Framework for developing a national surgical, obstetric and anaesthesia plan.

Background: Emergency and essential surgical, obstetric and anaesthesia (SOA) care are now recognized components of universal health coverage, necessary for a functional health system. To improve surgical care at a national level, strategic planning addressing the six domains of a surgical system is needed. This paper details a process for development of a national surgical, obstetric and anaesthesia plan (NSOAP) based on the experiences of frontline providers, Ministry of Health officials, WHO leaders, and consultants. Methods: Development of a NSOAP involves eight key steps: Ministry support and ownership; situation analysis and baseline assessments; stakeholder engagement and priority setting; drafting and validation; monitoring and evaluation; costing; governance; and implementation. Drafting a NSOAP involves defining the current gaps in care, synthesizing and prioritizing solutions, and providing an implementation and monitoring plan with a projected cost for the six domains of a surgical system: infrastructure, service delivery, workforce, information management, finance and governance. Results: To date, four countries have completed NSOAPs and 23 more have committed to development. Lessons learned from these previous NSOAP processes are described in detail. Conclusion: There is global movement to address the burden of surgical disease, improving quality and access to SOA care. The development of a strategic plan to address gaps across the SOA system systematically is a critical first step to ensuring countrywide scale-up of surgical system-strengthening activities.

Antecedentes: En la actualidad, se reconoce que la atención quirúrgica, obstétrica y anestésica urgente y esencial (surgical, obstetric, and anaesthesia, SOA) es uno de los componentes de la cobertura sanitaria universal y un elemento necesario para el funcionamiento de un sistema de salud. Para mejorar la atención quirúrgica a nivel nacional, se necesita una planificación estratégica que aborde los seis dominios de un sistema quirúrgico. En este artículo, se detalla el proceso para el desarrollo de un plan nacional de cirugía, obstetricia y anestesia (national surgical, obstetric, and anaesthesia plan, NSOAP) basado en las experiencias de los principales proveedores, los funcionarios del Ministerio de Salud, los líderes de la Organización Mundial de la Salud y consultores. Métodos: El desarrollo de un NSOAP incluye ocho pasos clave: (1) apoyo y dependencia del ministerio, (2) análisis de la situación y evaluaciones de referencia, (3) compromiso de los agentes implicados y establecimiento de prioridades, (4) redacción y validación, (5) seguimiento y evaluación, (6) análisis de costes, (7) gobernanza y (8) implementación. Redactar un NSOAP implica definir los déficits actuales en la atención, sintetizar y priorizar soluciones, y proporcionar un plan de implementación y seguimiento con unos costes proyectados para los seis dominios de un sistema quirúrgico: infraestructura, prestación de servicios, personal, gestión de la información, finanzas y gobernanza. Resultados: Hasta la fecha, cuatro países han completado un NSOAP y 23 más se han comprometido con su desarrollo. Las lecciones aprendidas de estos procesos previos de NSOAP se describen con detalle. Conclusiones: Existe un movimiento global para abordar la carga de las enfermedades que precisan cirugía, mejorar la calidad y el acceso a la atención SOA. El desarrollo de un plan estratégico para la aproximación sistemáticamente los déficits en todo el sistema SOA es un primer paso crítico para garantizar la ampliación a nivel nacional de las actividades de fortalecimiento del sistema quirúrgico.

A qualitative exploration of stakeholder perceptions of the implementation of place-based working and its potential to reduce health inequality.

Background: Local authorities (LAs) have statutory responsibility to reduce health inequalities and improve public health. Place-based approaches may positively influence service provision yet little is known about their implementation and potential for reducing inequality through health and wellbeing improvements. An English LA implemented a place-based working (PBW) pilot in a small geography during austerity measures in the north of England. This involved three strands (early intervention, estate services and community intelligence) which were introduced separately and covered overlapping geographies. Predominantly focusing on early intervention, this qualitative study investigates stakeholders' perceptions of the pilot and its potential to improve health and wellbeing by reducing inequality. Methods: In total, 15 face-to-face qualitative interviews with stakeholders were completed. Thematic analysis produced context, mechanism and outcome configurations in a process adapted from realist evaluation methodology. Results: Stakeholders described PBW as holistic, upstream and cutting across departmental boundaries to engage staff and the community. Collaborative working was considered important and was aided by PBW in our study. Conclusions: PBW has the potential to reduce health inequalities by improving health and wellbeing. LAs deliver services that affect health and wellbeing and PBW may help develop a more coordinated response to improve outcomes and potentially save money.

Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas.

BACKGROUND AND AIM: Recent studies have indicated that prior thermal stress causes upregulation of heat shock protein 70 (HSP70) expression in the pancreas and protects against secretagogue induced pancreatitis. The mechanisms responsible for the protective effect are not known. Similarly, the effects of prior non-thermal stress on HSP70 expression and pancreatitis are not known. The current studies were designed to specifically address these issues. METHODS: In the current studies pancreatitis was induced by administration of a supramaximally stimulating dose of caerulein 12 hours after thermal stress and 24 hours after non-thermal (that is, beta adrenergic stimulation) stress. RESULTS: Both thermal and non-thermal stresses caused pancreatic HSP70 levels to rise and resulted in increased expression of HSP70 in acinar cells. Both forms of stresses protected against caerulein induced pancreatitis and prevented the early intrapancreatic activation of trypsinogen which occurs in this model of pancreatitis. CONCLUSIONS: These results suggest that both thermal and non-thermal stresses protect against pancreatitis by preventing intrapancreatic digestive enzyme activation and that HSP70 may mediate this protective effect.

The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis-associated lung injury.

BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) and neutrophils play important roles in many inflammatory processes, but their importance in both acute pancreatitis and pancreatitis-associated lung injury has not been defined. METHODS: To address this issue, mice that do not express ICAM-1 were used and depleted of neutrophils by administration of antineutrophil serum. Pancreatitis was induced by administering either supramaximal doses of the secretagogue cerulein or feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was evaluated by quantitating serum amylase, pancreatic edema, acinar cell necrosis, and pancreas myeloperoxidase activity (i.e., neutrophil content). Lung injury was evaluated by quantitating lung myeloperoxidase activity and pulmonary microvascular permeability. ICAM-1 was quantitated by enzyme-linked immunosorbent assay and was localized by light-microscopic immunohistochemistry. RESULTS: It was found that serum, pancreas, and lung ICAM-1 levels increase during pancreatitis. Both pancreatitis and the associated lung injury are blunted, but not completely prevented, in mice deficient in ICAM-1. Neutrophil depletion also reduces the severity of both pancreatitis and lung injury. However, the combination of neutrophil depletion with ICAM-1 deficiency does not reduce the severity of pancreatitis or lung injury to a greater extent than either neutrophil depletion or ICAM-1 deficiency alone. Neither pancreatitis nor pancreatitis-associated lung injury are completely prevented by ICAM-1 deficiency, neutrophil depletion, or combined ICAM-1 deficiency plus neutrophil depletion. CONCLUSIONS: The observations indicate that ICAM-1 plays an important, neutrophil-mediated, proinflammatory role in pancreatitis and pancreatitis-associated lung injury. The studies also indicate that ICAM-1 and neutrophil-independent events also contribute to the evolution of pancreatitis and lung injury in these models.

The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis-associated lung injury.

CONCLUSION: A completely noninvasive animal model of acute pancreatitis-associated lung injury was used to show that neutrophils, activated by pancreatitis, play a key role in mediating pancreatitis-associated lung injury. BACKGROUND: Significant pulmonary complications have been known to occur in over 50% of patients with severe acute pancreatitis. Recent studies using a variety of animal models of pancreatitis have suggested that neutrophil activation may play an important role in mediating lung injury. However, in these models, the interpretation of the results is complicated because surgical manipulations alone could have resulted in the activation of neutrophils. METHODS: Young female mice were fed a choline deficient ethionine (CDE) supplemented diet. The severity of pancreatitis was evaluated by measuring hyperamylasemia, acinar cell necrosis, and pancreatic myeloperoxidase activity. Lung injury was quantified by measuring lung microvascular permeability and lung myeloperoxidase activity. To evaluate the role of neutrophils in CDE diet-induced pancreatitis-associated lung injury, animals were pretreated with antineutrophil serum. RESULTS: Mice fed the CDE diet develop pancreatitis-associated lung injury. Pretreatment of mice with antineutrophil serum results in marked depletion of circulating neutrophils. Under these conditions, the severity of pancreatitis is reduced and lung injury is completely prevented.

Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis.

In an effort to elucidate factors that determine the severity of an attack of acute pancreatitis, we have quantitated the extent of necrosis and of apoptosis in five different models of experimental acute pancreatitis. Severe pancreatitis was induced by obstructing the opossum common bile-pancreatic duct, by administering to mice 12 hourly injections of a supramaximally stimulating dose of caerulein, and by feeding young female mice a choline-deficient, ethionine-supplemented diet. In each of these models of severe pancreatitis, marked necrosis but very little apoptosis was found. Mild pancreatitis was induced by obstructing the rat common bile-pancreatic duct and by infusing rats with a supramaximally stimulating dose of caerulein. In contrast to our findings in severe pancreatitis, mild pancreatitis was characterized by very little necrosis but a high degree of apoptosis. Our finding that the severity of acute pancreatitis is inversely related to the degree of apoptosis suggests that apoptosis may be a teleologically beneficial response to acinar cell injury in general and especially in acute pancreatitis.

The role of oxygen-derived free radicals in two models of experimental acute pancreatitis: effects of catalase, superoxide dismutase, dimethylsulfoxide, and allopurinol.

The role of oxygen-derived free radicals was evaluated in two models of experimental acute pancreatitis by testing the effects of agents which either reduce oxygen-derived free radical generation or scavenge those free radicals. Those agents (catalase, superoxide dismutase, polyethylene glycol-superoxide dismutase, dimethylsulfoxide, and allopurinol) were evaluated using the choline-deficient ethionine-supplemented diet-induced model of acute hemorrhagic pancreatic necrosis and the supramaximal caerulein stimulation model of acute interstitial edematous pancreatitis. In both models, the only effect associated with administration of the test agents was a reduction in the degree of pancreatic edema. These results suggest that oxygen-derived free radicals may play an important role in the development of pancreatic edema during pancreatitis but that those free radicals do not play an important role in the development of acinar cell injury.

Effects of a choline-deficient ethionine-supplemented diet on phospholipase C activity in mouse pancreatic acinar cell membranes and in electropermeabilized mouse pancreatic acini.

The nonhydrolyzable guanyl nucleotide GTP gamma S stimulated phosphoinositidase C activity in two preparations obtained from mouse pancreatic acini labeled with myo[2-3H]inositol: a cell-free membrane fraction and intact electropermeabilized acini. This action was dose-dependent, was shared by other nonhydrolyzable guanyl nucleotides such as GMP-phencyclidine hydrochloride and GMP-PMP, as well as by fluoride, and was calcium-independent. Contrarily, no effect was observed even at doses of GTP gamma S as high as 10 microM when the same protocol was repeated on identical acinar preparations from mice fed a choline-deficient, ethionine-supplemented diet. This regimen is known to uncouple secretagogue-receptor occupancy from inositol 1,4,5-trisphosphate generation in pancreatic acinar cells and lead to necrotizing hemorrhagic pancreatitis. These data lead us to conclude that the ethionine-induced inactivation of guanyl nucleotide-dependent pancreatic phosphoinositidase C in pancreatic acinar cells is not the result of either a decrease in GTP level or a decrease in GTP availability. These findings further confirm previous work from this laboratory, which has shown that the biochemical lesion induced by this diet occurs after the agonist-receptor binding step. The diet-induced lesion could be either at the level of the G-protein that couples the enzyme with the receptor or at the level of the phospholipase itself.

Failure of a potent cholecystokinin antagonist to protect against diet-induced pancreatitis in mice.

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.

Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis.

Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist [3H]N-methylscopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of [3H]inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with [3H]myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion.

Membrane recycling and the control of secretory activity in pollen tubes.

Pollen tubes of Tradescantia growing on media containing 10(-3) M-Ca2+ and 10(-2)M-Ca2+ exhibit growth rates of 28 micrometers min-1 and 7 micrometers min-1, respectively. The rates of vesicle production by the dictyosomes in these tubes were determined from the rates at which vesicles accumulated in the cytoplasm after treatment with cytochalasin D. Although the vesicle requirements for these two growth rates are considerably different, it was found that vesicle production rates were the same. The results indicate that, in pollen tubes, membrane recycling is occurring and that dictyosome activity is not regulated according to the vesicle requirements for tube growth.

The effect of cycloheximide on dictyosome activity in Tradescantia pollen tubes determined using cytochalasin D.

Dictyosome activity in Tradescantia pollen tubes has been determined using a recently developed method based on the assumption that the rate of vesicle accumulation around the dictyosomes, after treatment with cytochalasin D, is equivalent to the actual rate of vesicle production. In tubes germinated in the presence of 1.0 micrograms/ml cycloheximide, reduced dictyosome activity could be detected as early as 10 min after sowing, although tube extension was not halted until later. After 30 min vesicle production had completely ceased. These observations are discussed in relation to previous reports on the effect of cycloheximide on pollen tube growth, and in relation to the synthesis and transfer of membrane proteins to secretory vesicles and the plasma membrane. It is concluded that the ability of pollen to germinate and produce short tubes in the presence of cycloheximide, does not necessarily indicate that protein synthesis is not a requirement for early pollen tube growth, as protein shortages would not be expected to become apparent over time periods less than the dictyosome turnover time and the secretory vesicle residence time.

Pancreatic effects of ethionine: blockade of exocytosis and appearance of crinophagy and autophagy precede cellular necrosis.

Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet for 24 h develop hemorrhagic pancreatic necrosis with a 5-day mortality rate of approximately 50%. At the end of the diet administration, the in vivo discharge of digestive enzymes is blocked, images of exocytosis and luminal membrane recycling disappear, and zymogen granules accumulate within acinar cells. The general ultrastructure, however, remains well preserved, protein synthesis is normal, and intracellular transport of secretory proteins is only slightly retarded. Thus, the CDE diet does not affect the general phenomenon of membrane fusion-fission but specifically inhibits that associated with exocytosis. Twenty-four hours after withdrawal of the CDE diet, discharge of zymogen granules into lysosomes (crinophagy) can be observed, and, 24 h latr, autophagocytosis is noted. Finally, shortly before the onset of pancreatic necrosis, cells of nearly normal appearance are noted to be scattered among cells showing varying degrees of lesion up to complete disruption. Thus, the CDE-induced pancreatic necrosis results from a sequence of events: blockade of exocytosis evolves to crinophagy and autophagy, which might lead to lysosomal activation of zymogens.

Determination of secretory vesicle production rates by dictyosomes in pollen tubes of Tradescantia using cytochalasin D.

Pollen tubes of Tradescantia were grown in vitro and exposed to 0.3 microgram/ml cytochalasin D for 5 or 10 min. Fine-structural observations revealed no visible effect of the drug on the organelles. Stereological analysis, using a method recently developed by Rose (1980) to obtain sphere size-distributions corrected for section thickness, revealed substantial increase in the number of secretory vesicles present in the cytoplasm around the dictyosomes. Equating the rate of vesicle accumulation with the rate of vesicle production, a total of 5388 vesicles per minute are formed by a growing tube. This corresponds to 2.4 vesicles per minute per dictyosome, and a turnover rate of 3.7 min for a single dictyosome cisterna, or about 15-18.5 min for a complete dictyosome. The calculated vesicle production rate agrees well with that required to sustain the observed growth rate of such tubes, based on the addition of membrane or wall material to the tube tip.

Effects of ethionine on digestive enzyme synthesis and discharge by mouse pancreas.

