Robot-assisted TAMIS: a systematic review of feasibility and outcomes.

BACKGROUND: In the advancement of transanal local excision, robot-assisted transanal minimal invasive surgery is the newest development. In the confined area of the rectum, robot-assisted surgery should, theoretically, be superior due to articulated utensils, video enhancement, and tremor reduction, however, this has not yet been investigated. The aim of this study was to review the evidence reported to-date on experience of using robot-assisted transanal minimal invasive surgery for treatment of rectal neoplasms. METHODS: A comprehensive literature search of Embase and PubMed from May to August 2021were performed. Studies including patients diagnosed with rectal neoplasia or benign polyps who underwent robot-assisted transanal minimal invasive surgery were included. All studies were assessed for risk of bias through assessment tools. Main outcome measures were feasibility, excision quality, and complications. RESULTS: Twenty-five studies with a total of 322 local excisions were included. The studies included were all retrospective, primarily case-reports, -series, and cohort studies. The median distance from the anal verge ranged from 3.5 to 10 cm and the median size was between 2.5 and 5.3 cm. Overall, 4.6% of the resections had a positive resection margin. The overall complication rate was at 9.5% with severe complications (Clavien-Dindo score III) at 0.9%. CONCLUSION: Based on limited, retrospective data, with a high risk of bias, robot-assisted transanal minimal invasive surgery seems feasible and safe for local excisions in the rectum.

The effect of alkylation on the micro-solvation of ethers revealed by highly localized water librational motion.

The specific far-infrared spectral signatures associated with highly localized large-amplitude out-of-plane librational motion of water molecules have recently been demonstrated to provide sensitive spectroscopic probes for the micro-solvation of organic molecules [Mihrin et al., Phys. Chem. Chem. Phys. 21(4), 1717 (2019)]. The present work employs this direct far-infrared spectroscopic approach to investigate the non-covalent intermolecular forces involved in the micro-solvation of a selection of seven ether molecules with systematically varied alkyl substituents: dimethyl ether, diethyl ether, diisopropyl ether, ethyl methyl ether, t-butyl methyl ether, and t-butyl ethyl ether. The ranking of the observed out-of-plane water librational band signatures for this selected series of ether-water complexes embedded in inert neon matrices at 4 K reveals information about the interplay of directional intermolecular hydrogen bond motifs and non-directional and long-range dispersion interactions for the micro-solvated structures. These far-infrared observables differentiate minor subtle effects introduced by specific alkyl substituents and serve as rigorous experimental benchmarks for modern quantum chemical methodologies of various levels of scalability, which often fail to accurately predict the structural variations and corresponding vibrational signatures of the closely related systems. The accurate interaction energies of the series of ether-water complexes have been predicted by the domain based local pair natural orbital coupled cluster theory with single-, double-, and perturbative triple excitations, followed by a local energy decomposition analysis of the energy components. In some cases, the secondary dispersion forces are in direct competition with the primary intermolecular hydrogen bonds as witnessed by the specific out-of-plane librational signatures.

High-Resolution Infrared Synchrotron Investigation of (HCN)2 and a Semi-Experimental Determination of the Dissociation Energy D0.

The high-resolution infrared absorption spectrum of the donor bending fundamental band ν 61 of the homodimer (HCN)2 has been collected by long-path static gas-phase Fourier transform spectroscopy at 207 K employing the highly brilliant 2.75 GeV electron storage ring source at Synchrotron SOLEIL. The rovibrational structure of the ν 61 transition has the typical appearance of a perpendicular type band associated with a Σ-Π transition for a linear polyatomic molecule. The total number of 100 assigned transitions are fitted employing a standard semi-rigid linear molecule Hamiltonian, providing the band origin ν0 of 779.05182(50) cm-1 together with spectroscopic parameters for the degenerate excited state. This band origin, blue-shifted by 67.15 cm-1 relative to the HCN monomer, provides the final significant contribution to the change of intra-molecular vibrational zero-point energy upon HCN dimerization. The combination with the vibrational zero-point energy contribution determined recently for the class of large-amplitude inter-molecular fundamental transitions then enables a complete determination of the total change of vibrational zero-point energy of 3.35±0.30 kJ mol-1 . The new spectroscopic findings together with previously reported benchmark CCSDT(Q)/CBS electronic energies [Hoobler et al. ChemPhysChem. 19, 3257-3265 (2018)] provide the best semi-experimental estimate of 16.48±0.30 kJ mol-1 for the dissociation energy D0 of this prototypical homodimer.

