Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor.

Activation of the hepatoportal glucose sensors by portal glucose infusion leads to increased glucose clearance and induction of hypoglycemia. Here, we investigated whether glucagon-like peptide-1 (GLP-1) could modulate the activity of these sensors. Mice were therefore infused with saline (S-mice) or glucose (P-mice) through the portal vein at a rate of 25 mg/kg. min. In P-mice, glucose clearance increased to 67.5 +/- 3.7 mg/kg. min as compared with 24.1 +/- 1.5 mg/kg. min in S-mice, and glycemia decreased from 5.0 +/- 0.1 to 3.3 +/- 0.1 mmol/l at the end of the 3-h infusion period. Coinfusion of GLP-1 with glucose into the portal vein at a rate of 5 pmol/kg. min (P-GLP-1 mice) did not increase the glucose clearance rate (57.4 +/- 5.0 ml/kg. min) and hypoglycemia (3.8 +/- 0.1 mmol/l) observed in P-mice. In contrast, coinfusion of glucose and the GLP-1 receptor antagonist exendin-(9-39) into the portal vein at a rate of 0.5 pmol/kg. min (P-Ex mice) reduced glucose clearance to 36.1 +/- 2.6 ml/kg. min and transiently increased glycemia to 9.2 +/- 0.3 mmol/l at 60 min of infusion before it returned to the fasting level (5.6 +/- 0.3 mmol/l) at 3 h. When glucose and exendin-(9-39) were infused through the portal and femoral veins, respectively, glucose clearance increased to 70.0 +/- 4.6 ml/kg. min and glycemia decreased to 3.1 +/- 0.1 mmol/l, indicating that exendin-(9-39) has an effect only when infused into the portal vein. Finally, portal vein infusion of glucose in GLP-1 receptor(-/-) mice failed to increase the glucose clearance rate (26.7 +/- 2.9 ml/kg. min). Glycemia increased to 8.5 +/- 0.5 mmol/l at 60 min and remained elevated until the end of the glucose infusion (8.2 +/- 0.4 mmol/l). Together, our data show that the GLP-1 receptor is part of the hepatoportal glucose sensor and that basal fasting levels of GLP-1 sufficiently activate the receptor to confer maximum glucose competence to the sensor. These data demonstrate an important extrapancreatic effect of GLP-1 in the control of glucose homeostasis.

Three Generation Family With Pattern Dystrophy and a Successful Treatment of Subfoveal Cnv Related to Pattern Dystrophy With Anti-vegf Intravitreal Injections

Purpose: To phenotype a large 3 generation Swiss family with pattern dystrophy and to report a successful result of treatment with ranibizumab of a subfoveal choroidal neovascularisation (CNV) associated with pattern dystrophy in 1 patient Patients and methods: 4 affected and 3 unaffected patients (3 female 4 male, age range: 19 - 80 years) were assessed with a complete ophthalmologic examination. AF images were taken using Heidelberg Retina Angiograph and the digital color photos, fluorescein angiogragraphy (FFA) using the same TOPCON 501 camera. Electroretinogram (full-field and multifocal) was performed in 1 affected patient. One 48 years old patient developed a subfoveal CNV, which was treated with 2 injections of ranibizumab, at 3 months interval. Blood sample was taken for molecular analysis (screening of the gene RDS). Results: Two patients had a typical fundoscopic appearance of pattern dystrophy with butterfly shaped deposit at the fovea and some peripheral flecks, as shown with AF imaging.. Two others affected patients had a more unusual appearance with some macular atrophy in one or both eyes, surrounded by flecks. The visual acuity ranged from 1.0 to 0.1 according to Snellen EDTRS chart. The patient with subfoveal CNV presented a drop of vision form 1.0 to 0.6 within 10 days prior to the diagnosis and also reported some metamorphopsia. FFA and optical computerized tomography (OCT) confirmed a classic CNV. After the 1st injection her vision improved to 1.0 but persistent metamorphopsia and fluid on OCT motivated a second injection. One month after the second injection the OCT was flat and the patient had no symptoms. The results of RDS screening will be presented at the meeting. Conclusion: We present a family with pattern dystrophy, with some members having an unusual fundus appearance, which was mistaken for an early onset dry AMD. The AF imaging is a useful tool in diagnosing this condition. A CNV associated with pattern dystrophy a rare. This is the first report of a successful treatment of the CNV with anti-VEGF intravitreal injections.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

BACKGROUND/AIMS: One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient's poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. METHODS: Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. RESULTS: At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (P = 0.03). CONCLUSIONS: The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.

