The Influence of Insecticide Resistance, Age, Sex, and Blood Feeding Frequency on Thermal Tolerance of Wild and Laboratory Phenotypes of Anopheles funestus (Diptera: Culicidae).

Resistance to insecticides is a global phenomenon and is increasing at an unprecedented rate. How resistant and susceptible strains of malaria vectors might differ in terms of life history and basic biology is often overlooked, despite the potential importance of such information in light of changing climates. Here, we investigated the upper thermal limits (ULT50) of wild and laboratory strains of Anopheles funestus Giles mosquitoes, including resistance status, sex, age, and blood feeding status as potential factors influencing ULT50. No significant differences in ULT50 were observed between strains displaying different resistance patterns, nor was there a significant difference between wild and laboratory strains. In some instances, strains showed a senescence response, displaying decreased ULT50 with an increase in age, and differences between males and females (females displaying higher ULT50 than males). Blood feeding did not seem to influence ULT50 in any way. For An. funestus, it seems evident that there is no cost to resistance despite what is displayed in other anopheline species. This could have significant impacts for vector control, with resistant populations of An. funestus performing just as well, if not better, than susceptible strains, especially under changing environmental conditions such as those expected to occur with climate change.

The stomach in health and disease.

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

Malaria in South Africa: 110 years of learning to control the disease.

In Africa today, the drive towards controlling malaria is comparable with efforts made in the 1950s and 1960s during the World Health Organization's Global Malaria Eradication Campaign. Unlike the Eradication Campaign that 'covered' the globe but excluded Africa, the current endeavours focus on Africa, but not to the exclusion of the rest of the tropical and sub-tropical world. Major donor agencies are partnering with African governments in an attempt to curb transmission of malaria parasites, and in some countries on the edges of the distribution of malaria, there is talk of eliminating the disease. South Africa is at the very southernmost fringe of malaria distribution on the African continent and has a long history of intense malaria control activities. This article looks at what South Africa has achieved in the past and where it needs to go in the future, not only to maintain the status quo, but hopefully to eliminate transmission of the disease within its borders. 

Altered physiology of acid secretion in depression-prone Flinders rats results in exacerbated NSAID and stress-induced gastric damage.

BACKGROUND: Flinders Sensitive Line (FSL) rats are characterized by hypersensitivity to cholinergic stimuli and have been extensively used for studying depressive disorders. A link between depression and peptic ulcers has long been established; however, there is a lack of data from animal models. METHODS: We studied the physiology of acid secretion in FSL and Flinders Resistant Line (FRL) rats in vivo and in vitro. We also examined the susceptibility of Flinders rats to water immersion restraint stress (WIRS) or NSAID-induced gastric damage and explored the effect of an anticholinergic agent, atropine, in reversing this effect. KEY RESULTS: Basal acid output was more than twofold greater in FSL compared with FRL rats in vivo, 213.5 and 92.8 µEq/3 h/100 g (P = 0.02), respectively. Carbachol was a more potent secretagog in vitro, and somatostatin was a less potent inhibitory agent, while paradoxically stimulating acid secretion over and above the carbachol response in gastric glands from FSL rats. The FSL rats were more susceptible to indomethacin and WIRS-induced gastric mucosal damage compared with FRL rats. Atropine reduced acid output, which resulted in a reduction in indomethacin and stress-induced gastric damage in FSL rats. CONCLUSIONS & INFERENCES: Our study, for the first time, demonstrates that the altered vagally mediated physiology of acid secretion in depression-prone FSL rats contributes to gastric hypersecretion and, consequently, results in exacerbated stress and NSAID-induced gastric damage. Flinders rats may be a useful animal model for studying acid-related and also gastrointestinal functional disorders in depression.

Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice.

SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD4(+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract.

The pharmacodynamics and pharmacokinetics of S-tenatoprazole-Na 30 mg, 60 mg and 90 mg vs. esomeprazole 40 mg in healthy male subjects.

