Anomalous spatial coherence changes in radiation and scattering.

The superposition of two partially correlated waves is shown to produce fields with drastically altered coherence properties. It is demonstrated, both theoretically and experimentally, that two strongly correlated sources may generate a field with practically zero correlation between certain pairs of points. This anomalous change in coherence is a general phenomenon that takes place in all cases of wave superposition, including Mie scattering, as is shown. Our results are particularly relevant to applications in which it is assumed that highly coherent radiation maintains its spatial coherence on propagation, such as optical systems design and the imaging of extended sources.

Propagation of Gaussian Schell-model beams in modulated graded-index media.

The evolution of partially coherent beams in longitudinally modulated graded-index media is studied. The special cases of Gaussian Schell-model beams and parametric modulation, when the modulation period is half the fiber self-imaging period, are examined in detail. We show that the widths of the intensity and coherence of Gaussian Schell-model beams undergo amplification in parametrically modulated parabolic graded-index media. The process is an analog of quantum mechanical parametric amplification and generation of squeezed states. Our work may find application in spatial and temporal imaging of partially coherent beams in fiber-based imaging systems.

Three-year outcome after transanal versus laparoscopic total mesorectal excision in locally advanced rectal cancer: a multicenter comparative analysis.

BACKGROUND: For patients with mid and distal rectal cancer, robust evidence on long-term outcome and causal treatment effects of transanal total mesorectal excision (TaTME) is lacking. This multicentre retrospective cohort study aimed to assess whether TaTME reduces locoregional recurrence rate compared to laparoscopic total mesorectal excision (LapTME). METHODS: Consecutive patients with rectal cancer within 12 cm from the anal verge and clinical stage II-III were selected from three institutional databases. Outcome after TaTME (Nov 2011 - Feb 2018) was compared to a historical cohort of patients treated with LapTME (Jan 2000 - Feb 2018) using the inverse probability of treatment weights method. The primary endpoint was three-year locoregional recurrence. RESULTS: A total of 710 patients were analysed, 344 in the TaTME group and 366 in the LapTME group. At 3 years, cumulative locoregional recurrence rates were 3.6% (95% CI, 1.1-6.1) in the TaTME group and 9.6% (95% CI, 6.5-12.7) in the LapTME group (HR = 0.4; 95% CI, 0.23-0.69; p = 0.001). Three-year cumulative disease-free survival rates were 74.3% (95% CI, 68.8-79.8) and 68.6% (95% CI, 63.7-73.5) (HR = 0.82; 95% CI, 0.65-1.02; p = 0.078) and three-year overall survival 87.2% (95% CI, 82.7-91.7) and 82.2% (95% CI, 78.0-86.2) (HR = 0.74; 95% CI, 0.53-1.03; p = 0.077), respectively. In patients who underwent sphincter preservation procedures, TaTME was associated with a significantly better disease-free survival (HR = 0.78; 95% CI, 0.62-0.98; p = 0.033). CONCLUSIONS: These findings suggest that TaTME may improve locoregional recurrence and disease-free survival rates among patients with mid and distal locally advanced rectal cancer.

The association of maternal thyroid function with placental hemodynamics.

STUDY QUESTION: What is the clinical association of maternal thyroid function with placental hemodynamic function? SUMMARY ANSWER: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance. WHAT IS KNOWN ALREADY: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion. STUDY DESIGN, SIZE, DURATION: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHOD: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women. MAIN RESULTS AND THE ROLE OF CHANCE: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively. LIMITATIONS, REASONS FOR CAUTION: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes. WIDER IMPLICATIONS OF THE FINDINGS: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Prenatal Prediction of the Type of Omphalocele Closure by Different Medical Consultants.