Cathepsin B-like and cell death in the unicellular human pathogen Leishmania.

In several studies reporting cell death (CD) in lower eukaryotes and in the human protozoan parasite Leishmania, proteolytic activity was revealed using pan-caspase substrates or inhibitors such as carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). However, most of the lower eukaryotes do not encode caspase(s) but MCA, which differs from caspase(s) in its substrate specificity and cannot be accountable for the recognition of Z-VAD-FMK. In the present study, we were interested in identifying which enzyme was capturing the Z-VAD substrate. We show that heat shock (HS) induces Leishmania CD and leads to the intracellular binding of Z-VAD-FMK. We excluded binding and inhibition of Z-VAD-FMK to Leishmania major metacaspase (LmjMCA), and identified cysteine proteinase C (LmjCPC), a cathepsin B-like (CPC) enzyme, as the Z-VAD-FMK binding enzyme. We confirmed the specific interaction of Z-VAD-FMK with CPC by showing that Z-VAD binding is absent in a Leishmania mexicana strain in which the cpc gene was deleted. We also show that parasites exposed to various stress conditions release CPC into a soluble fraction. Finally, we confirmed the role of CPC in Leishmania CD by showing that, when exposed to the oxidizing agent hydrogen peroxide (H(2)O(2)), cpc knockout parasites survived better than wild-type parasites (WT). In conclusion, this study identified CPC as the substrate of Z-VAD-FMK in Leishmania and as a potential additional executioner protease in the CD cascade of Leishmania and possibly in other lower eukaryotes.

Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.

Ambulatory Blood Pressure and Adherence Monitoring: Diagnosing Pseudoresistant Hypertension.

A small proportion of the treated hypertensive population consistently has a blood pressure greater than 140/90 mm Hg despite a triple therapy including a diuretic, a calcium channel blocker, and a blocker of the renin-angiotensin system. According to guidelines, these patients have so-called resistant hypertension. The prevalence of this clinical condition is higher in tertiary than primary care centers and often is associated with chronic kidney disease, diabetes, obesity, and sleep apnea syndrome. Exclusion of pseudoresistant hypertension using ambulatory or home blood pressure monitoring is a crucial step in the investigation of patients with resistant hypertension. Thus, among the multiple factors to consider when investigating patients with resistant hypertension, ambulatory blood pressure monitoring should be performed very early. Among other factors to consider, physicians should investigate patient adherence to therapy, assess the adequacy of treatment, exclude interfering factors, and, finally, look for secondary forms of hypertension. Poor adherence to therapy accounts for 30% to 50% of cases of resistance to therapy depending on the methodology used to diagnose adherence problems. This review discusses the clinical factors implicated in the pathogenesis of resistant hypertension with a particular emphasis on pseudoresistance, drug adherence, and the use of ambulatory blood pressure monitoring for the diagnosis and management of resistant hypertension.

Ubiquitin- and ubiquitin-like proteins-conjugating enzymes (E2s) in breast cancer.

Breast cancer is the most common malignancy in women and a significant cause of morbidity and mortality. Sub-types of breast cancer defined by the expression of steroid hormones and Her2/Neu oncogene have distinct prognosis and undergo different therapies. Besides differing in their phenotype, sub-types of breast cancer display various molecular lesions that participate in their pathogenesis. BRCA1 is one of the common hereditary cancer predisposition genes and encodes for an ubiquitin ligase. Ubiquitin ligases or E3 enzymes participate together with ubiquitin activating enzyme and ubiquitin conjugating enzymes in the attachment of ubiquitin (ubiquitination) in target proteins. Ubiquitination is a post-translational modification regulating multiple cell functions. It also plays important roles in carcinogenesis in general and in breast carcinogenesis in particular. Ubiquitin conjugating enzymes are a central component of the ubiquitination machinery and are often perturbed in breast cancer. This paper will discuss ubiquitin and ubiquitin-like proteins conjugating enzymes participating in breast cancer pathogenesis, their relationships with other proteins of the ubiquitination machinery and their role in phenotype of breast cancer sub-types.

Oncology clinicians' defenses and adherence to communication skills training with simulated patients: an exploratory study.

