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Tic disorders in childhood.

Despite our familiarity with tic disorders, their management remains challenging. The difficulty seldom relates to the diagnosis, which is usually based on the history, but rather in dealing with the impact of the tics and multiple comorbidities. The child and family must be educated and must be taught how to facilitate a positive attitude among others who come in contact with the patient. Knowledge and acceptance of the tics by other family members, peers, teachers, and coaches often become central to the child's well-being. Although many children can be managed without pharmacotherapy, medications are often central to achieving success. The goals of therapy and the appropriate choice of medication must be individualized. We are frequently challenged not only by the wide array of medication choices available but also by the decision of which symptom to treat first. The tics, despite being flamboyant, are often viewed by the child and family as less disabling than co-occurring conditions, such as attention-deficit hyperactivity disorder, obsessive-compulsiveness, or rage. Even when tics are the major issue, patients must define their goals for therapy. It is unreasonable to expect a complete resolution of tics and safety usually rules in favor of better tolerated but potentially less efficacious therapies. Developing strategies to minimize the lifelong impact of the multiple components of Tourette syndrome is an essential aspect of the care of these patients.

Adolescent↗

Molecular and cellular mechanisms of protective immunity to coccidioidomycosis.

Coccidioides immitis is endemic in the soil of the desert Southwest. It causes a respiratory infection that is usually mild, but can last months and may disseminate beyond the lung. Disseminated infections can be fatal or require life-long therapy. Development of an effective vaccine may be a successful method of preventing serious disease. In this paper, we show that immunostimulatory-oligodeoxynucleotides (ISS-ODN) are an effective adjuvant for a recombinant coccidioidal protein known as antigen 2/proline rich antigen. Protective immunity induced by this ISS-ODN-based vaccine requires IL-12, interferon-gamma and MHC Class II-restricted T-cells. Cytotoxic CD8 T-cells are not required. This study elucidates the mechanisms needed to elicit successful immunity against coccidioidomycosis, and holds promise for development of an effective coccidioidal vaccine against coccidioidomycosis.

Adjuvants, Immunologic↗

Assessment of sexual functioning: sexual history taking for health care practitioners.

It is important for clinicians to inquire about sexual functioning as part of routine mental and physical health care. General guidelines for taking a skillful and sensitive sexual history are given, including ways to initiate discussions and make the patient feel more at ease. In addition, a sample comprehensive sexual history is presented. This is a revised version of the Integrated Model of Sexual Therapy developed by Helen Singer Kaplan, M.D., Ph.D. It includes a large number of sample questions, which are organized according to such categories as exploring the chief complaint, the sexual status examination, and the medical, psychiatric, family, psychosexual, and relationship histories. Additional questions pertaining to epilepsy and the prevention of sexually transmitted diseases are also included.

Epilepsy↗

The genesis of RNA interference, its potential clinical applications, and implications in gynecologic cancer.

OBJECTIVE: This review will discuss the discovery and development of RNA interference (RNAi) technology, small interfering RNA (siRNA) design and delivery, and the implications of RNAi on gynecologic cancers. METHODS: Systematic review of English language literature using searches for RNAi and gynecologic cancers in established databases, including Pubmed and Ovid, was employed. RESULTS: The high degrees of efficiency and specificity are the main advantages of RNAi. Consequently, RNAi is used in functional genomics and developing therapies for the treatment of viral infection, dominant disorders, neurological disorders, and cancers, including gynecologic cancers. CONCLUSION: RNAi represents an exciting technology for functional genomics by selective targeting of genes. While issues regarding delivery remain, the therapeutic advantages of siRNA in cancer treatment warrant further investigation.

Animals↗

Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture.

