires complicated interaction between smooth muscle and endothelium in order to maintain homeostasis in the adult. The morphogen, Sonic hedgehog (Shh), is a crucial regulator of these processes, along with its down stream targets patched (Ptc), Hox, bone morphogenetic proteins (BMP's), vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS). Shh is critical for patterning and establishing tissue identity of the penis during embryonic development, is a crucial regulator of penile postnatal differentiation of the sinusoid morphology of the corpora cavernosa, and plays a fundamental role in maintaining sinusoidal structures pertinent to erectile function in the adult rat. Shh and its targets are active in human penes, and decreased in human diabetic penes in parallel with observations in the rat, thus lending clinical significance to the role of abnormal Shh signaling in erectile dysfunction (ED). Application of exogenous Shh protein to rat corpora cavernosa, induces VEGF and NOS proteins, suggesting a potential mechanism through which decreased Shh protein can cause ED. The studies outlined in this review provide in depth analysis of the Shh pathway and signal transduction, its role in penile development, how Shh signaling is altered in a rat model of ED and neuropathy, how abnormal Shh signaling can cause ED, and the clinical significance of the Shh pathway to human ED. These studies will provide valuable insight, at the molecular level, into understanding the mechanisms that under lie ED and lead to new treatment strategies for diabetic impotence.

Animals↗
PubMed2004

Iatrogenic skin cancer: induction by psoralen/ultraviolet A and immunosuppression of organ transplant recipients.

Photochemotherapy (psoralen/UVA (PUVA)) is an efficient therapeutic tool for a wide range of skin diseases. Concern, however, exists regarding the long-term carcinogenic effects of this treatment modality and, as a consequence, is being used less frequently. PUVA remains an important treatment in our therapeutic armamentarium but must be used with caution in those patients with risk factors and cumulative dose exposure must be limited. PUVA-induced cancers show features in common with skin cancers induced by immunosuppressed organ transplant recipients. Tumours in the latter group of individuals are, however, much more aggressive and difficult to manage.

Ficusin↗
PubMed2003

Combination TL01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial.

BACKGROUND: Previous studies have demonstrated the ultraviolet (UV)-sparing effect of combining topical calcipotriol with broadband UVB in the treatment of psoriasis. OBJECTIVES: To determine if the combination of narrowband TL01 UVB phototherapy and topical calcipotriol produces the same UVB-sparing effect. METHODS: This was a randomized, placebo-controlled, blinded clinical trial. Fifty psoriasis patients were recruited, 25 of whom were randomized into the active group who received TL01 phototherapy together with twice-daily application of calcipotriol cream 50 microg g(-1). The control group received TL01 phototherapy and twice-daily application of a topical emollient as placebo. TL01 phototherapy was given three times per week starting at 70% minimal erythema dose with 20% increments as tolerated for up to approximately 20 sessions. Patients were assessed using the Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI). They were evaluated at treatment sessions 8, 14 and 20, and followed up at 5 and 10 weeks post-treatment. Statistical analysis was performed using a two-tailed t-test. RESULTS: There were no significant differences in demographic characteristics and baseline PASI and PDI scores between the two groups. The mean PASI score declined significantly (P < 0.01) for both groups after treatment. The difference in mean PASI score reduction from baseline between the two groups was only significant during the first eight sessions, with a net reduction of 3.6 (95% confidence interval 1.0-6.2, P = 0.008) in the active group relative to the control group. The mean PDI score declined significantly (P < 0.05) for both groups, but there was no statistical difference in mean PDI score reduction between the two groups (P = 0.8) at the end of treatment. The mean cumulative UVB dose for the active group was significantly lower (P < 0.02) at 16 204 mJ cm-2 compared with 21 082 mJ cm-2 for the control group. CONCLUSIONS: We conclude that combining TL01 phototherapy with topical calcipotriol cream has a UVB-sparing effect.

Adult↗
PubMed2002

alpha(2a) and alpha(2c) adrenoceptors on spinal neurons controlling penile erection.