The aim of this exploratory study was to assess the impact of clinicians' defense mechanisms-defined as self-protective psychological mechanisms triggered by the affective load of the encounter with the patient-on adherence to a communication skills training (CST). The population consisted of oncology clinicians (N = 31) who participated in a CST. An interview with simulated cancer patients was recorded prior and 6 months after CST. Defenses were measured before and after CST and correlated with a prototype of an ideally conducted interview based on the criteria of CST-teachers. Clinicians who used more adaptive defense mechanisms showed better adherence to communication skills after CST than clinicians with less adaptive defenses (F(1, 29) = 5.26, p = 0.03, d = 0.42). Improvement in communication skills after CST seems to depend on the initial levels of defenses of the clinician prior to CST. Implications for practice and training are discussed. Communication has been recognized as a central element of cancer care [1]. Ineffective communication may contribute to patients' confusion, uncertainty, and increased difficulty in asking questions, expressing feelings, and understanding information [2, 3], and may also contribute to clinicians' lack of job satisfaction and emotional burnout [4]. Therefore, communication skills trainings (CST) for oncology clinicians have been widely developed over the last decade. These trainings should increase the skills of clinicians to respond to the patient's needs, and enhance an adequate encounter with the patient with efficient exchange of information [5]. While CSTs show a great diversity with regard to their pedagogic approaches [6, 7], the main elements of CST consist of (1) role play between participants, (2) analysis of videotaped interviews with simulated patients, and (3) interactive case discussion provided by participants. As recently stated in a consensus paper [8], CSTs need to be taught in small groups (up to 10-12 participants) and have a minimal duration of at least 3 days in order to be effective. Several systematic reviews evaluated the impact of CST on clinicians' communication skills [9-11]. Effectiveness of CST can be assessed by two main approaches: participant-based and patient-based outcomes. Measures can be self-reported, but, according to Gysels et al. [10], behavioral assessment of patient-physician interviews [12] is the most objective and reliable method for measuring change after training. Based on 22 studies on participants' outcomes, Merckaert et al. [9] reported an increase of communication skills and participants' satisfaction with training and changes in attitudes and beliefs. The evaluation of CST remains a challenging task and variables mediating skills improvement remain unidentified. We recently thus conducted a study evaluating the impact of CST on clinicians' defenses by comparing the evolution of defenses of clinicians participating in CST with defenses of a control group without training [13]. Defenses are unconscious psychological processes which protect from anxiety or distress. Therefore, they contribute to the individual's adaptation to stress [14]. Perry refers to the term "defensive functioning" to indicate the degree of adaptation linked to the use of a range of specific defenses by an individual, ranging from low defensive functioning when he or she tends to use generally less adaptive defenses (such as projection, denial, or acting out) to high defensive functioning when he or she tends to use generally more adaptive defenses (such as altruism, intellectualization, or introspection) [15, 16]. Although several authors have addressed the emotional difficulties of oncology clinicians when facing patients and their need to preserve themselves [7, 17, 18], no research has yet been conducted on the defenses of clinicians. For example, repeated use of less adaptive defenses, such as denial, may allow the clinician to avoid or reduce distress, but it also diminishes his ability to respond to the patient's emotions, to identify and to respond adequately to his needs, and to foster the therapeutic alliance. Results of the above-mentioned study [13] showed two groups of clinicians: one with a higher defensive functioning and one with a lower defensive functioning prior to CST. After the training, a difference in defensive functioning between clinicians who participated in CST and clinicians of the control group was only showed for clinicians with a higher defensive functioning. Some clinicians may therefore be more responsive to CST than others. To further address this issue, the present study aimed to evaluate the relationship between the level of adherence to an "ideally conducted interview", as defined by the teachers of the CST, and the level of the clinician' defensive functioning. We hypothesized that, after CST, clinicians with a higher defensive functioning show a greater adherence to the "ideally conducted interview" than clinicians with a lower defensive functioning.

A dynamic assessment of medication-taking behavior during pregnancy and postpartum: should cART adherence be reinforced during postpartum?