PURPOSE: To compare the clinical findings of the various forms of stationary night blindness caused by mutations in identified genes encoding proteins of photoreceptors or the retinal pigment epithelium. METHODS: Review of the visual acuities, visual fields, fundi, dark-adaptation curves, and electroretinograms from patients with stationary night blindness caused by mutations in the genes RHO, GNAT1, PDE6B, RHOK, SAG, RDH5, and CACNA1F, respectively encoding rhodopsin, the alpha subunit of rod transducin, the beta subunit of rod cGMP-phosphodiesterase, rhodopsin kinase, arrestin, 11-cis retinol dehydrogenase, and a retinal L-type calcium channel. RESULTS: In the evaluated forms of stationary night blindness, the time course of dark adaptation and the characteristics of the electroretinogram indicate that rod photoreceptors are present and that they function, although abnormally. In night blindness resulting from defects in rhodopsin, the alpha subunit of rod transducin, or the beta subunit of rod cGMP phosphodiesterase, rod photoreceptors respond only to light intensities far brighter than normal, and the sensitivity of rods to light is similar to that of normal individuals who are not dark adapted. In fundus albipunctatus and in Oguchi disease, the rod photoreceptors can achieve normal sensitivity to dim light but only after 2 or more hours of dark adaptation, compared with approximately 0.5 hours for normal individuals. In each of these forms of stationary night blindness, the poor rod sensitivity and the time course of dark adaptation correlate with the known or presumed physiologic abnormalities caused by the identified gene defects. Patients with some forms of stationary night blindness, such as fundus albipunctatus and Oguchi disease, may develop degeneration of the retina leading to severe loss of vision in later life. CONCLUSIONS: The identification of the mutant genes causing forms of stationary night blindness refines the classification of these diseases and enhances our understanding of the underlying physiologic defects. Ophthalmologists must be aware that although these diseases are traditionally categorized as "stationary," some of them lead to reduced visual acuity or constricted visual fields, especially in older patients. Efforts to develop therapies for these diseases should concentrate on these more severe forms.

Amino Acid Sequence↗

Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N-methyl-D-aspartate-evoked adenosine formation in cortex.

Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-D-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5'-amino-5'-deoxyadenosine (0.2 microM) or 5'-iodotubercidin (0.01 microM) with a low concentration of the adenosine deaminase inhibitor 2'-deoxycoformycin (0.2 microM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5'-amino-5'-deoxyadenosine (0.2 microM) or 5'-iodotubercidin (0.01 microM) with a maximal concentration of 2'-deoxycoformycin (200 microM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.

Adenosine↗

Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata.

OBJECTIVE: To review the available information regarding the role of cytokines, growth factors, and the extracellular matrix in the pathophysiology of uterine leiomyomata and to integrate this information in a suggested model of disease at the cellular level. DESIGN: A thorough literature and MEDLINE search was conducted to identify the relevant studies in the English literature published between January, 1966 and October, 2001. A model of disease at the cellular level was developed using the most likely cytokines to be involved in the pathogenesis of leiomyomata as determined by our assessment of the available literature. RESULT(S): A number of cytokines and growth factors, including transforming growth factor-beta (TGF-beta), epidermal growth factor, monocyte chemotactic protein-1, insulin-like growth factors 1 and 2, prolactin, parathyroid-hormone-related peptide, basic fibroblast growth factor, platelet-derived growth factor, interleukin-8, and endothelin, have been investigated in myometrium and leiomyoma. Among these cytokines, TGF-beta appears to be the only growth factor that has been shown to be overexpressed in leiomyoma vs. myometrium, be hormonally-regulated both in vivo and in vitro, and be both mitogenic and fibrogenic in these tissues. In addition to the cytokines, extracellular matrix components such as collagen, fibronectin, proteoglycans, matrix metalloproteinases, and tissue inhibitors of metalloproteinases seem to play pivotal roles in the pathogenesis of leiomyomata. CONCLUSION(S): We believe that, given the extent and depth of the current research on the cellular biology of leiomyomata, the cellular mechanisms responsible in the pathogenesis of leiomyomata will be identified clearly within the foreseeable future. This will enable researchers to develop therapy directed against the molecules and mechanisms at the cellular level.

Cytokines↗

CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys.