Highly localized H2O librational motion as a far-infrared spectroscopic probe for microsolvation of organic molecules.

The most prominent spectroscopic observable for the hydrogen bonding between individual molecules in liquid water is the broad absorption band detected in the spectral region between 300 and 900 cm-1. The present work demonstrates how the associated large-amplitude out-of-plane OH librational motion of H2O molecules also directly reflects the microsolvation of organic compounds. This highly localized OH librational motion of the first solvating H2O molecule causes a significant change of dipole moment and gives rise to a strong characteristic band in the far-infrared spectral region, which is correlated quantitatively with the complexation energy. The out-of-plane OH librational band origins ranging from 324.5 to 658.9 cm-1 have been assigned experimentally for a series of four binary hydrogen-bonded H2O complexes embedded in solid neon involving S-, O- and N-containing compounds with increasing hydrogen bond acceptor capability. The hydrogen bond energies for altogether eight binary H2O complexes relative to the experimental value of 13.2 ± 0.12 kJ mol-1 for the prototypical (H2O)2 system [Rocher-Casterline et al., J. Chem. Phys., 2011, 134, 211101] are revealed directly by these far-infrared spectroscopic observables. The far-infrared spectral signatures are able to capture even minor differences in the hydrogen bond acceptor capability of O atoms with slightly different alkyl substituents in the order H-O-C(CH3)3 > CH3-O-CH3 > H-O-CH(CH3)2 > H-O-CH2CH3.

High-resolution synchrotron terahertz investigation of the large-amplitude hydrogen bond librational band of (HCN)2.

The high-resolution terahertz absorption spectrum of the large-amplitude intermolecular donor librational band ν of the homodimer (HCN)2 has been recorded by means of long-path static gas-phase Fourier transform spectroscopy at 207 K employing a highly brilliant electron storage ring source. The rovibrational structure of the ν band has the typical appearance of a perpendicular type band of a Σ-Π transition for a linear polyatomic molecule. The generated terahertz spectrum is analyzed employing a standard semi-rigid linear molecule Hamiltonian, yielding a band origin ν0 of 119.11526(60) cm-1 together with values for the excited state rotational constant B', the excited state quartic centrifugal distortion constant DJ' and the l-type doubling constant q for the degenerate state associated with the ν mode. The until now missing donor librational band origin enables the determination of an accurate experimental value for the vibrational zero-point energy of 2.50 ± 0.05 kJ mol-1 arising from the entire class of large-amplitude intermolecular modes. The spectroscopic findings are complemented by CCSD(T)-F12b/aug-cc-pV5Z (electronic energies) and CCSD(T)-F12b/aug-cc-pVQZ (force fields) electronic structure calculations, providing a (semi)-experimental value of 17.20 ± 0.20 kJ mol-1 for the dissociation energy D0 of this strictly linear weak intermolecular CHN hydrogen bond.

Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

The single-dose pharmacokinetics of alitretinoin and its metabolites are not significantly altered in patients with cirrhosis.

