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Plasmodium vivax contributes significantly to global malaria morbidity. Key advances include the discovery of pathways facilitating invasion by P. vivax merozoites of nascent reticulocytes, crucial for vaccine development. Humanized mouse models and hepatocyte culture systems have enhanced understanding of hypnozoite biology. The spleen has emerged as a major reservoir for asexual vivax parasites, replicating in an endosplenic life cycle, and contributing to recurrent and chronic infections, systemic inflammation, and anemia. Splenic accumulation of uninfected red cells is the predominant cause of anemia. Recurring and chronic infections cause progressive anemia, malnutrition, and death in young children in high-transmission regions. Endothelial activation likely contributes to vivax-associated organ dysfunction. The many recent advances in vivax pathobiology should help guide new approaches to prevention and management., Competing Interests: Declaration of interests G.D.S. is an unpaid consultant to GSK on tafenoquine. All other authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3 , now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate.

Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition of the native immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms., (© 2023. Japanese Society of Hematology.)

This study examines the potential utility of using continuous glucose monitoring (CGM) to prescribe an exercise time to target peak hyperglycaemia in people with type 2 diabetes (T2D). The main aim is to test the feasibility of prescribing an individualised daily exercise time, based on the time of CGM-derived peak glucose, for people with T2D. Thirty-five individuals with T2D (HbA1c: 7.2 ± 0.8%; age: 64 ± 7 y; BMI: 29.2 ± 5.2 kg/m 2 ) were recruited and randomised to one of two 14 d exercise interventions: i) ExPeak (daily exercise starting 30 min before peak hyperglycaemia) or placebo active control NonPeak (daily exercise starting 90 min after peak hyperglycaemia). The time of peak hyperglycaemia was determined via a two-week baseline CGM. A CGM, accelerometer, and heart rate monitor were worn during the free-living interventions to objectively measure glycaemic control outcomes, moderate-to-vigorous intensity physical activity (MVPA), and exercise adherence for future translation in a clinical trial. Participation in MVPA increased 26% when an exercise time was prescribed compared to habitual baseline ( p < 0.01), with no difference between intervention groups ( p > 0.26). The total MVPA increased by 10 min/day during the intervention compared to the baseline (baseline: 23 ± 14 min/d vs. intervention: 33 ± 16 min/d, main effect of time p = 0.03, no interaction). The change in peak blood glucose (mmol/L) was similar between the ExPeak (-0.44 ± 1.6 mmol/L, d = 0.21) and the NonPeak (-0.39 ± 1.5 mmol/L, d = 0.16) intervention groups ( p = 0.92). Prescribing an exercise time based on CGM may increase daily participation in physical activity in people with type 2 diabetes; however, further studies are needed to test the long-term impact of this approach.

Patients with urothelial carcinoma tend to be older and frailer with a large number of chronic medical conditions. This is particularly pronounced in those with unresectable locally advanced and metastatic urothelial carcinoma. Prior to 2016, treatment options in advanced urothelial carcinoma were limited to chemotherapy, and as a result, a large number of patients were not receiving disease-directed management. Over the last 6 years, multiple alternative modalities including immune checkpoint inhibitors and targeted therapies have been introduced. They are being utilized clinically in older and frail patients, but there are limited studies investigating outcomes in these specific populations. Based upon current evidence, age does not impact the efficacy and tolerance of immune checkpoint inhibitors if patients are fit enough to receive therapy. In frailer patients, immune checkpoint inhibitors appear to be safe, but outcomes from largely retrospective studies demonstrate mixed data regarding their efficacy. Although there are indications from clinical trials that enfortumab vedotin, sacituzumab govitecan, and erdafitinib are also efficacious irrespective of age, there is still not enough evidence to draw definitive conclusions about their use in older and frail patients. Regardless, in all older patients with advanced urothelial carcinoma, it is critical to evaluate for frailty through geriatric screening tools and comprehensive assessments. Combining these evaluations with consideration of an individual patient's goals should be the foundation upon which therapeutic decisions are made in this population of patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The benefits of physical activity for glycaemic control in type 2 diabetes (T2D) are well-known. However, whether established glycaemic and cardiovascular benefits can be maximised by exercising at a certain time of day is unknown. Given postprandial glucose peaks contribute to worsening glycated haemoglobin (HbA1c) and cardiovascular risk factors, and that exercise immediately lowers blood glucose, prescribing exercise at a specific time of day to attenuate peak hyperglycaemia may improve glycaemic control and reduce the burden of cardiovascular disease in people with T2D., Methods and Analysis: A single-centre randomised controlled trial will be conducted by the University of Wollongong, Australia. Individuals with T2D (n=70, aged 40-75 years, body mass index (BMI): 27-40 kg/m 2 ) will be recruited and randomly allocated (1:1), stratified for sex and insulin, to one of three groups: (1) exercise at time of peak hyperglycaemia (ExPeak, personalised), (2) exercise not at time of peak hyperglycaemia (NonPeak) or (3) waitlist control (WLC, standard care). The trial will be 5 months, comprising an 8-week intervention and 3-month follow-up. Primary outcome is the change in HbA1c preintervention to postintervention. Secondary outcomes include vascular function (endothelial function and arterial stiffness), metabolic control (blood lipids and inflammation) and body composition (anthropometrics and dual-energy X-ray absorptiometry (DEXA)). Tertiary outcomes will examine adherence., Ethics and Dissemination: The joint UOW and ISLHD Ethics Committee approved protocol (2019/ETH09856) prospectively registered at the Australian New Zealand Clinical Trials Registry. Written informed consent will be obtained from all eligible individuals prior to commencement of the trial. Study results will be published as peer-reviewed articles, presented at national/international conferences and media reports., Trial Registration Number: ACTRN12619001049167., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