Lipoprotein(a) (Lp(a)), which is generated through the covalent association of apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independent risk factor for several vascular diseases. Therefore, there is interest in developing therapies for lowering Lp(a). This investigation was carried out to determine the effect of CI-1011, a potent lipid regulator in rodents, on Lp(a) and other lipid parameters in cynomolgus monkeys (Macaca fascicularis). Nine healthy male monkeys on a normal chow diet were orally treated with CI-1011 at 30 mg/kg per day for 3 weeks. Lp(a) and total cholesterol levels were significantly decreased after 1 week and maximally reduced to 68 and 73% of control levels, respectively, after 3 treatment weeks. The decreases in total cholesterol were mainly due to changes in low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides were unaffected by treatment. Lp(a) and total cholesterol levels returned to pretreatment values after stopping treatment suggesting a direct effect of the compound on their inhibition. Further studies demonstrated that CI-1011 was effective at a low dose of 3 mg/kg per day after 1 week of administration. CI-1011 also decreased apo B-100 to 80% of control levels, but this change was not sufficient to account for the Lp(a) lowering. There was also no correlation between the changes in Lp(a) and apo B-100 levels. Treatment of cynomolgus monkey primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition of Lp(a) levels suggesting a direct hepatic effect of the compound. Western blot analysis of the samples showed that changes in Lp(a) were associated mainly with decreased apo(a) (47%), but not apo B-100 (17%). These results demonstrate that CI-1011 effectively decreases Lp(a) levels both in vivo and in vitro.

Acetamides↗

Cell proliferation and apoptosis in experimental lung hypoplasia.

BACKGROUND/PURPOSE: Current treatment for lethal pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) may be hampered by uncertainty over its origin. Herniation of abdominal organs into the chest was thought to produce lung hypoplasia by compression. Experimental CDH models suggest that disturbed lung growth precedes these events. Mammalian development comprises cell differentiation, proliferation and programmed cell death or apoptosis. Could lung hypoplasia in CDH result from alterations in these processes well before visceral herniation takes place? The aim of this study was to compare cell proliferation and apoptosis in normal and hypoplastic embryonic lungs before normal diaphragmatic closure using a CDH model. METHODS: Sprague-Dawley rats were given 100 mg of nitrofen on day 9.5 of pregnancy to create lung hypoplasia and CDH in newborns (term, 22 days). Control rats received olive oil. Cell proliferation in embryonic lung specimens was measured by bromodeoxyuridine (BrdU) incorporation at 13.5 to 15.5 days' gestation, before normal diaphragmatic closure in this species (day 16.5). Apoptosis was measured by the in situ end-nick labelling (TUNEL) method in lung sections obtained from rat embryos of 13.5 to 16.5 days' gestation. RESULTS: High levels of cell proliferation were seen in both normal control and nitrofen-exposed lungs. However, 24 hours before normal diaphragmatic closure, nitrofen-exposed lungs had significant reductions in cell proliferation on day 15.5 of gestation (P = .009 v controls). Apoptosis occurred at low levels throughout the developmental stages examined (< 0.3%) without significant differences encountered between the study groups. CONCLUSIONS: These findings have shown high rates of cell division during normal lung development before diaphragmatic closure. Decreased levels over this critical period in gestation may contribute to early lung anomalies in the nitrofen CDH model. Strategies to promote cell proliferation in the fetal lung may therefore hold future promise in human CDH. Apoptosis appears not to play a major role in hypoplastic lung development. Therapies to inhibit apoptosis would seem unlikely to improve this early lung growth.

Animals↗

Xanthine calculi in the Lesch-Nyhan syndrome.

Urinary tract calculi composed primarily of xanthine are rare in adults and children. However, there is risk of xanthine calculi formation in children with hereditary xanthinuria and children on xanthine oxidase inhibitor therapy for hyperuricemia. We describe the clinical presentation and management of 2 children with the Lesch-Nyhan syndrome (a congenital disorder of purine metabolism) and xanthine calculi. Little information has been available to direct the urologic management of such patients. We have based a plan for management upon our clinical experience with these children, as well as upon in vitro dissolution studies of the calculi. We have had some clinical success using an alternating acid/base dissolution therapy developed in the laboratory.