BACKGROUND: Racemic tenatoprazole 40 mg/day provides more prolonged acid suppression than esomeprazole 40 mg/day. AIM: To compare pharmacodynamic and pharmacokinetic profiles of tenatoprazole and esomeprazole. METHODS: A single-centre, double-blind, double-dummy, randomized, 4-way, cross-over study was conducted in 32 healthy male subjects. S-tenatoprazole-Na 30, 60 or 90 mg, or esomeprazole 40 mg was administered once daily for 5 days with 10-day washout intervals. The 24-h intragastric pH was recorded at baseline and on day 5 of each period. RESULTS: On day 5, median pH (5.34 +/- 0.45 and 5.19 +/- 0.52 vs. 4.76 +/- 0.82, respectively, P < 0.002) and percentage time with pH > 4 (80 +/- 11 and 77 +/- 12, vs. 63 +/- 11 respectively, P < 0.0001) for 24-h were higher with S-tenatoprazole-Na 90 mg and 60 mg than esomeprazole. In nocturnal periods, S-tenatoprazole-Na 90 mg, 60 mg and 30 mg were superior to esomeprazole with regard to median pH (5.14 +/- 0.64, 4.94 +/- 0.65, 4.65 +/- 0.86 and 3.69 +/- 1.18 respectively, P < 0.0001) and percentage time with pH > 4 (77 +/- 12, 73 +/- 17, 64 +/- 17 and 46 +/- 17 respectively, P < 0.0001). Proportion of subjects with nocturnal acid breakthrough with S-tenatoprazole-Na 90 mg, 60 mg and 30 mg was significantly less than with esomeprazole (54.8, 43.3, 56.7 and 90.3 respectively, P < 0.04). The proportion of subjects with >16 hrs with pH >4 was significantly higher with S-tenatoprazole-Na 90 mg and 60 mg than with esomeprazole (87.1%, 83.3% and 41.9% respectively, P < 0.02). CONCLUSIONS: S-tenatoprazole-Na produced significantly greater and more prolonged dose-dependent 24-h and nocturnal acid suppression than esomeprazole. S-tenatoprazole-Na may provide greater clinical efficacy compared with current PPIs for patients with ineffective once-daily therapy.

Malaria vector composition and insecticide susceptibility status in Guinea Conakry, West Africa.

This study provides data on malaria vector species composition and insecticide susceptibility status from three localities in Guinea Conakry. A total of 497 mosquitoes were collected resting indoors and morphologically identified as belonging to the Anopheles gambiae complex. The majority of these were An. gambiae s.s. (99.6%), but a small percentage (0.4%) were identified as Anopheles arabiensis. Thirty-four Anopheles funestus s.s. were also collected. The molecular S form of An. gambiae s.s. was predominant over the M form in Siguiri (95%) and Boffa (97.4%), whereas at Mt Nimba the M form was more abundant (61.4%) than the S form (38.1%). One hybrid M/S specimen was recorded from Mt Nimba. Siguiri populations showed high levels of resistance to DDT, dieldrin and bendiocarb. Anopheles gambiae from Boffa were largely susceptible to the insecticides tested. At Mt Nimba, resistance to DDT and bendicocarb was detected. Biochemical enzyme analysis showed that an altered acetylcholinesterase is operating in the field at low levels. The frequency of the 1014F kdr allele in the An. gambiae S form was 0.24 at Siguiri and 0.14 at Mt Nimba. A single RR specimen was found in the M form. The heterogeneity in species composition and resistance profiles between sites requires vector control interventions to be tailored to each site based on the data collected from ongoing monitoring and surveillance.

Diagnosis and management of non-erosive reflux disease--the Vevey NERD Consensus Group.

BACKGROUND/AIMS: Although considerable information exists regarding gastroesophageal reflux disease with erosions, much less is known of non-erosive reflux disease (NERD), the dominant form of reflux disease in the developed world. METHODS: An expert international group using the modified Delphi technique examined the quality of evidence and established levels of agreement relating to different aspects of NERD. Discussion focused on clinical presentation, assessment of clinical outcome, pathobiological mechanisms, and clinical strategies for diagnosis and management. RESULTS: Consensus was reached on 85 specific statements. NERD was defined as a condition with reflux symptoms in the absence of mucosal lesions or breaks detected by conventional endoscopy, and without prior effective acid-suppressive therapy. Evidence supporting this diagnosis included: responsiveness to acid suppression therapy, abnormal reflux monitoring or the identification of specific novel endoscopic and histological findings. Functional heartburn was considered a separate entity not related to acid reflux. Proton pump inhibitors are the definitive therapy for NERD, with efficacy best evaluated by validated quality-of-life instruments. Adjunctive antacids or H(2) receptor antagonists are ineffective, surgery seldom indicated. CONCLUSIONS: Little is known of the pathobiology of NERD. Further elucidation of the mechanisms of mucosal and visceral hypersensitivity is required to improve NERD management.