The earliest changes noted during the evolution of pancreatitis induced by feeding mice a choline-deficient ethionine-supplemented (CDE) diet are an increase in the number of zymogen granules in pancreatic acinar cells and an increase in digestive enzyme content of the pancreas. We have studied the processes of protein and digestive enzyme synthesis and discharge at varying times after institution of the CDE diet, a choline-deficient diet (CD), and a diet containing ethionine but not choline-deficient (E). Both the CDE and E diets increased digestive enzyme content within 12 h of their institution. Both the CDE and E diets reduced the rate of protein and amylase synthesis and caused a marked reduction in the rate of protein and amylase discharge from the pancreas. These changes were greatest and were noted earliest in the CDE diet group. A marked reduction in secretagogue-induced in vivo and in vitro amylase discharge followed ingestion of either the CDE or E diet. These studies indicate that the increased pancreatic content of digestive enzymes noted after ingestion of the CDE and E diets results from an ethionine-induced decrease in the rat of digestive enzyme discharge. This phenomenon is enhanced by simultaneous choline deficiency. Subsequent intrapancreatic activation of zymogens may couple these changes in enzyme content to the development of hemorrhagic pancreatitis.

Protective effects of PGE2 on diet-induced acute pancreatitis in mice.

Prostaglandins have been noted to have a "protective" effect against gastrointestinal mucosal injury induced by a wide variety of agents although possible protective effects of prostaglandins on injury to other tissues have not been reported. We have tested the effect of prostaglandin E2 (PGE2) on acute experimental pancreatitis induced by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet for 24 hr. Administration of 0.05--0.20 microgram PGE2/g body wt 1 hr before and 4 hr after institution of the CDE diet lowered the mortality rate of diet-induced pancreatitis from 56% to 31%. Larger and smaller doses of PGE2 were without effect. Administration of PGE2 (0.10 microgram/g body weight) diminished the rise in in-vitro LDH discharge and the increase in "free" Cathepsin D activity which occur during diet-induced pancreatitis. Similarly, PGE2 (0.10 microgram/g body wt) diminished the magnitude of the increase in in-vitro protein discharge and the elevated concentrations of trypsinogen and chymotrypsinogen in pancreas fragments taken from mice given the CDE diet. These findings indicate the PGE2 has a protective effect against CDE diet-induced acute experimental pancreatitis. The Cathespin D and LDH changes noted during CDE diet-induced pancreatitis suggest that this diet may decrease membrane integrity and thus allow these enzymes to leak out of the lysosomes and acinar cell, respectively, during pancreatitis. Although the basis for the protective effect of PGE2 remains unclear, our observations suggest that the prostaglandin may act to reduce the alteration in membrane integrity which occurs during CDE-diet induced pancreatitis.

Differentiation of the tapetum in Avena. I. The cell surface.

The development of the tapetal cell surface and associated structures in Avena has been followed from cell formation to senescence. Plasmodesmata initially connect the tapetal cells to each other, the pollen mother cells, and the inner loculus wall cells. These connexions are subsequently severed, those to the sporogenous cells being broken first at the pollen mother cell surface during callose wall formation. Loss of cellulose from the tapetal walls was followed using the decline in the ability of the wall to bind the fluorescent brightener, Calcofluor White M2R New. Subplasma-membrane microtubules persist after loss of the cellulose wall. The tapetal plasma membrane facing the meiocytes then develops a series of depressions, or cups, over its surface, which are later the site of pro-orbicule formation. Sporopollenin is laid down over the pro-orbicules, to form orbicules, and over other tapetal cell surfaces. No morphological evidence was found for the intracytoplasmic formation of pro-orbicules or polymerized sporopollenin precursors. These observations on Avena are compared with those on other plants. The changes in the cell wall and associated structures, plasmodesmata and microtubules, are considered in detail, while the general significance of cell wall loss to the water relations of the tissue are assessed. Proposals that pro-orbicule formation results from non-specific accumulation of lipid at a free cell surface are rejected, instead this formation is considered to be related to the presence of a specially modified plasmamembrane surface.