Adolescent↗

Reversible galactorrhea and prolactin elevation related to fluoxetine use.

Fluoxetine, an antidepressant of the selective serotonin reuptake inhibitor class, may stimulate prolactin release by pituitary lactotrophs. A 71-year-old woman taking estrogen replacement therapy developed galactorrhea after initiation of fluoxetine for depression and was found to have an elevated prolactin level. Fluoxetine was discontinued with resolution of the patient's galactorrhea and normalization of her prolactin level.

Aged↗

Endovascular therapy for intracranial aneurysms: a historical and present status review.

Beginning in the 1960s, neurosurgeons and radiologists have made attempts to treat intracranial aneurysms using nonclip techniques. The evolution of such therapy has included acrylics, metallic particles, balloons, electric current, and nondetachable and detachable coils. This article will chronologically review these various techniques and the papers that reported their results so that the reader can understand how endovascular therapy developed and the position it currently holds in the treatment of intracranial aneurysms.

History, 20th Century↗

Surgical management of encapsulated filtering blebs.

Encapsulated filtering blebs associated with elevated intraocular pressure or symptomatic dellen formation, unresponsive to conservative therapy, developed in 24 of 222 eyes following glaucoma filtering surgery over a five-year period, an incidence of 11%. Nine of 13 eyes were treated successfully with primary needling of the bleb. Ten of 11 eyes were successfully treated with primary bleb revision. Four eyes were successfully treated with a combination of needling and surgical revision and one eye required cyclocryotherapy. The overall success rate of needling or bleb revision was 96% after an average follow-up of 20 months. Thus, encapsulation of the filtering bleb, although requiring additional surgery in many cases, carries a favorable long-term prognosis.

Cicatrix↗

A mutant streptokinase lacking the C-terminal 42 amino acids is less immunogenic.

Streptokinase (SK) is the most widely used compound for the treatment of myocardial infarction and the least expensive thrombolytic agent, but a drawback to its use is the widespread presence of anti-SK antibodies (Abs). Clinical failure of the activation of the fibrinolytic system by SK has been reported due to the presence of a high titer of anti-SK neutralizing Abs. Patients receiving SK therapy develop high anti-SK antibody titers, which might provoke severe allergic reactions. These Abs are sufficient to neutralize a standard dose of SK up to four years after initial SK administration. This is a clinical problem because of the increasing number of patients who have been treated once with SK for acute myocardial infarction (AMI) and are likely to require plasminogen activator treatment in the future. In previous in vitro studies, we have shown that a deletion mutant (mut-C42), lacking the 42 C-terminal residues, was significantly less antigenic when compared with the native molecule (SKC-2). In this study, 14 monkeys were subjected to treatment with SKC-2 and mut-C42 in order to compare their humoral response by determining SK neutralizing activity in monkey's sera. All monkeys developed anti-SKC-2 Ab titers, but in the case where treatment induced Abs directed against the C-terminus of SKC-2, neutralizing activity against the native protein was significantly higher than that developed against mutant SK mut-C42.

Animals↗

Qualitative research methods in otorhinolaryngology.

OBJECTIVE: Qualitative research methods explore the character and meaning of human phenomena. The methodology is unfamiliar to most clinicians, not only because of the different techniques and the type of studied issues, but also because of important differences regarding terminology and criteria for evaluating qualitative studies. This paper aims at discussing the potential contribution of qualitative methods to otorhinolaryngological research in general, and to describe a specific method with an otologic application in detail. METHOD: In order to explore different disturbing sound phenomena and coping strategies in patients with manifest tympanic membrane retractions, individual semi-structured interviews were performed. The transcripts were systematically analyzed by coding, categorizing, and interpreting the content of the text. The extracted themes, categories, and patterns were summarized. RESULTS: The method proved useful when exploring empirically known but non-measurable sound disturbances. Moreover, the findings provided further support for an alternative pathogenic theory suggesting the patient's playing an active role in the development of tympanic membrane retractions. CONCLUSIONS: Used as a complement to quantitative methods, qualitative methods offer a means for exploring the patient's experiences and role in the development, therapy, and prevention of disease. Otorhinolaryngology involves disorders of sensory functions such as hearing, equilibrium, smell and taste, as well as the vital functions of breathing and eating. The related symptoms might be experienced and coped with very differently depending on individual interpretations, fear of severe disease, etc. Furthermore, the clinician's and the patient's perspectives of symptoms and expectations regarding treatment may differ, which has implications for information, planning of therapy, and quality assessment in health care. There is no lack of study questions, but rather a lack of experience of alternative and pertinent methods.