Meta-analysis: incidence of endoscopic gastric and duodenal ulcers in placebo arms of randomized placebo-controlled NSAID trials.

BACKGROUND: The safety of NSAIDs is often evaluated by comparison with placebo in clinical trials. AIM: To investigate the incidence of gastric and duodenal ulcers (GDU) in placebo arms in NSAID trials over the last three decades. METHODS: Randomized placebo-controlled trials of oral NSAIDs from 1975 to 2006 were systematically reviewed. The pooled incidence of GDU in placebo arms was calculated and compared. Meta-regression was used to identify risk factors related to the incidence of the placebo ulcer at the study level. RESULTS: Thirty-six studies met inclusion criteria (duration of 6.5 days to 24 weeks). In total, 3.29% GDUs were reported in 36 placebo arms. The incidence of GDU in placebo arms was 0, 4.20% and 3.03% in the studies from 1975-1989, 1990-1999 and 2000-2006 respectively (P > 0.05). Eligible subjects with previous GI events and eligible subjects on co-therapy with low-lose aspirin/corticosteroids were associated with the increase in placebo ulcer incidence after adjusting for other factors. CONCLUSIONS: The incidence of GDU in placebo arms has not changed significantly over the last three decades, although has decreased in the past 10 years. Studies show that previous GI events and co-therapy with low-dose aspirin/corticosteroids were associated with increasing GDU in placebo arms.

Cryptic species within Anopheles longipalpis from southern Africa and phylogenetic comparison with members of the An. funestus group.

House-resting Anopheles mosquitoes are targeted for vector control interventions; however, without proper species identification, the importance of these Anopheles to malaria transmission is unknown. Anopheles longipalpis, a non-vector species, has been found in significant numbers resting indoors in houses in southern Zambia, potentially impacting on the utilization of scarce resources for vector control. The identification of An. longipalpis is currently based on classical morphology using minor characteristics in the adult stage and major ones in the larval stage. The close similarity to the major malaria vector An. funestus led to investigations into the development of a molecular assay for identification of An. longipalpis. Molecular analysis of An. longipalpis from South Africa and Zambia revealed marked differences in size and nucleotide sequence in the second internal transcribed spacer (ITS2) region of ribosomal DNA between these two populations, leading to the conclusion that more than one species was being analysed. Phylogenetic analysis showed the Zambian samples aligned with An. funestus, An. vaneedeni and An. parensis, whereas the South African sample aligned with An. leesoni, a species that is considered to be more closely related to the Asian An. minimus subgroup than to the African An. funestus subgroup. Species-specific primers were designed to be used in a multiplex PCR assay to distinguish between these two cryptic species and members of the An. funestus subgroup for which there is already a multiplex PCR assay.

Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z.

BACKGROUND: AGN 201904-Z is a new, slowly absorbed, acid-stable pro-proton pump inhibitor (pro-PPI) rapidly converted to omeprazole in the systemic circulation giving a prolonged residence time. AIM: To investigate pharmacodynamics and pharmacokinetics of AGN 201904-Z compared to esomeprazole. METHODS: A randomized, open-label, parallel group, investigator-blinded intragastric pH study was conducted in 24 healthy Helicobacter pylori negative male volunteers. AGN 201904-Z enteric-coated capsules (600 mg/day) or esomeprazole delayed-release tablets (40 mg/day) were administered for 5 days. Twenty-four-hour intragastric pH recordings were acquired at baseline, days 1, 3 and 5 with blood levels of omeprazole, AGN 201904-Z and gastrin. RESULTS: On day 1, median nocturnal pH and proportion of nocturnal time with pH >or=4 and 24-h and nocturnal time pH >or=5 were significantly higher with AGN 201904-Z than esomeprazole. At day 5, 24-h and median nocturnal pH were significantly higher for AGN 201904-Z than esomeprazole (P < 0.0001). There was also a marked reduction in periods of nocturnal pH <4.0. Area under curve of the AGN 201904-Z active metabolite (omeprazole) in the blood was twice that of esomeprazole at day 5. CONCLUSIONS: AGN 201904-Z produced a significantly greater and more prolonged acid suppression than esomeprazole, and nocturnal acid suppression was more prolonged over all 5 days. AGN 201904-Z should provide true once-a-day treatment and better clinical efficacy than current PPIs.