New Findings: What is the central question of this study? Is the estrous cycle affected during disuse atrophies and if so, how do estrous cycle changes relate to musculoskeletal outcomes? What is the main finding and its importance? Rodent estrous cycles are altered during disuse atrophy, which corresponds to musculoskeletal outcomes. However, the estrous cycle does not appear changed in Lewis Lung Carcinoma, which corresponded to no differences in muscle size compared to healthy controls. These findings suggest a relationship between estrous cycle and muscle size during atrophic pathologies., Abstract: Hyperglycemia can cause disruptions in vascular function, whereas exercise has been shown to restore vascular function. The primary aim of this study is to investigate the effect of performing whole-body resistance exercise, 30-min before, immediately following, or 30- or 60-min after a high carbohydrate meal, on endothelial function, measured by flow-mediated dilation (FMD). Healthy adults will be recruited to this randomized crossover trial to compare the postprandial glycaemic and vascular responses to four different exercise timing conditions and a control: i) C- control, high carbohydrate meal/no exercise, ii) 30Pre- 30 min of resistance exercises (~30% of 1RM [Repetition Maximum]), 30 min before a high carbohydrate meal, iii) IP- 30 min of resistance exercises (~30% of 1RM), immediately following a high carbohydrate meal, iv) 30Post- 30 min of resistance exercises, 30 min after a high carbohydrate meal and v) 60Post- 30 min of resistance exercises, 60 min after a high carbohydrate meal. Measures of metabolic and vascular function will be assessed at baseline and for two hours following the carbohydrate-based breakfast meal., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14-16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38-40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10-12°C) immersion. Before and after, participants completed a 20 min cycle work trial, V . O 2 max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m 2 , Female = 11) were analyzed using a fixed-effects linear mixed model. V . O 2 max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen's d = 1.35), but not WWI (CI: -0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI -1.9, -0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russell, Chang, Hill, Cotter and Francois.)

Background: A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival., Methods and Findings: We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted., Conclusions: Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Competing Interests: The authors have declared that no competing interests exist.