BACKGROUND: Alitretinoin (9-cis-retinoic acid, Toctino(®) ) has been marketed recently for oral therapy for chronic hyperkeratotic hand eczema. As alitretinoin is highly lipophilic and metabolized mainly in the liver, it is currently considered to be contraindicated in patients with liver disease. However, the pharmacokinetics and metabolism of alitretinoin have not been studied in these patients. OBJECTIVES: To study the single-dose pharmacokinetics and metabolism of alitretinoin and its metabolites in patients with cirrhosis following oral administration. METHODS: Eight patients with cirrhosis and eight matched volunteer healthy controls were given a single 30-mg oral dose of alitretinoin. Blood and urine samples were collected during the following 24-h study period. Samples were analysed for alitretinoin and for known metabolites using reverse-phase high-performance liquid chromatography. The pharmacokinetics were then evaluated using standard noncompartmental models. RESULTS: No significant differences were found between healthy controls and patients with cirrhosis when analysing the pharmacokinetic parameters of alitretinoin and its metabolites. Thus, the mean half-lives of alitretinoin were 5·3 and 5·6 h (P = 0.733) and the oral clearances were 1·92 and 1·39 L h(-1) kg(-1) (P = 0·243) in the patient group and the healthy control group, respectively. CONCLUSIONS: The metabolism and pharmacokinetics of alitretinoin following oral administration of the recommended dose of 30 mg for the treatment of severe hand eczema were similar in patients with cirrhosis and in healthy controls. If indicated, alitretinoin can be used in these patients with careful and close monitoring.

The protection afforded by the outer layer to procercoids of Schistocephalus solidus during passage through the stomach lumen of their vertebrate host (Gasterosteus aculeatus).

Intestinal cestodes with complex life cycles have to pass through the acid stomach lumen of their vertebrate host(s) in order to reach their preferred site of development. The cestode's tegument is the only organ in constant contact with this hostile environment. Procercoids of Schistocephalus solidus (order Diphyllobothriidea) lose their outer layer on passing through the acidic stomach of their second intermediate host (Gasterosteus aculeatus). We wanted to investigate if the outer layer is an adaptation that enables passage through this hostile environment. We used fish bile to force the procercoid larvae to shed their outer layer. This allowed us to compare the survival of the normal procercoids and the transformed ones when exposed to hydrochloric acid. We observed that the presence of the outer layer significantly improved the survival and active period of the procercoid larvae. Thus we conclude that in cestodes which inhabit the digestive tracts of vertebrates, the outer layer is an adaptation which enables them to pass through the acidic stomach environment of their vertebrate host(s).

In vitro transition of Schistocephalus solidus (Cestoda) from coracidium to procercoid and from procercoid to plerocercoid.

With the present study, a culture system for successive life-cycle stages of the tapeworm Schistocephalus solidus was developed and this report documents for the first time, cultivation of the procercoid stage of S. solidus from eggs. Additionally we have transformed procercoids dissected from experimentally infected copepods and cultured procercoids into the early plerocercoid stage in vitro. Observations in the culture suggest that the coracidia can interact with their external environment and need no host specific stimuli, except for the components in the culture medium, for activation and hatching from the embryophore. Increasing the culture medium pH from 7.3 to 8.0 improved escape rates and frequencies of hook contractions, suggesting that the oncosphere may recognize and respond to environmental conditions along the host intestine. Procercoids in the culture did not stop growing indicating that conditions within the copepod may be important to limit growth and to induce transformation to plerocercoids. When procercoids are dissected from copepods and transferred to the culture, the outer tegument layers and cercomer starts to loosen. Comparison of the lectin staining of the loosened outer tegument layers and cercomer in procercoids dissected from copepods confirms that transitions of both, the oncosphere to procercoid and procercoid to plerocercoids, has taken place in the in vitro cultures.

The metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea are not influenced by ethanol.

BACKGROUND: Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids also containing a carboxylic acid moiety are capable of undergoing an ethyl esterification with the metabolic formation of more lipophilic compounds with a much longer terminal half-life. OBJECTIVES: To determine if isotretinoin (13-cis-RA), its main metabolite 4-oxo-isotretinoin (4-oxo-13-cis-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined. PATIENTS/METHODS: Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple self-administered questionnaire and by measuring serum ethanol levels during treatment. The concentrations of isotretinoin, 4-oxo-isotretinoin and possible ethylated and nonethylated metabolites were measured by reverse-phase high-performance liquid chromatography. RESULTS: Although seven of 11 patients had a considerable weekly alcohol intake, no endogenous synthesis of ethyl derivatives of isotretinoin, the main 4-oxo metabolite or the all-trans compounds was chromatographically detectable in any of the patients' plasma samples during the treatment period. Multiple dose pharmacokinetic data for the parent drug and its main metabolite were comparable to previous studies. CONCLUSIONS: The metabolism and pharmacokinetics of isotretinoin and its main metabolites are not influenced by ethanol during long-term isotretinoin treatment. After ceasing long-term isotretinoin therapy the recommended period of 1 month for using anticonceptive measures in fertile women seems adequate.