Access to specialist gastroenterology care in Canada: the Practice Audit in Gastroenterology (PAGE) Wait Times Program.

BACKGROUND: Canadian wait time data are available for the treatment of cancer and heart disease, as well as for joint replacement, cataract surgery and diagnostic imaging procedures. Wait times for gastroenterology consultation and procedures have not been studied, although digestive diseases pose a greater economic burden in Canada than cancer or heart disease. METHODS: Specialist physicians completed the practice audit if they provided digestive health care, accepted new patients and recorded referral dates. For patients seen for consultation or investigation over a one-week period, preprogrammed personal digital assistants were used to collect data including the main reason for referral, initial referral and consultation dates, procedure dates (if performed), personal and family history, and patient symptoms, signs and test results. Patient triaging, appropriateness of the referral and timeliness of care were noted. RESULTS: Over 10 months, 199 physicians recorded details of 5559 referrals, including 1903 visits for procedures. The distribution of total wait times (from referral to procedure) nationally was highly skewed at 91/203 days (median/75th percentile), with substantial interprovincial variation: British Columbia, 66/185 days; Alberta, 134/284 days; Ontario, 110/208 days; Quebec, 71/149 days; New Brunswick, 104/234 days; and Nova Scotia, 42/84 days. The percentage of physicians by province offering average-risk screening colonoscopy varied from 29% to 100%. DISCUSSION: Access to specialist gastroenterology care in Canada is limited by long wait times, which exceed clinically reasonable waits for specialist treatment. Although exhibiting some methodological limitations, this large practice audit sampling offers broadly generalized results, as well as a means to identify barriers to health care delivery and evaluate strategies to address these barriers, with the goals of expediting appropriate care for patients with digestive health disorders and ameliorating the personal and societal burdens imposed by digestive diseases.

Access to specialist gastroenterology care in Canada: comparison of wait times and consensus targets.

BACKGROUND: Monitoring wait times and defining targets for care have been advocated to improve health care delivery related to cancer, heart, diagnostic imaging, joint replacements and sight restoration. There are few data on access to care for digestive diseases, although they pose a greater economic burden than cancer or heart disease in Canada. The present study compared wait times for specialist gastroenterology care with recent, evidence-based, consensus-defined benchmark wait times for a range of digestive diseases. METHODS: Total wait times from primary care referral to investigation were measured for seven digestive disease indications by using the Practice Audit in Gastroenterology program, and were benchmarked against consensus recommendations. RESULTS: Total wait times for 1903 patients who were undergoing investigation exceeded targets for those with probable cancer (median 26 days [25th to 75th percentiles eight to 56 days] versus target of two weeks); probable inflammatory bowel disease (101 days [35 to 209 days] versus two weeks); documented iron deficiency anemia (71 days [19 to 142 days] versus two months); positive fecal occult blood test (73 days [36 to 148 days] versus two months); dyspepsia with alarm symptoms (60 days [23 to 140 days] versus two months); refractory dyspepsia without alarm symptoms (126 days [42 to 225 days] versus two months); and chronic constipation and diarrhea (141 days [68 to 264 days] versus two months). A minority of patients were seen within target times: probable cancer (33% [95% CI 20% to 47%]); probable inflammatory bowel disease (12% [95% CI 1% to 23%]); iron deficiency anemia (46% [95% CI 37% to 55%]); positive occult blood test (41% [95% CI 28% to 54%]); dyspepsia with alarm symptoms (51% [95% CI 41% to 60%]); refractory dyspepsia without alarm symptoms (33% [95% CI 19% to 47%]); and chronic constipation and diarrhea (21% [95% CI 14% to 29%]). DISCUSSION: Total wait times for the seven indications exceeded the consensus targets; 51% to 88% of patients were not seen within the target wait time. Multiple interventions, including adoption of evidence-based management guidelines and provision of economic and human resources, are needed to ensure appropriate access to digestive health care in Canada. Outcomes can be evaluated by the 'point-of-care', practice audit methodology used for the present study.