Clinical practice guidelines on physical activity and diabetes currently stipulate physical activity can be accumulated in bouts of ≥10 minutes to meet recommendations for health benefits. Individuals are also encouraged to interrupt prolonged sitting with brief activity breaks of ∼1 to 5 minutes in duration. Growing research highlights accumulating activity in shorter bouts across the day as a potential strategy to improve glycemic control and to help those who are largely sedentary meet physical activity guidelines. Research has shown favourable glycemic benefits for postprandial glucose and glycated hemoglobin with either 3 short (10 to 15 minutes) or frequent brief (1 to 5 minutes) bouts of activity spread around meals or throughout the day. To date, most studies examining accumulated activity were done with people with type 2 diabetes compared with sedentary conditions, were short term and measured various indices of glycemic control using continuous glucose monitoring. The 7 trials comparing accumulating 3 short bouts to a single bout showed comparable benefits for glycemic control (i.e. fasting glucose, 24 h mean glucose and postprandial hyperglycemia). Furthermore, timing short bouts around meals may improve postprandial glucose and hyperglycemia more than a single bout. It is unknown whether a threshold for the duration of accumulated bouts exists---that is, "how much is enough?" In this narrative review, we focus on the glycemic effects of physical activity accumulated in short or brief bouts for people with prediabetes and diabetes as compared with a single continuous bout. Given that poor adherence to physical activity recommendations and that fewer opportunities exist in modern societies for incidental (nonexercise) physical activity, accumulating activity may be a choice strategy for improving glycemic control in those with and at risk of diabetes., (Copyright © 2020 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: Overweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration., Design: Cross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured., Results: Prior to treatment, IGFBP-3 (r = -0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = -0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ± 56 to 269 ± 66 μg/L, p < 0.0001) and bioactive IGF (1.29 ± 0.39 to 2.60 ± 1.12 μg/L, p < 0.0001). The treatment-related increase in bioactive IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = -0.43, p = 0.003)., Conclusions: Our data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes., Clinical Trial Registration Number: NCT00131378., (Copyright © 2018. Published by Elsevier Ltd.)

Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.

Our current understanding of how malaria parasites remodel their host red blood cells (RBCs) and ultimately cause disease is largely based on studies of Plasmodium falciparum. In this review, we expand our knowledge to include what is currently known about pathophysiological changes to RBCs that are infected by non-falciparum malaria parasites. We highlight the potential folly of making generalizations about the rheology of malaria infection, and emphasize the need for more systematic studies into the erythrocytic biology of non-falciparum malaria parasites. We propose that a better understanding of the mechanisms that underlie the changes to RBCs induced by malaria parasites other than P. falciparum may be highly informative for the development of therapeutics that specifically disrupt the altered rheological profile of RBCs infected with either sexual- or asexual-stage parasites, resulting in drugs that block transmission, reduce disease severity, and help delay the onset of resistance to current and future anti-malaria drugs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Although growth hormone (GH) replacement is prescribed for patients with hypopituitarism due to many etiologies, it is not routinely prescribed for patients with GH deficiency (GHD) after cure of acromegaly (acroGHD). This study was designed to investigate the effect of GH replacement on cardiac parameters in acroGHD., Design: We prospectively evaluated for 12months 23 patients with acroGHD: 15 subjects on GH replacement and eight subjects not on GH replacement. Main outcome measures included LV mass corrected for body surface area (LVM/BSA) and measures of diastolic dysfunction (E/A ratio and deceleration time), as assessed by echocardiography., Results: After 12months of follow-up, there were no differences between the GH-treated group and the untreated group in LVM/BSA (GH: 74.4±22.5g/m(2) vs untreated: 72.9±21.3g/m(2), p=0.89), E/A ratio (GH: 1.21±0.39 vs untreated: 1.08±0.39, p=0.50) or deceleration time (GH: 224.5±60.1ms vs untreated: 260±79.8ms, p=0.32). The overall degree of diastolic function was similar between the groups with 42.9% of untreated subjects and 50% of GH-treated subjects (p=0.76) classified as having normal diastolic function at follow-up., Conclusions: There were no significant differences in LVM/BSA or parameters of diastolic function in patients with a history of acromegaly treated for GHD as compared to those who were untreated. These data are reassuring with respect to cardiovascular safety with GH use after treatment for acromegaly, although further longer term study is necessary to evaluate the safety and efficacy of GH treatment in this population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Data suggest that anorexia nervosa (AN) and obesity are complicated by elevated fracture risk, but skeletal site-specific data are lacking. Traditional bone mineral density (BMD) measurements are unsatisfactory at both weight extremes. Hip structural analysis (HSA) uses dual-energy X-ray absorptiometry data to estimate hip geometry and femoral strength. Factor of risk (φ) is the ratio of force applied to the hip from a fall with respect to femoral strength; higher values indicate higher hip fracture risk., Objective: The objective of the study was to investigate hip fracture risk in AN and overweight/obese women., Design: This was a cross-sectional study., Setting: The study was conducted at a Clinical Research Center., Patients: PATIENTS included 368 women (aged 19-45 y): 246 AN, 53 overweight/obese, and 69 lean controls., Main Outcome Measures: HSA-derived femoral geometry, peak factor of risk for hip fracture, and factor of risk for hip fracture attenuated by trochanteric soft tissue (φ(attenuated)) were measured., Results: Most HSA-derived parameters were impaired in AN and superior in obese/overweight women vs controls at the narrow neck, intertrochanteric, and femoral shaft (P ≤ .03). The φ(attenuated) was highest in AN and lowest in overweight/obese women (P < .0001). Lean mass was associated with superior, and duration of amenorrhea with inferior, HSA-derived parameters and φ(attenuated) (P < .05). Mean φ(attenuated) (P = .036), but not femoral neck BMD or HSA-estimated geometry, was impaired in women who had experienced fragility fractures., Conclusions: Femoral geometry by HSA, hip BMD, and factor of risk for hip fracture attenuated by soft tissue are impaired in AN and superior in obesity, suggesting higher and lower hip fracture risk, respectively. Only attenuated factor of risk was associated with fragility fracture prevalence, suggesting that variability in soft tissue padding may help explain site-specific fracture risk not captured by BMD.