Experiences of being diagnosed with osteoporosis: a meta-synthesis.

This systematic review provides synthesised knowledge and guidance to health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. Using individuals' experiences and meanings can promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory. INTRODUCTION: To be diagnosed with osteoporosis with or without fragility fractures affects individuals differently. The aim of this review was firstly to aggregate existing qualitative evidence regarding an individual's experience of being diagnosed with osteoporosis at different stages, and secondly, to use a systematic approach to develop a conceptual understanding of central issues relevant for health professionals in order to provide support and guidance to patients/individuals. METHODS: This study used a systematic review methodology and methods for qualitative synthesis as recommended by Cochrane and integrated the findings of qualitative research from eight databases (Medline, PubMed, CINAHL, Embase, SweMed+, PsycINFO, ERIC, Web of Science) to July 2016. Selection and assessment were performed by three authors while four authors were involved in the analysis. Findings were cross-checked with the original article to ensure consistency with the individual's accounts. RESULTS: Our findings have revealed that individuals diagnosed with osteoporosis do not perceive osteoporosis as a biomedical trajectory but as a self-perceived continuum of severity and health. To be diagnosed with osteoporosis affects individuals differently depending on, for example, personal experience, pre-conceived notions of or knowledge about the disease, fragility fractures or pain. Hence, individuals will create a meaning of the diagnosis based on self-perceived fracture risk, self-perceived severity of osteoporosis and at the same time, self-perceived health. CONCLUSIONS: This meta-synthesis provides knowledge for health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. The experience, meaning and significance of osteoporosis must be taken into consideration and can be used to promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory.

Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

PURPOSE: To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS: A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS: Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION: A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group.

PURPOSE: To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS: Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS: Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION: An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.

Size Dependent Male Reproductive Tactic in the Two-Spotted Goby (Gobiusculus flavescens).

Male investment in testes and sperm duct gland in the polygamous nest breeding two-spotted goby Gobiusculus flavescens (Fabricius) was investigated in relation to time in reproductive season and individual physical parameters. This small teleost fish is most likely the most abundant species found along the rocky shores of the North East Atlantic. The two-spotted goby has a single reproductive season, during which nest-caring males can raise several clutches of offspring. According to the literature the males are on average larger than the females. Here we report for the first time a population showing a reversal of this trend, with males on average being smaller than females, a difference likely caused by a large proportion of small males. Early in the breeding season these small males have typical sneaker characters, with relatively large testes and small seminal duct glands compared to the larger dominant territorial males. The presence of these two alternative male reproductive tactics is confirmed by histological studies, which shows the presence of sperm in the sperm duct glands (SDG) of smaller males, but not in the SDG of intermediate and larger males. To our knowledge, males with typical sneaker characters have not been reported in earlier studied populations of two-spotted goby. Interestingly we found that testes investment declined significantly over the course of the breeding season, and that this reduction was significantly more pronounced in small compared to the large males. Further, a significant increase in seminal duct gland (SDG) mass was observed for the smaller males over the breeding season. We propose that this indicates a possible shift in mating tactic by smaller males from a parasitic to a nest-holding tactic over the course of the breeding season. Thus, the observed size dependent plasticity in investment in SDG over time suggests that the reproductive tactic of G. flavescens is conditional, and possibly influenced by mate availability and male--male competition.

Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome.

