Design of a Novel Online, Modular, Flipped-classroom Surgical Curriculum for East, Central, and Southern Africa.

Objective: We describe a structured approach to developing a standardized curriculum for surgical trainees in East, Central, and Southern Africa (ECSA). Summary Background Data: Surgical education is essential to closing the surgical access gap in ECSA. Given its importance for surgical education, the development of a standardized curriculum was deemed necessary. Methods: We utilized Kern's 6-step approach to curriculum development to design an online, modular, flipped-classroom surgical curriculum. Steps included global and targeted needs assessments, determination of goals and objectives, the establishment of educational strategies, implementation, and evaluation. Results: Global needs assessment identified the development of a standardized curriculum as an essential next step in the growth of surgical education programs in ECSA. Targeted needs assessment of stakeholders found medical knowledge challenges, regulatory requirements, language variance, content gaps, expense and availability of resources, faculty numbers, and content delivery method to be factors to inform curriculum design. Goals emerged to increase uniformity and consistency in training, create contextually relevant material, incorporate best educational practices, reduce faculty burden, and ease content delivery and updates. Educational strategies centered on developing an online, flipped-classroom, modular curriculum emphasizing textual simplicity, multimedia components, and incorporation of active learning strategies. The implementation process involved establishing thematic topics and subtopics, the content of which was authored by regional surgeon educators and edited by content experts. Evaluation was performed by recording participation, soliciting user feedback, and evaluating scores on a certification examination. Conclusions: We present the systematic design of a large-scale, context-relevant, data-driven surgical curriculum for the ECSA region.

Primary structure of the human chorionic somatomammotropin (HCS) molecule.

The complete amino acid sequence of the human chorionic somatomammotropin molecule been proposed; and then compared with that of human growth hormone and ovine lactogenic hormone.

Retention of the biological potency of human pituitary growth hormone after reduction and carbamidomethylation.

The reduced alkylated derivative of human pituitary growth hormone was prepared by reacting the native hormone in 8M urea solution, first with mercaptoethanol and then with iodoacetamide. On the basis of amino acid analyses, the product isolated after gel filtration on Sephadex G-100 is completely devoid of unreduced cystine but otherwise has a composition identical to that of the native hormone. When assayed in both the rat tibia test and the pigeon crop-sac assay,it appears that the full potency of the native hormone is retained in the reduced alkylated derivative.

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.

The ensemble approach to distance geometry: application to the nicotinic pharmacophore.

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.

Docking flexible ligands to macromolecular receptors by molecular shape.

We present a method to explore the interaction of flexible ligands with receptors of known geometry on the basis of molecular shape. This method is an extension of that described by Kuntz et al. (J. Mol. Biol. 1982, 161, 269). The shape of a binding site on a macromolecular receptor is represented as a set of overlapping spheres. Each ligand is divided into a small set of large rigid fragments that are docked separately into the binding site and then rejoined later in the calculation. The division of ligands into separate fragments allows a degree of flexibility at the position that joins them. The rejoined fragments are then energy minimized in the receptor site. We illustrate the method with two test cases: dihydrofolate reductase/methotrexate and prealbumin/thyroxine. For each test case, the method finds binding geometries for the ligand near that observed crystallographically as well as others that provide good steric fit with the receptor.

Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure.

Finding novel leads from which to design drug molecules has traditionally been a matter of screening and serendipity. We present a method for finding a wide assortment of chemical structures that are complementary to the shape of a macromoleculer receptor site whose X-ray crystallographic structure is known. Each of a set of small molecules from the Cambridge Crystallographic Database (Allen; et al. J. Chem. Doc. 1973, 13, 119) is individually docked to the receptor in a number of geometrically permissible orientations with use of the docking algorithm developed by Kuntz et al. (J. Mol. Biol. 1982, 161, 269). The orientations are evaluated for goodness-of-fit, and the best are kept for further examination using the molecular mechanics program AMBER (Weiner; Kollman J. Comput. Chem. 1981, 106, 765). The shape-search algorithm finds known ligands as well as novel molecules that fit the binding site being studied. The highest scoring orientations of known ligands resemble binding modes generated by interactive modeling or determined crystallographically. We describe the application of this procedure to the binding sites of papain and carbonic anhydrase. While the compounds recovered from the Cambridge Crystallographic Database are not, themselves, likely to be inhibitors or substrates of these enzymes, we expect that the structures from such searches will be useful in the design of active compounds.