Context: Obesity is associated with diminished GH secretion, which may result in the overdiagnosis of adult GH deficiency (GHD) in overweight/obese pituitary patients. However, there are no body mass index (BMI)-specific peak GH cutoffs for the glucagon stimulation test (GST), the favored dynamic test for assessing adult GHD in the United States., Objective: The objective of the study was to determine a peak GH cutoff level for the diagnosis of adult GHD in overweight/obese individuals using the GST., Design: This was a retrospective, cross-sectional study., Setting: The study was conducted at Massachusetts General Hospital and Oregon Health and Science University., Methods: A total of 108 subjects with a BMI ≥ 25 kg/m(2) were studied: healthy controls (n = 47), subjects with total pituitary deficiency (TPD) (n = 20, ≥ 3 non-GH pituitary hormone deficiencies), and subjects with partial pituitary deficiency (PPD) (n = 41, 1-2 non-GH pituitary hormone deficiencies)., Intervention: The intervention consisted of a standard 4-hour GST., Main Outcome Measures: The main outcome measure was peak GH level on GST., Results: Using the standard peak GH cutoff of 3 ng/mL, 95% of TPD cases (19 of 20), 80% of PPD (33 of 41), and 45% of controls (21 of 47) were classified as GHD. In receiver-operator characteristic curve analysis (controls vs TPD), a peak GH value of 0.94 ng/mL provided the greatest sensitivity (90%) and specificity (94%). Using a peak GH cutoff of 1 ng/mL, 6% of controls (3 of 47), 59% of PPDs (24 of 41), and 90% of TPDs (18 of 20) were classified as GHD. BMI (R = -0.35, P = .02) and visceral adipose tissue (R = -0.32, P = .03) negatively correlated with peak GH levels in controls., Conclusion: A large proportion of healthy overweight/obese individuals (45%) failed the GST using the standard 3 ng/mL GH cutoff. Overweight/obese pituitary patients are at risk of being misclassified as GHD using this cutoff level. A 1-ng/mL GH cutoff may reduce the overdiagnosis of adult GHD in overweight/obese patients.

There is now a growing body of evidence that challenges the current view that Plasmodium vivax-infected erythrocyte (Pv-iE) are unable to sequester. Here we used ex vivo adhesion assays with Pv-iE before and after maturation to demonstrate a higher binding potential of schizonts compared to other asexual stages. These experimental results are correlated with our observations in a panel of 50 vivax malaria patients where schizonts were completely absent in 27 isolates, and few schizonts were observed in the remaining patients. These observations prompt a paradigm shift in P. vivax biology and open avenues to investigate the role of Pv-iE sequestration.

Background: Human lung cancer patients exhibit different KRAS mutations depending on smoking status. In a mouse model of human cancer, A/J and BALB/cBy mice treated with the tobacco carcinogen, 3-methylcholanthrene (MCA), followed by butylated hydroxytoluene (BHT)-elicited chronic inflammation develop a high multiplicity of lung tumors., Methods: DNA was isolated from MCA-induced lung tumors in A/J and BALB/cByJ mice. Kras codon 12 sequences from these tumors were compared to those in human lung tumors from smokers and never-smokers., Results: The distribution of Kras codon 12 mutations in MCA-induced A/J lung tumors is strikingly similar to those found in adenocarcinomas from human smokers. In contrast, codon 12 mutations in BALB/cBy mice contain predominantly G --> D mutations, which is the most common mutation in never smokers., Conclusions: A single lung carcinogen induces different tumor initiating mutations in different strains of mice. This may be useful for investigating the role of specific KRAS mutations in adenocarcinoma pathogenesis in smokers versus never smokers, identifying mechanisms that select for certain KRAS mutations and developing new drugs that specifically target cells with different KRAS mutations.

