[Fatal nutrient deficiencies after gastric bypass]. / Syndrome multicarentiel catastrophique post bypass gastrique.

INTRODUCTION: Bariatric surgery is a very effective treatment for obesity. After gastric bypass, micronutrient deficiencies frequently occur which can have dramatic consequences. CASE REPORT: We report the case of a 55-year-old woman who was admitted for psychomotor retardation, bilateral leg pitting edema and psoriasis-like rash that had been ongoing for 3 months. Pancytopenia, encephalopathy and heart failure rapidly occurred leading to multiorgan dysfunction syndrome and death. We retrospectively identified severe selenium deficiency with possible secondary cardiomyopathy, niacin deficiency resulting in pellagrous encephalopathy with skin lesions and gelatinous transformation of bone marrow. CONCLUSION: Micronutrient deficiency should systematically be assessed when new symptoms occur in a patient with a history of bariatric surgery. Selenium deficiency should be considered in the presence of any heart failure in this context.

Prevalence of chronic renal failure stage 3 or more in HIV-infected patients in Antwerp: an observational study.

The introduction of Highly Active Antiretroviral Therapy has transformed HIV-infection from an inevitably lethal disease to a chronic condition with a life expectancy comparable to that of people with diabetes mellitus. In recent years it has become evident that people living with HIV/AIDS have an increased risk of developing cardiovascular disease and it is expected that the prevalence of chronic kidney disease will rise accordingly. To investigate the prevalence of chronic kidney disease in patients with HIV, we conducted a retrospective observational analysis using the clinical database of a large centre (Institute of Tropical Medicine) in the urban area of Antwerp, Belgium. The prevalence of chronic kidney disease among HIV infected subjects was found to be 3.0%. The development of chronic kidney disease was associated with age above 50 years, lower CD4 cell counts and Caucasian origin. Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS.

Role of fasting plasma glucose, glycated haemoglobin and homeostatic model assessment in the detection of glucose intolerance in adult hypopituitary patients during growth hormone replacement therapy.

AIMS: This study was designed to determine the sensitivity and specificity of conventional criteria for diagnosis of impaired glucose tolerance (IGT) in a high-risk population of GH-treated GH deficient (GHD) adults. METHODS: 33 hypopituitary GHD patients with HbA(1c) >5.1% and 13 gender- and age-matched control GHD patients were selected. Oral glucose tolerance test (OGTT), fasting plasma glucose (FPG), HbA(1c), and homeostatic model assessment (HOMA) parameters were determined in all patients. Receiver operator characteristic curves were used to determined sensitivity and specificity for the detection of glucose intolerance as defined by plasma glucose >7.8 mmol/l at 120 min during OGTT. RESULTS: Sensitivity and specificity for this purpose for HbA(1c) (>5.1%) were 89 and 17%; for FPG (>5.5 mmol/l): 78 and 67%; for FPG (>6.1 mmol/l): 56 and 89%; for HOMA-derived beta-cell function (betaCF) (<40%): 78 and 58%; for HOMA-derived insulin sensitivity (IS) (<70%): 11 and 89%, and for betaCF-IS hyperbolic product (betaCF-IS) (<54%): 89 and 75%, respectively. CONCLUSIONS: This study shows that FPG (>5.5 mmol/l) and betaCF-IS have high sensitivity and relatively high specificity for the detection of IGT and confirms that measurement of FPG or calculation of betaCF-IS provides appropriate safety surveillance in hypopituitary patients on GH replacement.

Metabolic (glycaemic, lipidic) and blood pressure control in 101 type 2 diabetic patients on first admission to diabetes centres.

The aim of our study was to analyse the quality of metabolic and blood pressure control in a cohort of 101 patients with type 2 diabetes (54 males; 47 females), previously followed in primary care settings and admitted for the first time to the diabetes centres of Saint-Luc (n=66) or Mont-Godinne (n=35) University Hospitals. Age and (known) duration of diabetes were 64 +/-12 and 6 +/- 7 years (mean +/- SD), respectively. Body mass index was 31 +/- 7 kg/m2. Systolic and diastolic blood pressures were 140 +/-12 and 81 +/-11 mmHg. Homeostasis model assessment (HOMA) showed insulin sensitivity at 63 +/-32% and P-cell function at 49 +/- 44% (n=34). Forty-seven percent of patients received either diet alone or combined with an oral antidiabetic monotherapy. Seven-teen percent of all patients were on insulin monotherapy or associated with oral drugs. HbAlc was 9.0 +/- 2.3%, with 22% of patients within HbAlc targets of < or = 7%. Only a subset of patients reached international targets of care in terms of blood pressure and lipidic profile, despite antihypertensive and lipid-lowering agents in 62% and 36% of patients, respectively. Forty-five percent of individuals had at least one diabetes-related long-term complication. In view of this unsatisfactory control, our results suggest that "anti-diabetic" treatment should be intensified earlier in primary care settings.