5-Aryl-3-azabicyclo[3.2.0]heptan-6-one ketals, compounds with morphine-like analgesic activity.

A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.

Evidence of poor conduction of muscle excitation in the longitudinal axis of guinea-pig isolated trachea.

1 Mechanical activity was recorded from one segment of guinea-pig trachealis muscle while intracellular electrical activity was simultaneously recorded from a contiguous segment. When the tissue was stimulated by 1-32 mmol/l tetraethylammonium (TEA) it became clear that the electrical and mechanical records were not directly correlated. 2 Dual recording of mechanical activity from two contiguous segments of trachealis revealed that one tissue segment could exhibit phasic activity whilst the other could exhibit tonic activity, despite exposure to the same concentration of TEA. 3 Histological studies revealed that the trachealis muscle was organized into bundles largely separated from one another by spaces filled with connective tissue. However, muscle bundles branched and formed anastomotic connections with near neighbours. 4 It is concluded that the cell to cell spread of muscle excitation is very poor along the longitudinal axis of the trachea. The trachealis muscle as a whole does not function as a single unit. Rather it may represent a series of effector units each comprising a small number of smooth muscle bundles.

The effects of epithelium removal on the actions of cholinomimetic drugs in opened segments and perfused tubular preparations of guinea-pig trachea.

1. Isolated segments of guinea-pig trachea or perfused tracheal tubes were arranged for the recording of trachealis tension changes in Krebs solution containing indomethacin (2.8 microM). 2. In opened tracheal segments, epithelium removal caused modest (2-3 fold) potentiation of the effects of acetylcholine (ACh) and methacholine (MeCh) but failed to potentiate carbachol (CCh), bethanechol (BeCh), oxotremorine or KCl. 3. Pretreatment with ecothiopate potentiated effects of ACh and MeCh but not of CCh or BeCh. Removal of epithelium in ecothiopate-treated tissue potentiated effects of ACh and MeCh but not of CCh or BeCh. 4. Guinea-pig ileum challenged with ACh was used as a bioassay system for cholinesterase activity. Scrapings of tracheal epithelium did not hydrolyse ACh. 5. Histochemical staining revealed no fibres positive for acetylcholinesterase or pseudocholinesterase in the tracheal epithelium. However, the underlying tissues contained acetylcholinesterase-positive nerve fibres and the trachealis muscle itself stained positively for pseudocholinesterase activity. 6. Neither tetrodotoxin (3 microM) nor hexamethonium (500 microM) modified the ability of epithelium removal to potentiate ACh. 7. In perfused tracheal tubes where spasmogens were added to the luminal perfusate, epithelium removal potentiated effects of ACh (31 fold), CCh (10 fold), oxotremorine (2 fold) and KCl. 8. In perfused tracheal tubes where spasmogens were added to the Krebs solution superfusing the adventitial surface of the tissue, epithelium removal significantly reduced the potency of CCh, oxotremorine and KCl. 9. It is concluded that the selectivity and magnitude of the potentiation of cholinomimetics caused by epithelium removal depends on the route by which the cholinomimetic agent gains access to the trachealis muscle. The potentiation of acetic acid esters of choline seen in opened tracheal segments does not reflect the loss of epithelial cholinesterase activity and does not depend on the activity of nervous reflex arcs in the tracheal wall. The reduced potency of adventitially-applied cholinomimetics and KCl seen in epithelium-denuded tissue strongly suggests that the epithelium can moderate trachealis sensitivity to cholinomimetic agents not only by releasing epithelium-derived relaxing factor but also by acting as a barrier to drug diffusion.

5-Aminosalicylic acid or sulphapyridine. Which is the active moiety of sulphasalazine in rheumatoid arthritis?