The aim of this study was to develop a simple, field-practical, and effective in vitro method for determining the sensitivity of fresh erythrocytic Plasmodium vivax isolates to a range of antimalarials. The method used is a modification of the standard World Health Organization (WHO) microtest for determination of P. falciparum drug sensitivity. The WHO method was modified by removing leukocytes and using a growth medium supplemented with AB(+) serum. We successfully carried out 34 in vitro drug assays on 39 P. vivax isolates collected from the Mae Sod malaria clinic, Tak Province, Thailand. The mean percentage of parasites maturing to schizonts (six or more merozoites) in control wells was 66.5% +/- 5.9% (standard deviation). This level of growth in the control wells enabled rapid microscopic determination (5 min per isolate per drug) of the MICs of chloroquine, dihydroartemisinin, WR238605 (tafenoquine), and sulfadoxine. P. vivax was relatively sensitive to chloroquine (MIC = 160 ng/ml, 50% inhibitory concentration [IC(50)] = 49.8 ng/ml) and dihydroartemisinin (MIC = 0.5 ng/ml, IC(50) = 0.47 ng/ml). The poor response of P. vivax to both tafenoquine (MIC = 14,000 ng/ml, IC(50) = 9,739 ng/ml) and sulfadoxine (MIC = 500,000 ng/ml, IC(50) = 249,000 ng/ml) was due to the slow action of these drugs and the innate resistance of P. vivax to sulfadoxine. The in vitro assay developed in our study should be useful both for assessing the antimalarial sensitivity of P. vivax populations and for screening new antimalarials in the absence of long-term P. vivax cultures.

This study details the novel application of predacious copepods, genus Mesocyclops, for control of Ochlerotatus tremulus (Theobald) group and Aedes aegypti (L.) mosquito larvae in subterranean habitats in north Queensland, Australia. During June 1997, 50 Mesocyclops sp. 1 were inoculated into one service manhole in South Townsville. Wet season rainfall and flooding in both 1998 and 2000 was responsible for the dispersal of copepods via the underground pipe system to 29 of 35 manholes over an area of 1.33 km2. Significant reductions in Aedes and Ochlerotatus larvae ensued. In these habitats, Mesocyclops and Metacyclops were able to survive dry periods, when substrate moisture content ranged from 13.8 to 79.9%. At the semiarid inland towns of Hughenden and Richmond, cracking clay soil prevents drainage of water from shallow service pits where Oc. tremulus immatures numbered from 292-18,460 per pit. Introduction of Mesocyclops copepods into these sites during May 1999 resulted in 100% control of Oc. tremulus for 18 mo. One uninoculated pit subsequently became positive for Mesocyclops with resultant control of mosquito larvae.

The objective of this study wasto determine the epidemiological significance of subterranean mosquito breeding sites to the 1993 outbreak of dengue fever (type 2) in the northern Queensland town of Charters Towers, Australia. In recent studies on subterranean mosquito breeding, containers such as wells and service manholes have been shown to be important breeding sites to Australia's only dengue vector, Aedes aegypti (L.). This study demonstrates a direct epidemiological association between subterranean breeding sites and dengue virus infection. The mean distance between residents seropositive for dengue 2 and the nearest subterranean container (113 m) was significantly less than for a randomly selected control (191 m), (F = 81.9; df = 1, 478; P < 0.001). Residents positive for dengue 2 antibodies was 2.47 (95% confidence interval 1.88-3.24) times higher for those living within 160 m of a well or service manhole, compared with those residing further away. These findings emphasize the importance of incluuding subterranean water containers in Ae. aegypti surveillance and control programs.