Auditory Perception↗

Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis.

Tuberculosis (TB) remains a leading cause of infectious disease in the world today and therapies developed over the last forty years are becoming increasingly ineffective against resistant strains of Mycobacterium tuberculosis. In an effort to explore new mechanisms for drug development, we have investigated the enzymes of the diaminopimelate biosynthetic pathway as potential targets. Specifically, dihydrodipicolinate reductase, the essential gene product of dapB, was screened for novel inhibitors. Inhibitors were identified both by a molecular modeling approach which utilized the available crystal structure of the enzyme with an inhibitor bound at the active site as well as by more conventional screening strategies. The resulting compounds contain a number of structural motifs and were all found to be competitive with respect to the DHDP substrate. The K(i) values for the inhibitors range from 10 to 90 microM. The molecular modeling approach was very effective in identifying novel inhibitors of the enzyme. These compounds were obtained at a higher frequency based on the number of compounds analyzed than those inhibitors discovered via conventional screening. However, conventional screening proved beneficial in identifying compounds with greater structural diversity.

Antitubercular Agents↗

Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: a retrospective analysis of 149 patients.

PURPOSE: In order to obtain the standard treatment results of medically inoperable non-small cell lung cancer (NSCLC) in Stage I in the post-CT scan era, a retrospective analysis of patients who were treated by radical radiotherapy was performed. METHODS AND MATERIALS: 149 cases treated between 1980 and 1989 were accumulated from ten large hospitals in Japan. All patients received a total dose of 55-75 Gy (mean 64.7 Gy) with conventional fractionation. For evaluation of treatment results, complete response (CR) rate, median survival period and long-termed survival rates were used. RESULTS: The median survival of the all cases was 27.2 months and the actuarial 3- and 5-year survival rates were 34.2% and 22.2%, respectively. CR was obtained in 57 cases (38%). The CR rate was strongly correlated with the long-term survival (5-year survival rate in CR group: 35.1% compared with PR + NC group: 14.1% (P < 0.0001)). The size of tumor was also of prognostic importance. In 116 patients who died within 5 years after treatment, 66 patients (57%) died of local tumor regrowth. CONCLUSION: Although the medically inoperable NSCLC patients in Stage I should be offered curative radiation therapy, development of some new steps to increase the CR rate and local control rate is urgently needed.

Aged↗

Congenital "self-healing" Langerhans cell histiocytosis: the need for long-term follow-up.

Congenital self-healing Langerhans cell histiocytosis (CSHLCH) is a rare disorder initially seen at birth or in the newborn period with spontaneously involuting skin lesions. In contrast to other forms of Langerhans cell histiocytosis in infancy, such as Letterer-Siwe disease, the prognosis of CSHLCH is generally good. We describe four children with widespread CSHLCH at birth. In all patients a congenital infection was initially suspected. All patients, except one who had transient lower extremity edema and pulmonary symptoms, had an uncomplicated neonatal course, and in all patients skin lesions resolved spontaneously. Two patients showed no further evidence of disease, but one had a cutaneous relapse at age 3 months, and in another a bony relapse that required systemic therapy developed at 6 months of age. CSHLCH is usually a benign, self-limited condition, but careful evaluation for systemic disease must be performed. Long-term follow-up for evidence of relapse or progression of disease is essential.

Female↗