Thirty patients with active rheumatoid arthritis participated in an open study of 6 months' treatment with either 5-aminosalicylic acid or sulphapyridine, the two moieties of sulphasalazine. Patients were assessed at regular intervals using a number of clinical and biochemical tests designed to detect specific antirheumatic activity. Patients taking sulphasalazine showed significant improvement in most parameters of disease activity, but those taking 5-aminosalicylic acid did not improve despite the fact that high serum concentrations of 5-aminosalicylic acid and acetyl 5-aminosalicylic acid were achieved. These results suggest that sulphapyridine is the active moiety of sulphasalazine. Its possible mode of action is discussed. Nausea was a frequent problem in patients taking sulphapyridine. Unless this problem can be overcome, sulphapyridine is unlikely to offer any therapeutic advantages over sulphasalazine in the treatment of rheumatoid arthritis.

Short report: long-term management of peptic ulcer disease with ranitidine in Germany.

One hundred and twenty-five patients with duodenal ulcer disease were given continuous ranitidine therapy after initial acute healing. Cumulative remission rates indicated that 95% of patients were ulcer-free after 1 year, 89% at 2 years, 81% at 3 years, 70% at 4 years and 60% at 5 and 6 years. Nine patients had a second recurrence after healing of the first. No patient developed an ulcer complication. These results support the view that long-term continuous ranitidine therapy prevents ulcer recurrence and complications.

Geographical differences of gastric ulcer healing rate in patients treated with ranitidine or placebo.

The literature was searched for clinical trials evaluating the use of 300 mg ranitidine daily in the acute treatment of gastric ulcer. All available trials were examined, and the results compared between countries to determine the extent of any geographical variation in ulcer healing rates. Published placebo studies in gastric ulcer were also reviewed for comparison. Sixty-six publications were inspected to determine the trial design, country of origin, gastric ulcer healing rates, determined endoscopically, and details of patient demography. Overall worldwide healing rates for ranitidine treatment were 63% at week 4 and 86% at week 8 (n = 2349 and 2256 respectively), compared with 34% at week 4 and 52% at week 8 for placebo (n = 790 and 231 respectively). Statistically significant differences were found between the healing rates for individual countries at week 4 (P less than 0.001) and week 8 (P less than 0.001). However, after exclusion of the results from Japan (35%, n = 278) and Yugoslavia (97%, n = 32) at week 4, and from Japan (80%, n = 467) and France (65%, n = 52) at week 8, the healing rates from the remaining countries were not statistically different from one another. The limited data available in relation to age, sex and smoking habits, or placebo healing rates contributed little to explaining these aberrant results. It is concluded that there is variation in gastric ulcer healing rates between countries, but only results from Japan seem to be out of line with the rest of the world.

Gastric histology and plasma gastrin response to a meal in patients with duodenal ulcer disease after five years treatment with ranitidine.

Fifty asymptomatic patients with duodenal ulcer disease, aged 31-82 years, who had received ranitidine maintenance therapy continuously for five or more years without a symptomatic recurrence, were studied. Fasting plasma gastrin concentrations were normal (mean 24 pmol/L, S.D. +/- 22) while the post-prandial gastrin response was variable with maximum plasma concentrations ranging from 16 to 309 pmol/L. Endoscopy revealed six asymptomatic peptic ulcers. Histological examination of gastric biopsies showed mild, superficial inflammatory cell infiltration of the fundic mucosa, but more extensive inflammatory cell infiltration with some atrophy of the mucosal glands in the antral mucosa. Patchy intestinal metaplasia was evident in the antral mucosa of 18 patients. No fundic ECL cell hyperplasia was seen. Helicobacter pylori were detected in the corpus and antrum of most patients. These results suggest that maintenance treatment with ranitidine for 5 years is not associated with either significant hypergastrinaemia or with changes in the fundic mucosa which could be interpreted as pre-malignant.

A placebo-controlled investigation of duodenal ulcer recurrence after withdrawal of long-term treatment with ranitidine.

