GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness

Traditional Chinese drugs (TCDs) have played a key role for Chinese people in the treatment of diseases since ancient times. The use of TCDs has generated a great amount of information in the past thousand years about the relationship between natural products and the human body. However, up to now, our understanding on the mode of action of the TCD is still limited. Considering that the basic mechanism of all drug function involves the interaction between the drug and biological receptors at the molecular level, we propose to connect TCDs with modern medicine theory through molecular structures. We propose to explain functions of TCDs by using the knowledge developed in modern molecular biology, pharmacology, computer chemistry, and biochemistry. We are working on a computer-aided Chinese drug study that is discussed in this paper. A short introduction on the progress of our research is also given.     

Modification of a receptor-binding surface of epidermal growth factor (EGF): analogs with enhanced receptor affinity at low pH or at neutrality

Six mutants of human epidermal growth factor (EGF), which carry single point substitutions within a surface patch proposed to juxtapose the bound receptor, were prepared and characterized for receptor affinity and mitogenicity. Receptor affinities relative to EGF are G12Q > H16D > Y13W > Q43A approximately = H16A approximately = EGF >> L15A. Notably, the reduced receptor affinity of mutant L15A indicates that Leu15 probably contributes substantially to receptor binding whereas unaltered receptor affinities observed for analogs H16A and Q43A indicate that neither His16 nor Gln43 contributes significantly to this interaction. On the other hand, the observed enhanced receptor affinities of analogs G12Q, Y13W and H16D highlight surface loci where additional productive receptor-binding contacts can be introduced. Interestingly, at acidic pH analog H16A reveals substantially greater receptor affinity than that of EGF, a property which may offer enhanced therapeutic utility in acidic environments in vivo.      

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.     

Indications and outcomes of strabismus repair in visually mature patients

OBJECTIVE: To identify and examine the indications, outcomes and potential risks of strabismus surgery in visually mature patients. DESIGN: Case series. SETTING: University-based referral practice in Edmonton. PATIENTS: A total of 222 patients (115 females and 107 males) aged 9 to 69 (mean 29) years who underwent strabismus surgery for various types of strabismus (as grouped by original diagnosis). All patients were followed for at least 6 weeks postoperatively. OUTCOME MEASURES: Previous surgery and deviation in prism dioptres (delta) (distance and near), sensory status (measured by the Titmus stereotest at near) and the presence of symptoms (diplopia, abnormal head posture or asthenopia), recorded preoperatively, 6 weeks postoperatively and at the last postoperative visit. RESULTS: The patients were followed for an average of 14 months postoperatively. At the last postoperative visit 187 patients (84%) were aligned to within 15 delta of orthotropia. Overall, 116 patients (52%) demonstrated some degree of stereopsis postoperatively, compared with 78 (35%) preoperatively. A total of 116 patients (52%) had symptoms preoperatively, including diplopia, abnormal head posture or asthenopia; 88 (76%) of the 116 had complete resolution of their symptoms. Six patients (4%) without diplopia preoperatively were found to have this symptom postoperatively. CONCLUSIONS: The findings suggest that most visually mature patients under-going strabismus surgery can expect functional benefits, including improvement of alignment, preservation and occasionally restoration of sensory fusion, and elimination of diplopia, abnormal head posture and asthenopia.     

The Sleep Heart Health Study: design, rationale, and methods

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.     

Is it PAO-GAO competition or metabolic shift in EBPR system? Evidence from an experimental study

Reduced EBPR performance in full and bench-scale EBPR studies was linked to the proliferation of GAOs but often time with the lack of any evidence. In this study, a detailed enzymatic study was coupled with batch tests and electron microscopy results for a realistic explanation. The results eliminated the possibility of population shift from PAO to GAO or other non-PAO due to the short batch test period provided which would not allow a population shift and further justified with the electron microscopy results. The results indicate that glycogen serves not only as source of reducing power for PHA production but also serves as an alternative energy source when the poly-P pool of the PAOs is depleted. Slow generation of ATP via glycolytic pathway at 5 degrees C cannot satisfy energy requirements of EBPR cells to complete several cell functions including acetate uptake and PHA storage. However, the glycolytic pathway is efficiently operable at warm temperatures (> 20 degrees C). The reduced performance of enhanced EBPR facilities operated at warm temperature may not be a result of GAO proliferation; instead it may be related the efficient use of the glycolytic pathway by PAOs which results in more glycogen storage and less P uptake, thereby reducing the EBPR performance.     

Chemically dependent doctors

Overcoming denial and admitting to having a chemical dependency problem is a hurdle that is extraordinarily difficult for anyone to handle without professional assistance. Addicted health care professionals often become even more deeply enmeshed in denial of their problem. They refuse help because they see themselves as educated beyond the level of those who are attempting to help them, and because they fear professional humiliation. Dental professionals who become aware of a colleague's chemical dependence, have an ethical duty to intervene in a constructive way. Reporting to a dental society wellness committee will accomplish this goal while protecting patients, the profession, the addicted provider, and the provider's family. Nonetheless, assisting chemically dependent colleagues to seek treatment can be an enormous burden. Thus, the dental hygienist in the case presented has few choices. She clearly has sufficient evidence of the dentist's chemical dependency problem and, ethically, she must act to prevent harm to patients. If a wellness program is available, it will help her. However, she should not expect gratitude from the dentist at the time of her intervention. Addicted persons rarely thank those who try to help them until much later and whistle-blowers are rarely appreciated. As is often the case, doing the right thing may be a challenge that risks losing a relationship or, as in the case presented, a job.