OBJECTIVE: To investigate the longitudinal changes in serum HIV RNA, and to clarify whether the viral load early in infection has a predictive value for the clinical outcome; also, to correlate viral phenotype at seroconversion and changes in CD4 cell counts with viral burden. DESIGN: Twenty seroconverters with HIV isolates available at seroconversion had HIV RNA quantified by polymerase chain reaction (PCR) at seroconversion and thereafter every 6 months. Mean follow-up time was 65 months. Patients were classified according to viral phenotype at seroconversion, time to AIDS progression, serum viral load within the first year (less or more than 1.5 x 10(4) copies/ml). RESULTS: High viral load at seroconversion was followed by a significant decline within the first months (P < 0.0005). Decline to < 1.5 x 10(4) copies/ml was correlated with slower progression to AIDS (P < 0.05). A correlation between the rate of CD4 decline and the median viral load during the ensuing viral load plateau phase was also shown (P < 0.05). Subsequent to this phase the viral burden increased. Rapid progressors had higher viral load than slow- or non-progressors; this was particularly pronounced late in infection. Harbouring syncytium-inducing (SI) virus at seroconversion was associated with faster progression to AIDS than non-SI (NSI; P < 0.005). The increased in vitro replication rate of SI over NSI was not translated into significantly higher serum HIV RNA. CONCLUSION: Serum HIV RNA is high around the time of seroconversion. A significant decline within the first months hereafter is followed by a plateau phase, which in turn is followed by an increase in HIV RNA. HIV RNA early in infection has a predictive value for the clinical outcome. The increased virulence of SI over NSI virus did not translate into significantly higher HIV RNA values.

Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol.

Acitretin has recently been introduced to replace etretinate in the treatment of severe psoriasis due to a considerable shorter terminal half-life. The previously recommended 2-month anticonceptive period after acitretin treatment has been extended to 2 years after the detection of etretinate in certain acitretin recipients. In the present study, 10 patients with severe psoriasis were treated with 30 mg acitretin daily for 3 months. Seven patients had detectable mean steady-state plasma etretinate concentrations in the range of 2.5 to 56.7 ng/ml. Four of the patients showed teratogenic levels of plasma etretinate. Consumption of alcohol appeared to be an important contributing factor for the formation of etretinate. As judged from the dose- and body-weight-normalized AUC values (AUCcor) there was a great inter-individual variation (sixfold) in the systemic availability of acitretin. After discontinuation of therapy, the rate of elimination of both acitretin (t1/2 range 1.0 to 25.4 d) and 13-cis-acitretin (t1/2 range 1.5 to 25.7 d) was found to be related to the observed mean steady-state level of etretinate as evidenced by a longer terminal t1/2 of patients with high levels of etretinate in plasma. A mean terminal elimination half-life of etretinate was found to be 45.7 d +/- 10.6 (mean +/- SD; range 27.0 to 59.3 d). The risk of metabolic formation of etretinate in acitretin recipients makes it impossible to draw any definite conclusion with regard to recommendation of length of anticonceptive period following acitretin therapy in psoriatics. Monitoring of plasma etretinate levels in acitretin-treated fertile women is advisable.

Diagnosis of growth hormone (GH) deficiency in adults with hypothalamic-pituitary disorders: comparison of test results using pyridostigmine plus GH-releasing hormone (GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia as GH secretagogues.