INTRODUCTION: To evaluate differences between consultants of different disciplines in the prenatal prediction of the type of postnatal surgical closure of an omphalocele. MATERIAL AND METHODS: Twenty-one images of prenatally detected omphaloceles prior to 24 weeks of gestation were included. A standardized form provided known prenatal information and an ultrasound image for each case. Nineteen consultants were asked to assess the probability of primary closure of an omphalocele and to state which information was the most important for their assessment. RESULTS: Primary closure (13/21 images) was predicted correctly in 5/13 images. The number of correct predictions per image ranged from 63 to 89%. The type of closure was predicted correctly in 7/8 images of cases which were not closed primarily, ranging from 58 to 84% correct predictions per image. There was no significant difference between consultants of different disciplines. Individual accuracy ranged from 10 to 62%. The consultants regarded omphalocele content as the most important information (34%) for counseling. DISCUSSION: The consultants did not differ in their prenatal judgment of the primary closure of an omphalocele. The consultants tended to be too negative in their assessment, since 75% assessed the probability of primary closure overall to be <60%, whereas 62% of the cases were primarily closed. Omphalocele content was the most important information for the consultants' judgment.

MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats.

Wolff-Chaikoff effect is characterized by the blockade of thyroid hormone synthesis and secretion due to iodine overload. However, the regulation of monocarboxylate transporter 8 during Wolff-Chaikoff effect and its possible role in the rapid reduction of T4 secretion by the thyroid gland remains unclear. Patients with monocarboxylate transporter 8 gene loss-of-function mutations and monocarboxylate transporter 8 knockout mice were shown to have decreased serum T4 levels, indicating that monocarboxylate transporter 8 could be involved in the secretion of thyroid hormones from the thyroid gland. Herein, we aimed to evaluate the regulation of monocarboxylate transporter 8 during the Wolff-Chaikoff effect and the escape from iodine overload, besides the importance of iodine organification for this regulation. Monocarboxylate transporter 8 mRNA and protein levels significantly decreased after 1 day of NaI administration to rats, together with decreased serum T4; while no alteration was observed in LAT2 expression. Moreover, both monocarboxylate transporter 8 expression and serum T4 was restored after 6 days of NaI. The inhibition of thyroperoxidase activity by methimazole prevented the inhibitory effect of NaI on thyroid monocarboxylate transporter 8 expression, suggesting that an active thyroperoxidase is necessary for MCT8 downregulation by iodine overload, similarly to other thyroid markers, such as sodium iodide symporter. Therefore, we conclude that thyroid monocarboxylate transporter 8 expression is downregulated during iodine overload and that the normalization of its expression parallels the escape phenomenon. These data suggest a possible role for monocarboxylate transporter 8 in the changes of thyroid hormones secretion during the Wolff-Chaikoff effect and escape.

The thyroid axis 'setpoints' are significantly altered after long-term suppressive LT4 therapy.

The aim of the study was to investigate the changes in the thyroid axis setpoint after long-term suppressive levothyroxine therapy for differentiated thyroid carcinoma and the resulting changes in levothyroxine requirement. Ninety-nine differentiated thyroid cancer patients were reviewed. All patients had at least one known TSH-level≥0.01 mU/l (lower detection limit) and <1.0 mU/l within 2 years of initial treatment (time 1) and had at least one TSH-value≥0.01 mU/l and <1.0 mU/l after continuous LT4 therapy for a minimum of 5 years (time 2).At time 2 the mean LT4 dosage/kg body weight, TSH, FT3, and FT4 levels were significantly lower than at time 1, while body weight was higher. At time 2, the FT3/FT4 ratio rate had dropped significantly (p<0.001). At time 1, patients would require 2.96 µg/kg body weight to reach total TSH suppression. The dose of levothyroxine/kg required for suppression can be lowered by about 0.05 µg/kg body weight for each year of suppressive therapy. After a median of 12.7 years of continuous suppressive levothyroxine therapy, patients would require 2.25 µg/kg body weight (-23.5%) to reach total TSH-suppression. At least part of this reduction was independent of aging. As a result of changes in thyroid hormone metabolism and thyroid axis setpoint, long-term TSH-suppressive therapy contributes to a reduction in the dosage of levothyroxine per kilogram body weight required for full TSH suppression over time.

A cluster-randomized trial of client and provider directed financial interventions to align incentives with appropriate case management in private medicine retailers: results of the TESTsmART Trial in Lagos, Nigeria.