The thoracolumbar and lumbosacral spinal cord contain respectively sympathetic and parasympathetic preganglionic neurons that supply the organs of the pelvis including the penis. These neurons are influenced by supraspinal information and receive aminergic projections from the brainstem. The presence of the alpha(1)- and alpha(2)-adrenoceptor subtypes has been demonstrated in the rat spinal cord. In this species, we looked for the presence of alpha(2a)- and alpha(2c)-adrenoceptor subtypes in the sympathetic and parasympathetic preganglionic neurons controlling erection. In adult male rats, transsynaptic axonal transport of pseudorabies virus injected into the penis was combined with immunohistochemistry against alpha(2a)- and alpha(2c)-adrenoceptor subtypes. At 4 days survival time, neurons infected with the pseudorabies virus were solely found in the intermediolateral cell column and dorsal gray commissure of segment T12-L2 and in the intermediolateral cell column of segment L6-S1. Neurons and fibers immunoreactive for alpha(2a)- and alpha(2c)-adrenoceptor subtypes were mainly present in the intermediolateral cell column, the dorsal gray commissure and the ventral horn of the T12-L2 and L5-S1 spinal cord, the dorsal horn displayed only immunoreactive fibers. Pseudorabies virus-infected neurons in the autonomic nuclei were both immunoreactive for alpha(2a)- and alpha(2c)-adrenoceptor subtypes and closely apposed by alpha(2a)- and alpha(2c)-immunoreactive fibers. The results suggest an intraspinal modulation of the noradrenergic and adrenergic control of the autonomic outflow to the penis by pre- and postsynaptic alpha(2) adrenoceptors.

Animals↗
PubMed2001

Analysis of NOS isoform changes in a post radical prostatectomy model of erectile dysfunction.

Optimal treatment of erectile dysfunction (ED) following radical prostatectomy remains a subject of much controversy and is a significant concern for prostate cancer patients requiring surgical intervention. Neural stimulation involving nitric oxide synthase (NOS) is a crucial aspect of the normal erection process. In this study NOS isoform interaction was evaluated to improve our understanding of molecular changes pertaining to erection post radical prostatectomy. Bilateral cavernous nerve (CN) resected and control adult male Sprague-Dawley rats were killed 7, 14 and 21 days after injury. RT-PCR, in situ hybridization, Western blot and immunohistochemical analysis were used to evaluate changes in NOS isoform expression and distribution. NOS-I protein was dramatically decreased after CN injury while NOS-III and NOS-II remained unchanged. A profound decrease in smooth muscle and endothelium was observed in the corpora. To our knowledge this is the first report of differential altered NOS isoform protein abundance under conditions which mimic radical prostatectomy. These results show the importance of maintaining at least partial innervation of the penis after surgical intervention and that endothelial and smooth muscle changes resulting from loss of innervation may account for the ED observed in prostatectomy patients.

Actins↗
PubMed2001

Neural circuitry involved in sexual function.

BACKGROUND: Neurological injury results in devastating sexual deficits in both men and women. Effective treatment requires an understanding of the central nervous system (CNS) pathways and physiology. This article emphasizes the essential similarities in the pathways and physiology of sexual function in men and women. METHODS: Literature review. FINDINGS: Systems within the spinal cord are fully capable of generating a large number of sexual responses. Spinal sexual centers may be activated by genital afferents or by descending commands from higher CNS sites. Normal functioning probably involves activation of spinal centers by both descending pathways and afferent stimulation. Afferent stimulation also modulates the activity of supraspinal sites, creating a positive feedback system. Descending control consists of powerful inhibitory and excitatory pathways. An important serotonergic inhibitory pathway has been demonstrated. The medial preoptic region participates in the integration of hormonal and sensory cues necessary for sexual behavior. The medial amygdala and paraventricular nucleus of the hypothalamus also play essential excitatory roles. The paraventricular nucleus projects directly to relevant spinal sites, indicating another important pathway for excitatory control. CONCLUSIONS: Recent advances have markedly enhanced our understanding of the physiology, pharmacology, molecular biology and pathology of sexual mechanisms. This knowledge base is essential in order to understand changes in sexual mechanisms that follow spinal cord injury, and for the development of effective interventions to maximize sexual function in men and women with spinal cord injury.

