Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins

Therapeutic proteins have revolutionized the treatment of many diseases but low activity or rapid clearance limits their utility. New approaches have been taken to design drugs with enhanced in vivo activity and half-life to reduce injection frequency, increase convenience, and improve patient compliance. One recently used approach is glycoengineering, changing protein-associated carbohydrate to alter pharmacokinetic properties of proteins. This technology has been applied to erythropoietin and resulted in the discovery of darbepoetin alfa (DA), a hyperglycosylated analogue of erythropoietin that contains two additional N-linked carbohydrates, a threefold increase in serum half-life and increased in vivo activity compared to recombinant human erythropoietin (rHuEPO). The increased serum half-life allows for less frequent dosing to maintain target hemoglobin levels in anemic patients. Carbohydrates on DA and other molecules can also increase molecular stability, solubility, increase in vivo biological activity, and reduce immunogenicity. These properties are discussed.     

Dysmorphology and the spectacle of the clinic

Dysmorphology is the medical study of abnormal forms in the human and is concerned with the identification and classification of a variety of congenital malformations. Such diagnostic work rests on the inspection of images of affected individuals. Based on physical appearance individuals are classified in terms of a wide range of conditions, often with 'exotic' nomenclatures. This paper will describe the features of clinical dysmorphology and the process of classification. It derives from an ethnographic study of clinical consultations and meetings among medical geneticists in UK hospitals. We suggest that contemporary dysmorphology can be understood in terms of long-standing forms of medical knowledge, medical representations and medical discourse. Notwithstanding the new forms of technology provided by genetic science, 'the clinic' still asserts its symbolic and functional power: the 'gaze' of the clinician and the clinician's warrant of personal knowledge exert their influence. The adjudication of dysmorphology is a contemporary exemplar of the spectacular.     

Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter

We tested the hypothesis that inhibiting glycogen degradation accelerates compound action potential (CAP) failure in mouse optic nerve (MON) during aglycemia or high-intensity stimulation. Axon function was assessed as the evoked CAP, and glycogen content was measured biochemically. Isofagomine, a novel inhibitor of central nervous system (CNS) glycogen phosphorylase, significantly increased glycogen content under normoglycemic conditions. When MONs were bathed in artificial cerebrospinal fluid (aCSF) containing 10 mM glucose, the CAP failed 16 min after exposure to glucose-free aCSF. MONs bathed in aCSF plus isofagomine displayed accelerated CAP failure on glucose removal. Similar results were obtained in MONs bathed in 30 mM glucose, which increased baseline glycogen concentration. The ability of isofagomine to increase glycogen content thus was not translated into delayed CAP failure. This is likely due to the inability of the tissue to metabolize glycogen in the presence of isofagomine, highlighting the importance of glycogen in sustaining neural function during aglycemia. The hypothesis that glycogen breakdown supports intense neural activity was tested by blocking glycogen breakdown during periods of high-frequency stimulation. The CAP area declined more rapidly when glycogen metabolism was inhibited by isofagomine, explicitly showing an important physiological role for glycogen metabolism during neural activity.     

Zonisamide monotherapy for epilepsy in children and young adults

Several of the newer antiepilepsy drugs have not been tested as monotherapy in controlled trials. Zonisamide is a broad-spectrum antiepilepsy drug indicated for the adjunctive treatment of partial seizures in adults. However, several small, open-label studies have indicated that it may be safe and effective as monotherapy. The present chart review study was conducted to evaluate the safety and effectiveness of zonisamide monotherapy in a pediatric and young adult patient group. Patient records at the Blue Bird Circle Clinic for Pediatric Neurology were reviewed to identify patients receiving zonisamide monotherapy. Efficacy was assessed from seizure diaries and patients' subjective evaluations. Safety and tolerability were evaluated by analysis of adverse events and change in body weight. The study included 131 patients aged 1 to 21.8 years with a broad spectrum of seizure types and epilepsy syndromes. A total of 101 patients (77.1%) achieved a 50% or greater decrease in seizure frequency, including 39 patients who achieved seizure freedom. Zonisamide monotherapy was well tolerated, with three patients (2.3%) discontinuing for adverse events. These results support open-label studies from Japan reporting that zonisamide monotherapy is safe and effective in pediatric and young adult patients.     

Determinants of Maternity Length of Stay: A Gamma Mixture Risk-Adjusted Model

With obstetrical delivery being the most frequent cause for hospital admissions, it is important to determine health- and patient-related characteristics affecting maternity length of stay (LOS). Although the average inpatient LOS has decreased steadily over the years, the issue of the appropriate LOS after delivery is complex and hotly debated, especially since the introduction of the mandatory minimum-stay legislation in the USA. The purpose of this paper is to identity factors associated with maternity LOS and to model variations in LOS. A Gamma mixture risk-adjusted model is proposed in order to analyze heterogeneity of maternity LOS within obstetrical Diagnosis Related Groups (DRGs). The determination of pertinent factors would benefit hospital administrators and clinicians to manage LOS and expenditures efficiently.     

Proliferation of lens epithelial cells on the Acrysof intraocular lens: clinical and histological features of a case

Postoperative deposits on the surface of intraocular lenses (IOLs) have been demonstrated in vivo for many IOL material types. The Acrysof acrylic lens develops a granular material extending from the capsulorhexis margin onto the IOL's anterior surface during the first 4 weeks after surgery in a significant proportion of cases. Complete resolution of this membrane occurs by 3 months in almost all cases. The case is presented of an 81‐year‐old woman who had a persisting membrane covering the IOL surface at 6 months. This membrane was removed surgically and pathology showed the constituent cells to be of lens epithelial cell origin.     

Two-dimensional fractal growth properties of the filamentous fungus Cryphonectria parasitica: the effects of hypovirus infection

Whole-colony two-dimensional fractal growth patterns produced by hypovirus-infected Cryphonectria parasitica (EP155/CHV1-EP713) were measured and compared with those produced by the isogenic virus-free strain (EP155) on solid medium. We have quantified statistically significant differences in the rates of expansion and spatial dynamics of colony growth between the two strains and concluded that fractal dimension is affected by the presence of the hypovirus. Therefore, fractal dimension measurement is an effective quantitative tool for testing the effects of mycovirus infection on fungal growth parameters.