The ability of 2 freshwater fishes, eastern rainbow fish Melanotaenia splendida splendida and fly-specked hardyhead Craterocephalus stercusmuscarum stercusmuscarum, native to North Queensland to prey on immature Aedes aegypti was evaluated under laboratory conditions. The predation efficiency of the 2 species was compared to the exotic guppy, Poecilia reticulata, which is commonly used as a biological control agent of mosquito larvae. Of the 3 fish species tested, M. s. splendida was shown to be the most promising agent for the biological control of Ae. aegypti that breed in wells. Melanotaenia s. splendida consumed significantly greater numbers of immature Ae. aegypti than P. reticulata, irrespective of developmental stage or light conditions. Unlike C s. stercusmuscarum, M. s. splendida could be handled, transported, and kept in captivity for extended periods with negligible mortality. However, M. s. splendida was also an efficient predator of Litoria caerulea tadpoles, a species of native frog found in wells during the dry season. This result may limit the usefulness of M. s. splendida as a biological control agent of well-breeding Ae. aegypti and suggests that predacious copepods, Mesocyclops spp., are more suitable. However, the use of M. s. splendida as a mosquito control agent in containers that are unlikely to support frog populations (e.g., aquaculture tanks and drinking troughs) should be given serious consideration.

The effect of a protracted dry season on the viability of Ae. aegypti (L.) eggs was examined in Townsville, northern Queensland, Australia. Eggs were placed in several different surface and subterranean larval habitats; and after four dry season months, only 1-10% of eggs remained viable in the surface and subterranean sites, respectively. Low humidity and predation by Periplaneta americana (L.) were the major causes of egg mortality in eggs in surface sites. P. americana was the most significant cause of egg predation in subterranean breeding sites but fungi, especially Penicillium citrinum Thom, covered egg batches within 15 d. Mycotoxins produced by the spores of P. citrinum are believed to have killed embryonating eggs. The high mortality rate of Ae. aegypti eggs during the dry season suggests that this survival strategy is unlikely to contribute to rapid and successful recolonization of surface sites at the end of the wet season.

In north Queensland, 14 localities were surveyed for mosquito larvae (third and fourth instar) during summer/autumn and winter from 1996 to 1999. Absolute population numbers in subterranean habitats, mainly service manholes and pits (97%) but also some wells, septic tanks, storm drains, and sumps, were expressed as a proportion of total numbers in these sites plus surface sites within a 100-m radius. When correction factors were applied to subterranean samples, the 472,477 larvae mainly of Aedes tremulus (Theobald) group, Aedes notoscriptus (Skuse), and Aedes aegypti (L.) comprised 78% of the total population. In relation to the proportion of the overall immature mosquito population from subterranean habitats (propsub), linear regression coefficients for minimum temperature, relative humidity, and Mesocyclops copepod prevalence were significant for winter data; but for summer, only relative humidity was significant. Linear regression coefficients for Mesocyclops prevalence approached significance (P = 0.061) in summer. When multiple linear regression was used to model propsub, 68% of the variation was accounted for by relative humidity and the prevalence of Mesocyclops. In the drier and cooler towns, increased use of subterranean sites during winter was caused by reduced availability of surface oviposition sites because of the dry season. In the wetter coastal towns, no such restrictions applied and ambient conditions remained more equitable all year round. Mesocyclops were surprisingly common, particularly in these coastal towns. Release of known numbers of Mesocyclops indicated that 3-sweep netting in service manholes was sensitive down to densities of one Mesocyclops per 10 liters, and overall recovery varied from 1 to 4%. In relation to control, service manholes represent a stable habitat for mosquito (7% positive overall) and Mesocyclops populations. If they remained wet, service manholes positive for mosquito immatures or Mesocyclops during summer/autumn had 96% and 85% chance, respectively, of being positive the following winter. Even allowing for the effect of drying, a mosquito-positive manhole had a 79% chance of remaining positive the following winter. In view of the importance of these sites as refuges from adverse ambient conditions, it is proposed that a winter control strategy using Mesocyclops presents a cost-effective control option to reduce the recolonization of surface sites when conditions become more suitable.

This paper addresses the problems of sampling adult Aedes aegypti and other mosquitoes which utilize subterranean habitats such as wells and service manholes. The sticky pipe trap is a simple device with an adhesive paper insert that can be clipped to the undersides of service manholes to record the entry and exit of adult mosquitoes through the keyhole openings. This trap was 1st used successfully in Townsville, Charters Towers, and Saunders Beach in north Queensland, Australia, in dry seasons of 1996-97 to record usage by 5 species, mainly the Aedes tremulus group and Ae. aegypti, which together comprised 91% of the 1,140 adults collected. Both males and predominantly nulliparous females were recorded exiting manholes, whereas all freshwater-breeding species entering manholes were gravid, presumably seeking oviposition sites.