Animals↗
PubMed2001

Characterization and localization of nitric oxide synthase isoforms in the BB/WOR diabetic rat.

PURPOSE: Erectile dysfunction is a common pathological development in individuals with diabetes mellitus. Nitric oxide synthase (NOS) is essential for regulation of normal penile erection and NOS protein activity has been shown to be altered with diabetes. Several different isoforms and subtypes of NOS exist. However, little is known about how the distribution and abundance of these isoforms are altered with diabetes. We characterized the distribution and abundance of NOS isoforms and explored how they are altered with diabetes and result in erectile failure. MATERIALS AND METHODS: In situ hybridization and quantitative reverse transcriptase-polymerase chain reaction were done to measure the abundance and distribution of NOS-Ia, NOS-Ib, NOS-Ic, NOS-II and NOS-III in control and diabetic (BB/WOR) rats. Protein was localized by immunohistochemical analysis and alterations in protein abundance with diabetes were examined by Western blot analysis. RESULTS: NOS-I, NOS-II and NOS-III were observed in the endothelium lining the cavernous spaces and in the epithelium of the urethra. NOS-I protein was also present in the nerves of control and diabetic penes. We observed an increase in NOS-II expression around the dorsal nerves of diabetic penes, a decrease in NOS-III expression in diabetic pelvic ganglia and a decrease in NOS-Ib expression in the diabetic penis. NOS-I protein abundance was significantly decreased in diabetic pelvic ganglia. CONCLUSIONS: To our knowledge this is the first report of regional differences in the distribution of NOS-III in the urethra and altered NOS-Ib gene expression with diabetes.

Animals↗
PubMed2000

Some proposals regarding the organization of the central nervous system control of penile erection.

Recent research on the central nervous control of penile erection is discussed. A framework for this control is based upon principles put forward by Frank Beach regarding the neuroendocrine regulation of male copulatory behavior. The current discussion is focused primarily on a subset, penile erection. The spinal cord contains all the necessary components for the production of penile erection. This requires a multisegmental coordination among penile vasodilator and vasoconstrictor autonomic neurons, pudendal motoneurons responsible for penile rigidity and autonomic neurons which control extra-penile blood flow. Genital sensory stimulation can activate this spinal network. The spinal cord is also under excitatory and inhibitory control from supraspinal sites. Penile erection can be driven by supraspinal input alone and supraspinal control can inhibit the erectile effects of genital stimulation.An important aspect of the CNS control of penile erection is that there are extensive interconnections between most of the brain sites identified to date. Most of the pathways are characterized by reciprocal connections. A large number of the CNS sites also receive genital sensory information. Thus, descending control may itself be modulated by ascending sensory pathways which relay information from the genitalia. This raises the possibility that penile erection may involve a positive feedback system. Receptors for gonadal hormones have been identified throughout the neuraxis. However, strong evidence for the control of male sexual function by gonadal hormones has been identified only for forebrain sites. The functional role of brainstem and spinal gonadal hormone receptors has not yet been clarified.

Animals↗
PubMed2000

Pulmonary toxicity in a patient with psoriasis receiving methotrexate therapy.

We report a 34-year-old woman with psoriasis who developed shortness of breath during methotrexate therapy. Methotrexate had been started 4 months earlier and the patient had ingested a cumulative dose of 232 mg. Pulmonary function tests showed a reduction in transfer factor to 76% of predicted. Methotrexate was stopped and her symptoms rapidly resolved. Pulmonary function tests deteriorated further despite stopping methotrexate but with no recurrence of symptoms with a transfer factor of 66% of predicted 2 months later. At 5 months after stopping methotrexate the patient remained well and pulmonary function had improved with a transfer factor of 79% of predicted. Pulmonary toxicity is a rare but important adverse effect of methotrexate therapy in patients with psoriasis.

Adult↗