Malaria remains a major health priority in Nigeria. Among children with fever who seek care, less than a quarter gets tested for malaria, leading to inappropriate use of the recommended treatment for malaria; Artemether Combination Therapies (ACT). Here we test an innovative strategy to target ACT subsidies to clients seeking care in Nigeria's private retail health sector who have a confirmed malaria diagnosis. We supported point-of-care malaria testing (mRDTs) in 48 Private Medicine Retailers (PMRs) in the city of Lagos, Nigeria and randomized them to two study arms; a control arm offering subsidized mRDT testing for USD $0.66, and an intervention arm where, in addition to access to subsidized testing as in the control arm, clients who received a positive mRDT at the PMR were eligible for a free (fully subsidized) first-line ACT and PMRs received USD $0.2 for every mRDT performed. Our primary outcome was the proportion of ACTs dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients who were tested at the PMR and adherence to diagnostic test results. Overall, 23% of clients chose to test at the PMR. Test results seemed to inform treatment decisions and resulted in enhanced targeting of ACTs to confirmed malaria cases with only 26% of test-negative clients purchasing an ACT compared to 58% of untested clients. However, the intervention did not offer further improvements, compared to the control arm, in testing rates or dispensing of ACTs to test-positive clients. We found that ACT subsidies were not passed on to clients testing positive in the intervention arm. We conclude that RDTs could reduce ACT overconsumption in Nigeria's private retail health sector, but PMR-oriented incentive structures are difficult to implement and may need to be complemented with interventions targeting clients of PMRs to increase test uptake and adherence. Clinical Trials Registration Number: NCT04428307.

Dynamic beam steering from a subwavelength slit by selective excitation of guided modes.

Dynamic control of the direction of radiation of the light emanating from a subwavelength slit carved out of a thin metal film is experimentally demonstrated. This is achieved by selective excitation of the individual guided modes in the slit by setting the phase of three coherent laser beams. By changing the voltage across a piezoelement, we obtain unprecedented directional steering, without relying on any mechanical alignment of optical elements. The angular range over which this maximum can be swept is determined by the intensity setting of one of the incident beams. Through simulations, we show that this method can also be applied to steer the radiation from a square hole in two independent directions. Our method can be applied to create a directional nanoemitter which can selectively address one or more detectors, or as an optical switch in photonic circuits.

A cluster-randomized trial of client and provider-directed financial interventions to align incentives with appropriate case management in retail medicine outlets: results of the TESTsmART Trial in western Kenya.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years. These reductions would not have been possible without publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to their overconsumption. We test an innovative, scalable, and sustainable strategy to target ACT subsidies to clients with a confirmatory diagnosis. We supported point-of-care malaria testing (mRDTs) in 39 retail medicine outlets in western Kenya and randomized them to three study arms; control arm offering subsidized RDT testing for 0.4USD, client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully subsidized) first-line ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions and resulted in targeting of ACTs to confirmed malaria cases - 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates (RD=0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients (RD=0.01,95% CI: -0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain.

Added diagnostic value of routinely measured hematology variables in diagnosing immune checkpoint inhibitor mediated toxicity in the emergency department.

BACKGROUND: Immune checkpoint inhibitors (ICI) show remarkable results in cancer treatment, but at the cost of immune-related adverse events (irAE). irAE can be difficult to differentiate from infections or tumor progression, thereby challenging treatment, especially in the emergency department (ED) where time and clinical information are limited. As infections are traceable in blood, we were interested in the added diagnostic value of routinely measured hematological blood cell characteristics in addition to standard diagnostic practice in the ED to aid irAE assessment. METHODS: Hematological variables routinely measured with our hematological analyzer (Abbott CELL-DYN Sapphire) were retrieved from Utrecht Patient Oriented Database (UPOD) for all patients treated with ICI who visited the ED between 2013 and 2020. To assess the added diagnostic value, we developed and compared two models; a base logistic regression model trained on the preliminary diagnosis at the ED, sex, and gender, and an extended model trained with lasso that also assessed the hematology variables. RESULTS: A total of 413 ED visits were used in this analysis. The extended model showed an improvement in performance (area under the receiver operator characteristic curve) over the base model, 0.79 (95% CI 0.75-0.84), and 0.67 (95% CI 0.60-0.73), respectively. Two standard blood count variables (eosinophil granulocyte count and red blood cell count) and two advanced variables (coefficient of variance of neutrophil depolarization and red blood cell distribution width) were associated with irAE. CONCLUSION: Hematological variables are a valuable and inexpensive aid for irAE diagnosis in the ED. Further exploration of the predictive hematological variables could yield new insights into the pathophysiology underlying irAE and in distinguishing irAE from other inflammatory conditions.