Ninety-two patients with duodenal ulcer disease, who had received long-term continuous treatment with ranitidine for an average of 7.5 years, participated in a double-blind, placebo-controlled study to determine whether stopping ranitidine resulted in ulcer recurrence. Patients were randomized to continue with ranitidine (n = 46) or to receive placebo (n = 46) and were followed up for six months. Treatment failure was defined as the first symptomatic recurrence of ulcer. The occurrence of epigastric pain during the follow-up period was significantly less frequent in the ranitidine group (13%) than in the placebo group (43%) (P = 0.001). At six months, 9% of the ranitidine group had developed ulcer recurrence, compared with 48% in the placebo group (P < 0.001, logrank test). Multivariate analysis using the Cox proportional hazards model showed that younger age (P = 0.041) and a long history of ulcer disease (P = 0.025) were risk factors for ulcer recurrence but gender, smoking and duration or dose of previous ranitidine treatment were not predictive of relapse during treatment with placebo. In conclusion, withdrawal of ranitidine after more than five years of continuous treatment results in almost half of the patients developing symptomatic ulcer recurrence within six months. Thus, long-term continuous therapy does not alter the natural history of duodenal ulcer disease. Younger patients and those with a long history of ulcer disease appear to be at increased risk of developing ulcer recurrence if long-term treatment is withdrawn.

Ranitidine in the treatment of duodenal ulcer disease: relationship between antisecretory effect and ulcer healing rate.

The relationship between drug-induced suppression of intragastric acidity and the rate of duodenal ulcer healing was examined using data for a single drug, ranitidine, from 156 clinical trials involving 16,362 patients together with data on acid suppression from 37 studies of intragastric acidity in 630 subjects. In these studies ranitidine was given in doses ranging from 150 mg to 1200 mg per day administered in 9 different dosage regimens. The overall percentage of patients whose duodenal ulcers healed at 2 and 4 weeks on the different regimens was highly correlated with the percentage suppression of 24-hour intragastric acidity induced by different regimens. Thus the therapeutic benefit of a given ranitidine dosage regimen in healing duodenal ulcers relates directly to its antisecretory effect.

Review article: safety of bismuth in the treatment of gastrointestinal diseases.

Bismuth preparations are commonly used to treat a variety of gastrointestinal disorders, including peptic ulcers and dyspepsia. The safety profile of currently approved bismuth preparations, such as tripotassium dicitrato bismuthate (De-Nol), bismuth subsalicylate (Pepto-Bismol) and ranitidine bismuth citrate (Pylorid, Tritec), is excellent. Adverse reactions to these agents are mild, transient and infrequent, and reports of serious adverse reactions are rare. This, in part, reflects the low systemic bioavailability of bismuth from these medicines: less than 1% of the bismuth dose administered is absorbed. During repeated dosing with ranitidine bismuth citrate 200, 400 or 800 mg b.d. trough plasma bismuth concentrations remain well below 50 micrograms/L. After 4 weeks of treatment median concentrations of 3.4 micrograms/L or less were reported amongst 1210 duodenal ulcer patients receiving this new chemical entity, while mean concentrations of 5.1 micrograms/L (plasma) and 12.3 micrograms/L (blood) have been reported in two studies of patients receiving tripotassium dicitrato bismuthate 120 mg q.d.s. for 4 weeks. Transient peak plasma bismuth concentrations greater than 50 micrograms/L are observed 30-60 min after dosing with tripotassium dicitrato bismuthate in some patients, but are not associated with any toxic effects. After discontinuation of treatment with bismuth preparations its excretion in urine may continue for up to 3 months, by which time blood bismuth concentrations have declined to pretreatment values.

Design of anticancer drugs using modeling techniques.