Growth hormone deficiency and replacement in patients with treated Cushing's Disease, prolactinomas and non-functioning pituitary adenomas: effects on body composition, glucose metabolism, lipid status and bone mineral density.

BACKGROUND/AIMS: This study was designed to determine whether previous Cushing's disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. METHODS: Fasting plasma glucose, HbA(1c), lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. RESULTS: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA(1c) increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA(1c )remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3-5 years. CONCLUSIONS: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.

Thyrotropin-releasing hormone analogs.

Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2.

Sentinel node mapping in colon carcinoma: in-vivo versus ex-vivo approach.

AIM: The aim of this study was to determine if ex-vivo and in-vivo technique of lymphatic mapping for colorectal cancer (CCR) result in similar sentinel lymph node (SLN) identification and accuracy rates. METHODS: Thirty consecutive patients with 32 CCR underwent in vivo SLN mapping. After completion of the colectomy, we remapped the SLN in the operative specimens from patients who had undergone successful in vivo lymphatic mapping. RESULTS: At least one SLN was identified by in vivo approach in 32 tumours. 1.5 SLNs (1-3) and 1.8 SLNs (1-4) (p=0.24) were identified by the in vivo and the ex vivo technique, respectively. All SLNs identified by the in vivo technique were also identified by the ex vivo technique. In six cases one and in two cases two additional SLNs were identified with the ex vivo technique. Twelve percent of tumours were upstaged. CONCLUSION: Ex vivo SLN mapping is as accurate as the in vivo technique in defining SLN and does have the ability to upstage some patients with CCR. The ex vivo technique could be used either as a primary lymphatic mapping procedure or secondarily for failed in vivo attempts at lymphatic mapping.

Sentinel lymph node mapping in colon cancer.

BACKGROUND: By systematically reviewing the literature on sentinel lymph node mapping of colon cancers, this study aimed to evaluate this technique as it applies to colon cancers. METHODS: Human studies on lymphatic mapping for colon cancers were reviewed. Multiple publications of the same studies, abstracts, and case reports were excluded. Current Contents, MEDLINE, EMBASE, and Cochrane Library databases were investigated. RESULTS: Lymphatic mapping appears to be readily applicable to colon cancers, identifying lymph nodes most likely to harbor metastases. Identification of sentinel lymph nodes varied from 58% to 100% and carried a false-negative rate of approximately 10% in larger studies, but potentially rose 4% to 25% among patients representing a range from node-negative to node-positive (micrometastases) conditions. The prognostic implication of these micrometastases requires further evaluation. Lymphatic mapping in 6% to 29% of cases identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. CONCLUSIONS: Further follow-up evaluation to assess the prognostic significance of micrometastases for colon cancers is required before the staging benefits of sentinel node mapping can have therapeutic implications. Lymphatic mapping offers the possibility of improving staging by identifying patients with early disseminated disease who should be considered for adjuvant treatment or included in trials of adjuvant treatment to speed up the breakthrough of more effective adjuvant regimens. Large studies are needed to determine whether the sentinel node concept is as valid for colon cancers as studies so far have shown it is for malignant melanoma and breast cancer.

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I.

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.

Hierarchy of simulation models in predicting molecular recognition mechanisms from the binding energy landscapes: structural analysis of the peptide complexes with SH2 domains.