Plasmon switching: observation of dynamic surface plasmon steering by selective mode excitation in a sub-wavelength slit.

We report a plasmon steering method that enables us to dynamically control the direction of surface plasmons generated by a two-mode slit in a thin metal film. By varying the phase between different coherent beams that are incident on the slit, individual waveguide modes are excited. Different linear combinations of the two modes lead to different diffracted fields at the exit of the slit. As a result, the direction in which surface plasmons are launched can be controlled. Experiments confirm that it is possible to distribute an approximately constant surface plasmon intensity in any desired proportion over the two launching directions. We also find that the anti-symmetric mode generates surface plasmons more efficiently than the fundamental symmetric mode.

Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis.

OBJECTIVE: The type 2 deiodinase (D2)-Thr92Ala polymorphism has been associated with decreased D2 activity in some in vitro experiments but not in others. So far no association between the D2-Thr92Ala polymorphism and serum thyroid hormone levels has been observed in humans, but in a recent study in athyroid patients, it was suggested that patients homozygous for the Ala(92) allele needed higher T4 doses to achieve TSH suppression. We studied the association between the D2-Thr92Ala polymorphism with thyroid hormone levels and T4 dosage, in patients treated for differentiated thyroid carcinoma (DTC) and in a group of patients treated for Hashimoto thyroiditis. DESIGN: Cross-sectional study. PATIENTS: We studied 154 patients with DTC treated with TSH suppressive thyroid hormone replacement therapy for longer than 3 years and 141 patients with Hashimoto thyroiditis treated for at least 6 months with T4. MEASUREMENTS: In all patients, serum levels of TSH, free T4, T3 and reverse T3 were measured and genotypes of the D2-Thr92Ala polymorphism were determined by Taqman assay. Univariate regression analysis was performed to determine the relation between T4 dosages and the D2-Thr92Ala polymorphism corrected for age, gender, BMI and serum TSH levels. RESULTS: Both in DTC patients and Hashimoto patients, no association was observed between serum thyroid hormone levels or T4 dosages in presence of the D2-Thr92Ala polymorphism. Categorization of DTC patients according to degree of TSH suppression did not change these results. CONCLUSION: The D2-Thr92Ala polymorphism is not associated with thyroid hormone levels or T4 dose in patients treated for DTC or Hashimoto thyroiditis.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.

BACKGROUND: Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P. OBJECTIVE: To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. DESIGN AND METHODS: We assessed mRNA expression of the GRalpha, GRbeta and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. RESULTS: GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 0.010 +/- 0.002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0.001 for all). Serum cortisol levels were negatively associated with liver GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01). CONCLUSION: We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

Sulfation preceding deiodination of iodothyronines in rat hepatocytes.

In man and animals iodothyronines are metabolized by deiodination and conjugation with glucuronic acid or sulfate. Until now these processes have been regarded as independent reactions. However, in the present study a close interaction of these pathways was observed in the hepatic metabolism of 3,3'-diiodothyronine and 3,3',5-triiodothyronine. Studies with rat hepatocytes and liver microsomes indicated that sulfation of the phenolic hydroxyl group facilitates the deiodination of these compounds.

Cerebral cortex responds rapidly to thyroid hormones.

In rats subjected to thyroidectomy there was a two- to fourfold increase in cerebral cortex iodothyronine 5'-deiodinase activity within 24 hours. This increase was prevented by thyroxine replacement. The increased cortical 5'-deiodinase in chronically hypothyroid rats was normalized within 4 hours by a single intravenous injection of triiodothyronine. These results indicate that the adult central nervous system can give a very rapid biochemical response to thyroid hormone.