Our article addresses the problems of sampling and quantifying the abundance of immature Aedes aegypti (L.) and other mosquitoes that use subterranean habitats such as wells and service manholes. Two versions of the funnel trap, Austrap and Vietrap, were extremely sensitive for detecting the presence of Ae. aegypti larvae in wells, and the modified version, the Vietrap, sampled on average 20.5% of 3rd and 4th instars when set overnight for 12 h. For both models, regression analyses between trap catch and absolute abundance indicated high coefficients of determination (R2 = 0.932 and 0.992) enabling accurate direct calibration. The effects of immature age, mosquito species, well diameter, and trap size on catch size were investigated. Because of its simplicity, efficacy, and inexpensiveness, the Vietrap will facilitate the comprehensive assessment of key larval habitats for Ae. aegypti, data critical for the development of effective control programs.

Skeletal anomalies in patients with a 22q11.2 deletion are reported infrequently. We report the skeletal findings in 108 patients with a 22q11.2 deletion, of whom 37 (36%) had a skeletal anomaly. Twenty-two patients (20%) had anomalies of the limbs, 7 of the upper limb, including preaxial or postaxial polydactyly. An anomaly of the lower limb was found in 16 patients, including postaxial polydactyly, clubfoot, severely overfolded toes, and 2-3 toe cutaneous syndactyly. Chest films of 63 patients were examined; 30% of them had abnormal findings, most commonly supernumerary ribs (17%) or a "butterfly" vertebral body (11%). Hypoplastic vertebrae, hemivertebrae, and vertebral coronal clefts were also noted. Thus, skeletal anomalies are not uncommon in patients with a 22q11.2 deletion and may occur more frequently than recognized previously.

A survey of the dengue vector mosquito Aedes aegypti was undertaken using funnel traps to detect immature stages (larvae and pupae) in flooded disused mine shafts and wells in Charters Towers, Queensland, Northern Australia. The town has a history of dengue fever since 1885 when goldminers were the first recorded victims. During the latest dengue epidemic in 1993, 2% of the population had laboratory-confirmed dengue virus Type 2, despite source reduction of Ae.aegypti breeding-sites at ground level or above. This led to suspicions that dengue vector Ae.aegypti breeding-sites might be below ground level. When surveyed in March 1994, Ae.aegypti immatures were found in 9/10 wells and 1/6 mine shafts. The water in wells and mines had similar characteristics-except that turbidity was higher in the mines, which more often contained predators of mosquito immatures. The copepod Mesocyclops aspericornis was collected from water in 1/10 wells and 2/6 mine shafts. Laboratory predation trials resulted in 95.5-100% predation by 25 copepods/l on Ae.aegypti first-instar larvae up to 200 larvae/l. Five wells containing Ae.aegypti in the survey were inoculated with fifty indigenous M.aspericornis, and five wells (one positive and four negative in the survey) were left untreated as controls. Nine months later, in December 1994, Ae.aegypti had been eliminated from all five treated wells but all untreated control wells contained Ae.aegypti, except for one well that contained a natural population of M.aspericornis. The role of wells and mines as winter/ dry season refuges of Ae.aegypti in northern Australia is reviewed, and we recommend the use of M.aspericornis as a cost-effective, environmentally acceptable and persistent agent for the sustainable control of Ae.aegypti, especially in inaccessible breeding sites.

Thirty-two eyes of 28 patients who underwent radial keratotomy had a hyperopic overcorrection after the surgical procedure. Anisometropia, with associated aniseikonia and depth perception problems were present in many of these patients. The patients were subsequently fit with contact lenses. Conventional methods of fitting contact lenses in these patients were unsuccessful. A trial lens technique is used with the initial lens having a base curve equal to the preoperative keratometry measurements and the power equal to the preoperative spherical equivalent. Superficial neovascularization developed within the radial incisions in 33% of the eyes fitted with soft contact lenses. Gas permeable contact lenses offered patients the best-corrected visual acuity as well as minimal complications. In addition, the anisometropia was minimized, and fluctuating vision was eliminated in cases in which it was a problem.