Flexibility of intercalation site geometries within a B-DNA helix was investigated in the twist-shift plane using energy minimization methods. The parameters optimized included sugar conformation, the glycosidic angles and phosphodiester torsion angles. Our calculations show several regions of energetically favorable intercalation geometries in the twist-shift plane. Modeling studies using interactive computer graphics and electrostatic potential surface compatibility provided initial hypotheses for the structures of the drug-DNA complexes. These hypotheses were supported and extended by energy minimizations of these complexes. Binding positions, conformational features and relative minimum binding energies of two anticancer drugs, mitoxantrone and bisantrene, were computed for intercalation complexes with DNA in the theoretically defined intercalation sites. Mitoxantrone intercalates DNA from the minor groove and the side chain OH or NH groups are involved in hydrogen bonds with the main chain phosphate groups of DNA, thereby cross-linking the complementary strands. The hydroxyl groups of mitoxantrone can also participate in hydrogen bonding with phosphate oxygens of another chain, thereby cross-linking DNA helices. Bisantrene intercalates DNA favorably from the major groove and the NH group of the dihydroimidazole ring can participate in hydrogen bonding with the phosphate oxygens of the backbone. These models are consistent with the physicochemical and electron microscopic studies of the interaction of mitoxantrone and bisantrene with DNA. Our results are now being used to guide the design of novel anticancer drugs that should interact with DNA in a manner similar to that proposed for our representative drugs.

Structure and autonomic innervation of the human vas deferens: a review.

The motor innervation of the smooth muscle coat of the human vas deferens is predominantly noradrenergic in type while a less dense and differently distributed presumptive cholinergic innervation is also in evidence, although the precise role of the latter is undetermined. Immunohistochemical studies have confirmed the presence of catecholamine-synthesizing enzymes tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) in the majority of fine, varicose intramuscular nerves, about two-thirds of which also contain neuropeptide Y (NPY). Minor populations of noradrenergic nerves contain enkephalin (ENK), galanin (GAL), somatostatin (SOM), or nitric oxide synthase (NOS). The presumptive cholinergic intramuscular nerves contain vasoactive intestinal polypeptide (VIP) and NPY. The subepithelial nerves of the vas deferens are assumed to have a secretomotor function and are rich in acetylcholinesterase and NPY, many also containing either VIP or NOS. The muscle coat of the human vas deferens is poorly differentiated until after birth, the intramuscular nerves in the fetus being relatively thick and non-varicose. Development of a subepithelial nerve plexus lags behind that in the muscle coat but its density in the neonatal vas deferens resembles that seen in the adult. Observations on specimens of human vas deferens obtained at vasovasostomy carried out 1 to 15 years after vasectomy have shown a marked reduction in the density of noradrenergic nerves in the muscle coat of the testicular portion while that in the urethral portion remains unaltered. Furthermore, the subepithelial secretomotor nerves degenerate in the testicular portion. These long-term changes in the pattern of innervation of the vas deferens consequent upon vasectomy may have profound effects upon the outcome of vasovasostomy with respect to subsequent sperm maturation, transport, and viability.

Tyrosine hydroxylase and vesicular acetylcholine transporter are coexpressed in a high proportion of intramural neurons of the human neonatal and child urinary bladder.

Autonomic ganglia of the human pelvic plexus contain sympathetic and parasympathetic neurons which innervate the internal reproductive organs and the lower urinary tract while the urinary bladder also receives innervation from small intramural ganglia embedded in the detrusor muscle. Previous studies have used the immunocytochemical demonstration of tyrosine hydroxylase (TH), either alone or in combination with dopamine beta-hydroxylase, to identify noradrenergic neurons in these ganglia. However until recently a reliable marker for cholinergic neurons in the human autonomic nervous system was not available since antibodies to choline acetyltransferase do not react in this tissue. The present immunohistochemical study has used an antibody to human vesicular acetylcholine transporter (VAChT) to identify cholinergic neurons in the pelvic plexus and intramural bladder ganglia in a series of specimens from human male neonates and children. Immunostaining for TH was also carried out on the same sections and the results showed that while the vast majority of pelvic ganglion neurons were either cholinergic or noradrenergic (as seen by the presence of VAChT or TH respectively), approximately 50% of the neurons in the intramural ganglia were labeled with both immunomarkers. The presence of TH in cholinergic neurons may be due to the immaturity of the tissues examined since previous data on intramural bladder ganglia in the adult have shown that a much smaller proportion of the neurons contain TH than was observed in the present study. It is concluded that the presence of TH alone cannot be regarded as a specific marker for noradrenergic neurons in the genitourinary system of the human neonate and child.