Microspheres with ultrahigh holmium content for radioablation of malignancies.

PURPOSE: The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter. METHODS: Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT). RESULTS: Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT. CONCLUSIONS: HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Downstream processing of human antibodies integrating an extraction capture step and cation exchange chromatography.

In this paper we explore an alternative process for the purification of human antibodies from a Chinese hamster ovary (CHO) cell supernatant comprising a ligand-enhanced extraction capture step and cation exchange chromatography (CEX). The extraction of human antibodies was performed in an aqueous two-phase system (ATPS) composed of dextran and polyethylene glycol (PEG), in which the terminal hydroxyl groups of the PEG molecule were modified with an amino acid mimetic ligand in order to enhance the partition of the antibodies to the PEG-rich phase. This capture step was optimized using a design of experiments and a central composite design allowed the determination of the conditions that favor the partition of the antibodies to the phase containing the PEG diglutaric acid (PEG-GA) polymer, in terms of system composition. Accordingly, higher recovery yields were obtained for higher concentrations of PEG-GA and lower concentrations of dextran. The highest yield experimentally obtained was observed for an ATPS composed of 5.17% (w/w) dextran and 8% (w/w) PEG-GA. Higher purities were however predicted for higher concentrations of both polymers. A compromise between yield and purity was achieved using 5% dextran and 10% PEG-GA, which allowed the recovery of 82% of the antibodies with a protein purity of 96% and a total purity of 63%, determined by size-exclusion chromatography. ATPS top phases were further purified by cation exchange chromatography and it was observed that the most adequate cation exchange ligand was carboxymethyl, as the sulfopropyl ligand induced the formation of multi-aggregates or denatured forms. This column allowed the elution of 89% of the antibodies present in the top phase, with a protein purity of 100% and a total purity of 91%. The overall process containing a ligand-enhanced extraction step and a cation exchange chromatography step had an overall yield of 73%.

Species-specific alterations in Anopheles mosquito olfactory responses caused by Plasmodium infection.

Mosquitoes infected with malaria parasites have demonstrated altered behaviour that may increase the probability of parasite transmission. Here, we examine the responses of the olfactory system in Plasmodium falciparum infected Anopheles gambiae, Plasmodium berghei infected Anopheles stephensi, and P. berghei infected An. gambiae. Infected and uninfected mosquitoes showed differential responses to compounds in human odour using electroantennography coupled with gas chromatography (GC-EAG), with 16 peaks triggering responses only in malaria-infected mosquitoes (at oocyst, sporozoite or both stages). A selection of key compounds were examined with EAG, and responses showed differences in the detection thresholds of infected and uninfected mosquitoes to compounds including lactic acid, tetradecanoic acid and benzothiazole, suggesting that the changes in sensitivity may be the reason for differential attraction and biting at the oocyst and sporozoite stages. Importantly, the different cross-species comparisons showed varying sensitivities to compounds, with P. falciparum infected An. gambiae differing from P. berghei infected An. stephensi, and P. berghei infected An. gambiae more similar to the P. berghei infected An. stephensi. These differences in sensitivity may reflect long-standing evolutionary relationships between specific Plasmodium and Anopheles species combinations. This highlights the importance of examining different species interactions in depth to fully understand the impact of malaria infection on mosquito olfactory behaviour.

Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8.

CONTEXT: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T(3) levels. Lack of MCT8 transport of T(3) in neurons could explain the neurological phenotype. OBJECTIVE: Our objective was to determine whether the high T(3) levels could also contribute to some critical features observed in these patients. RESULTS: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T(3) (FT(3)) level (11.3 pmol/liter), without FT(4) and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT(4)) was tested. After PTU (200 mg/d), serum FT(4) was undetectable, FT(3) was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU prescription was continued, high LT(4) doses (100 microg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At that time, serum FT(4) was normal (16.4 pmol/liter), and FT(3) was slightly high (6.6 pmol/liter). Tachycardia was abated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 nmol/liter. CONCLUSIONS: 1) When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT(4) could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.