Computer simulations using the simplified energy function and simulated tempering dynamics have accurately determined the native structure of the pYVPML, SVLpYTAVQPNE, and SPGEpYVNIEF peptides in the complexes with SH2 domains. Structural and equilibrium aspects of the peptide binding with SH2 domains have been studied by generating temperature-dependent binding free energy landscapes. Once some native peptide-SH2 domain contacts are constrained, the underlying binding free energy profile has the funnel-like shape that leads to a rapid and consistent acquisition of the native structure. The dominant native topology of the peptide-SH2 domain complexes represents an extended peptide conformation with strong specific interactions in the phosphotyrosine pocket and hydrophobic interactions of the peptide residues C-terminal to the pTyr group. The topological features of the peptide-protein interface are primarily determined by the thermodynamically stable phosphotyrosyl group. A diversity of structurally different binding orientations has been observed for the amino-terminal residues to the phosphotyrosine. The dominant native topology for the peptide residues carboxy-terminal to the phosphotyrosine is tolerant to flexibility in this region of the peptide-SH2 domain interface observed in equilibrium simulations. The energy landscape analysis has revealed a broad, entropically favorable topology of the native binding mode for the bound peptides, which is robust to structural perturbations. This could provide an additional positive mechanism underlying tolerance of the SH2 domains to hydrophobic conservative substitutions in the peptide specificity region.

Paronychia in association with indinavir treatment.

To assess a possible association between antiretroviral treatment and paronychia, we conducted a retrospective cohort study of 288 human immunodeficiency virus-positive protease inhibitor recipients. Indinavir treatment-adjusted for age, sex, CD4 count, diabetes status and other antiretroviral drug exposures-was significantly associated with paronychia of the great toe (hazard ratio 4.7; 95% confidence interval 1.6-13.9).

Immuno-crossreactivity of an anti-Pichia anomala killer toxin monoclonal antibody with a Williopsis saturnus var. mrakii killer toxin.

A monoclonal antibody (mAbKT4), produced against the Pichia anomala ATCC 96603 killer toxin (PaKT) was used to detect the toxin (WmKT) produced by Williopsis saturnus var. mrakii MUCL 41968 which inhibits the growth of a PaKT-sensitive P. anomala strain MUCL 41969. Immunofluorescence studies revealed that mAbKT4 specifically labels the surface of P. anomala and W. saturnus var. mrakii, suggesting that both taxa secrete a killer toxin bearing a common epitope. Immunoblot analyses of concentrated supernatants from P. anomala and W. saturnus var. mrakii cultures showed that in both taxa mAbKT4 reacts with high molecular weight secreted proteins ranging 85-200 kDa. However, immunoblot experiments showed that the molecular weights of PaKT and WmKT are quite different, indicating that the two toxins are related but not identical molecules.

Deciphering common failures in molecular docking of ligand-protein complexes.

Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as 'soft' and 'hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.

Potentiation of growth hormone-induced liver suppressors of cytokine signaling messenger ribonucleic acid by cytokines.

Endotoxin and proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) induce a state of GH resistance. A new family of suppressors of cytokine signaling (SOCS), induced by cytokines activating the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, has been recently identified as a negative feedback loop of intracellular signaling. Overexpression of some SOCS (SOCS-3, CIS, and SOCS-2) has been reported to inhibit the JAK-STAT pathway stimulated by GH. To assess the possible role of these three SOCS proteins in the GH resistance induced by endotoxin and cytokines, we investigated the regulation of their gene expression by endotoxin and GH in rat liver and by proinflammatory cytokines and GH in primary culture hepatocytes. Both GH and lipopolysaccharide induced the three SOCS messenger RNAs (mRNAs) in vivo. In vitro, GH also increased the liver mRNAs encoding SOCS-2, SOCS-3, and CIS. Although IL-1/beta and TNFalpha alone induced only weakly the expression of SOCS-3 and CIS, these cytokines strongly potentiated the induction of these two SOCS by GH. In contrast, IL-6 alone markedly induced SOCS-3 mRNA, but did not potentiate the GH action on SOCS-3 and CIS mRNAs. The GH induction of SOCS-2 was not potentiated by any of these cytokines. Considering the ability of these SOCS to inhibit the JAK-STAT pathway induced by GH, these results suggest that the overexpression of SOCS-3 and CIS mRNAs induced by IL-1beta and TNFalpha or by endotoxin in vivo may play a role in the GH resistance induced by sepsis.

Solid-supported synthesis of a peptide beta-turn mimetic.

[structure: see text]The solid-supported synthesis of a bicyclic diketopiperazine, a potential peptide beta-turn mimetic, is described. The Ugi reaction between the resin ester of alpha-N-Boc-diaminopropionic acid (an amine input), alpha-bromo acid, aldehyde, and isocyanide is the key step in the proposed protocol.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal--infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group.

OBJECTIVES: Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. METHODS: The reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. RESULTS: Twenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P= 0.0001) and higher plasma HIV-1 RNA (P=0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P=0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P= 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P=0.009] were independently associated with transmission in multivariate analysis. CONCLUSION: Maternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.

The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.