This study compared adherence (persistence and execution) during pregnancy and postpartum in HIV-positive women having taken part in the adherence-enhancing program of the Community Pharmacy of the Department of Ambulatory Care and Community Medicine in Lausanne between 2004 and 2012. This interdisciplinary program combined electronic drug monitoring and semi-structured, repeated motivational interviews. This was a retrospective, observational study. Observation period spread over from first adherence visit after last menstruation until 6 months after childbirth. Medication-taking was recorded by electronic drug monitoring. Socio-demographic and delivery data were collected from Swiss HIV Cohort database. Adherence data, barriers and facilitators were collected from pharmacy database. Electronic data were reconciled with pill-count and interview notes in order to include reported pocket-doses. Execution was analyzed over 3-day periods by a mixed effect logistic model, separating time before and after childbirth. This model allowed us to estimate different time slopes for both periods and to show a sudden fall associated with childbirth. Twenty-five pregnant women were included. Median age was 29 (IQR: 26.5, 32.0), women were in majority black (n_17,68%) and took a cART combining protease and nucleoside reverse transcriptase inhibitors (n_24,96%). Eleven women (44%) were ART-naı¨ve at the beginning of pregnancy. Twenty women (80%) were included in the program because of pregnancy. Women were included at all stages of pregnancy. Six women (24%) stopped the program during pregnancy, 3 (12%) at delivery, 4 (16%) during postpartum and 12 (48%) stayed in program at the end of observation time. Median number of visits was 4 (3.0, 6.3) during pregnancy and 3 (0.8, 6.0) during postpartum. Execution was continuously high during pregnancy, low at beginning of postpartum and increased gradually during the 6 months of postpartum. Major barriers to adherence were medication adverse events and difficulties in daily routine. Facilitators were motivation for promoting child-health and social support. The dramatic drop and very slow increase in cART adherence during postpartum might result in viral rebound and drug resistance. Although much attention is devoted to pregnant women, interdisciplinary care should also be provided to women in the community during first trimester of postpartum to support them in sustaining cART adherence.

Human Plasma-derived Polymeric IgA and IgM Antibodies Associate with Secretory Component to Yield Biologically Active Secretory-like Antibodies.

Immunotherapy with monoclonal and polyclonal immunoglobulin is successfully applied to improve many clinical conditions, including infection, autoimmune diseases, or immunodeficiency. Most immunoglobulin products, recombinant or plasma-derived, are based on IgG antibodies, whereas to date, the use of IgA for therapeutic application has remained anecdotal. In particular, purification or production of large quantities of secretory IgA (SIgA) for potential mucosal application has not been achieved. In this work, we sought to investigate whether polymeric IgA (pIgA) recovered from human plasma is able to associate with secretory component (SC) to generate SIgA-like molecules. We found that ∼15% of plasma pIgA carried J chain and displayed selective SC binding capacity either in a mixture with monomeric IgA (mIgA) or after purification. The recombinant SC associated covalently in a 1:1 stoichiometry with pIgA and with similar efficacy as colostrum-derived SC. In comparison with pIgA, the association with SC delayed degradation of SIgA by intestinal proteases. Similar results were obtained with plasma-derived IgM. In vitro, plasma-derived IgA and SIgA neutralized Shigella flexneri used as a model pathogen, resulting in a delay of bacteria-induced damage targeted to polarized Caco-2 cell monolayers. The sum of these novel data demonstrates that association of plasma-derived IgA or IgM with recombinant/colostrum-derived SC is feasible and yields SIgA- and SIgM-like molecules with similar biochemical and functional characteristics as mucosa-derived immunoglobulins.

Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes.

We have recently cloned the human homologue of the murine pT49 cDNA (hpT49h), a transcript encoding a protein homologous to the beta- and gamma-chains of fibrinogen. Here, we report the identification of the hpT49h gene product using mAbs generated against a peptide corresponding to the carboxyl-terminal end of the deduced protein and a recombinant protein fragment expressed in Escherichia coli. mAbs 23A6, 7B12, and 3F4 specifically recognized a protein of 70 kDa in reducing SDS-PAGE in the culture supernatant of 293T cells transiently transfected with the full length hpT49h cDNA and freshly isolated PBMC. Under nonreducing conditions, the material migrated with a molecular mass of 250 to 300 kDa, indicating that the 70-kDa protein forms a disulfide bonded complex. Because of its homology with fibrinogen, we have termed this protein fibroleukin. Fibroleukin is spontaneously secreted in vitro by freshly isolated CD4+ and CD8+ T lymphocytes. RT-PCR analysis revealed preferential expression of fibroleukin mRNA in memory T lymphocytes (CD3+/CD45R0+) compared with naive T lymphocytes (CD3+/CD45RA+). Fibroleukin production by PBMC was rapidly lost in culture. Production could be partially maintained in the presence of IFN-gamma, while T lymphocyte activation had no effect. To demonstrate fibroleukin production in vivo, we analyzed colon mucosa by immunohistology. Fibroleukin staining was detected in the extracellular matrix of the T lymphocyte-rich upper portion of the lamina propria mucosa. While the exact function of fibroleukin remains to be defined, these data suggest that fibroleukin may play a role in physiologic lymphocyte functions at mucosal sites.

Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse

Rrésumé: La première description dans une publication médicale des douleurs neuropathiques remonte à 1872, le Dr S.W. Mitchell les résumant ainsi [...]" la causalgie est la plus terrible des tortures qu'une lésion nerveuse puisse entraîner "[...]. Par définition, la douleur neuropathique est une douleur chronique faisant suite à une lésion ou dysfonction du système nerveux. Malgré les progrès faits dans la compréhension de ce syndrome, le détail des mécanismes impliqués nous échappe encore et son traitement reste insuffisant car moins de 50% des patients sont soulagés par les thérapies actuelles. Différents modèles expérimentaux ont été élaborés chez l'animal de laboratoire, en particulier des modèles de lésion de nerfs périphériques chez le rat, permettant des investigations tant moléculaires que fonctionnelles des mécanismes impliqués dans le développement de ces douleurs. En revanche, peu de modèles existent chez la souris, alors que cet animal, grâce à la transgénèse, est très fréquemment utilisé pour l'approche fonctionnelle ciblée sur un gène. Dans l'étude présentée ici, nous avons évalué chez la souris C57BL/6 l'adaptation d'un modèle neuropathique, proposé une nouvelle modalité de mesure de la sensibilité douloureuse adaptée à la souris et défini une méthode d'analyse performante des résultats. Ce modèle, dit de lésion avec épargne nerveuse (spared Werve injury, SNI), consiste en la lésion de deux des trois branches du nerf sciatique, soit les nerfs peronier commun et tibial. La troisième branche, le nerf sural est laissé intact et c'est dans le territoire cutané de ce dernier que la sensibilité douloureuse à des stimulations mécaniques est enregistrée. Des filaments calibrés de force croissante sont appliqués sur la surface de la patte impliquée et la fréquence relative de retrait de la patte a été modélisée mathématiquement et analysée par un modèle statistique intégrant tous les paramètres de l'expérience (mixed-effects model). Des variantes chirurgicales lésant séquentiellement les trois branches du nerf sciatique ainsi que la réponse en fonction du sexe de l'animal ont également été évaluées. La lésion SNI entraîne une hypersensibilité mécanique marquée comparativement aux souris avec chirurgie contrôle; cet effet est constant entre les animaux et persiste durant les quatre semaines de l'étude. De subtiles différences entre les variables, y compris une divergence de sensibilité mécanique entre les sexes, ont été démontrées. La nécessité de léser le nerf tibial pour le développement des symptômes a également été documentée par notre méthode d'évaluation et d'analyse. En conclusion, nous avons validé le modèle SNI chez la souris par l'apparition d'un symptôme reproductible et apparenté à l'allodynie mécanique décrite par les patients souffrant de douleurs neuropathiques. Nous avons développé des méthodes d'enregistrement et d'analyse de la sensibilité douloureuse sensibles qui permettent la mise en évidence de facteurs intrinsèques et extrinsèques de variation de la réponse. Le modèle SNI utilisé chez des souris génétiquement modifiées, de par sa précision et reproductibilité, pourra permettre la discrimination de facteurs génétiques et épigénétiques contribuant au développement et à la persistance de douleurs neuropathiques.

TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings.

BACKGROUND: To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. METHODS: The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. RESULTS: A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel-Behnke corneal dystrophy. CONCLUSIONS: The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.

HIV-associated neurocognitive disorders (HAND): a changing pattern

Combination antiretroviral therapy has dramatically decreased the incidence of HIV-related mortality and serious opportunistic diseases, among which is HIV- associated dementia. However, minor forms of cognitive dysfunction have not disappeared and may even have increased in frequency. Aging of HIV+ patients, insufficient penetration of antiretroviral drugs into the brain with continuous low- grade viral production and inflammation may play a role. A putative neurotoxicity of combination antiretroviral therapy is controversial. In this article, we will discuss these aspects, as well as clinical and pathophysiological features shared by HIV-associated neurocognitive disorders and other neurodegenerative diseases, especially Alzheimer's disease. This article will briefly summarize the current clinical trials on neuroprotective agents, and the management of patients with neurocognitive disorders will be discussed