The insulin tolerance test (ITT) is widely accepted as the method of choice to evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders. However, the test is not suitable in the elderly or in patients with cardiovascular disease or seizure disorders. In recent years alternatives to the ITT have been introduced. The purpose of the present study was to investigate the diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in an unselected group of patients with hypothalamic-pituitary disease. An evaluation of the reproducibility of the different stimulation tests was included in the study. Based on repeated testing with the various GH stimulation tests in healthy adult males and females, the lower limits of normality for the ITT, the PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L, respectively. A consecutive group of 26 unselected patients with hypothalamic-pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested twice with all stimulation tests, except that only 10 patients were tested once with the CLO+GHRH test due to side-effects related to clonidine. The peak GH responses between test 1 and test 2 correlated significantly in both the ITT and the PD + GHRH test (P < 0.02), and no significant difference was observed in the median peak response to repeated testing. In addition, no sex difference was observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH), but in the majority of patients low values were repeatedly low. The peak GH response was significantly higher during the PD+GHRH test than during the ITT (P = 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was no significant difference in the peak GH response (P = 0.398). When the test specific cut-off values were used, no significant difference in diagnostic outcome was observed between the various tests (P > 0.3). In contrast, the diagnosis obtained with IGF-I differed significantly from all GH stimulation tests (P < 0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients with multiple pituitary failure (>2 hormones affected), GH deficiency was present in more than 90% regardless of the type of stimulation test used. The IGF-I levels were only subnormal in 42% of the patients and did not correlate with the peak GH responses in any of the stimulation tests (P > 0.05). Except for 1 patient all patients with subnormal IGF-I were GH deficient in all stimulation tests. It is concluded that in patients with hypothalamic-pituitary disease and a normal IGF-I level 2 stimulation tests should be performed to establish a diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH stimulation test should be sufficient to confirm the presence of GH deficiency.

Urine and plasma propranolol.

Eight hypertensive patients who had been followed in an outpatient clinic during long-term therapy with propranolol (40 to 160 mg twice daily) were studied during a 24-hr stay in the ward. The usual oral dose was given and the total and free plasma concentrations were determined during the 24 hr and the urinary excretion of unchanged drug was measured. Average free plasma concentration of propranolol (y free) was calculated from: y free = Excreted propranolol (ng/24 hr)/Creatinine clearance (ml/24 hr). There was a significant relationship between log y free and average free plasma concentration (means free) determined from the directly measured plasma concentration curve: log y free = 0.0743 means free - 0.0466 (r = 0.98, P less than 0.001). In another group of propranolol-treated hypertensive patients there was a significant positive relationship between orosomucoid concentration and reciprocal of the free propranolol fraction in plasma. From this relationship the average total drug concentration (y total) was calculated from y free; there was a significant correlation with directly measured total plasma level: log y total = 0.0038 . means total + 1.0895 (r = 0.91, P less than 0.001). It is suggested that individually determined values of y free below 30 ng/ml and y total below 400 ng/ml (the concentration range studied) can be used to calculate the average mean 24-hr free and total plasma concentrations.

3,4-O-diacetylisoproterenol. Preparation, structure proof, and beta-receptor effect.

Direct acetylation of isoproterenol by selective O-acetylation using CH3COCl/CF3COOH was shown to lead to the formation of 2-(3,4-diacetoxyphenyl)-2-chloro-N-isopropyl-1-ethanamine and not to 3,4-O-diacetylisoproterenol. The latter was prepared by reduction of 3,4-diacetoxy(2-isopropylamino)acetophenone and its structure confirmed by IR, 1H, 13C NMR, mass spectral, and elemental analysis. The two compounds were tested for activity on beta-receptors. Efficacy and affinity on beta 1-receptors were found identical with the effect of isoproterenol. So was efficacy on beta2-receptors, while affinity was lower for the chloro compounds than for isoproterenol and diacetylisoproterenol which exhibited identical affinity.

Antibody reactivity to conserved linear epitopes of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1).

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family of protein antigens are involved in adhesion of P. falciparum infected erythrocytes to the capillary endothelium of the host. Antibodies to variable regions of these proteins, measured by agglutination, correlates with clinical protection against falciparum malaria. In this study we investigated the occurrence of antibodies to conserved sequences of these very variable proteins in a population living in an area endemic for falciparum malaria. Using the ELISA method, we were able to measure an antibody response to three synthetic peptides derived from conserved regions of PfEMP1. The antibody responses to these peptides increased with age and were higher in individuals with asymptomatic P. falciparum infection compared to individuals presenting with fever attributable to falciparum malaria. This indicates that antibodies recognising the conserved regions of PfEMP1 arise upon exposure to the parasite, and that these may be involved in the development of protection against malaria. Antibodies to the Pfalhesin peptide of the human aniontransporter, band3, were measured by the same method. The magnitude of this antibody response did not correlate with neither age nor clinical protection.