Hospitalization of HIV positive patients: Significant demand affecting all hospital sectors.

BACKGROUND: In a context of the evolution of severe morbidities in patients living with HIV (PLWH), the aim of this study was to describe reasons for hospitalization and the mode of care for the patients requiring hospitalization. METHODS: All admissions (≥24h) of PLWH to 10 hospitals in the south of Paris (COREVIH Ile-de-France Sud) between 1/1/2011 and 12/31/2011 were identified. The hospital database and the file of patients followed in the HIV referral department of each hospital were matched. Detailed clinical and biological data were collected, by returning to the individual medical records, for a random sample (65% of hospitalized patients). RESULTS: A total of 3013 hospitalizations (1489 patients) were recorded in 2011. The estimated rate of hospitalized patients was about 8% among the 10105 PLWH routinely managed in COREVIH Ile-de-France Sud in 2011. The majority (58.5%) of these hospitalizations occurred in a unit other than the HIV referral unit. Non-AIDS-defining infections were the main reason for admission (16.4%), followed by HIV-related diseases (15.6%), hepatic/gastrointestinal diseases (12.0%), and cardiovascular diseases (10.3%). The median length of stay was 5 days overall (IQR: 2-11), it was longer among patients admitted to a referral HIV care unit than to another ward. HIV infection had been diagnosed >10 years previously in 61.4% of these hospitalized patients. They often had associated comorbidities (coinfection HCV/HVB 40.5%, smoking 45.8%; hypertension 33.4%, dyslipidemia 28.8%, diabetes 14.8%). Subjects over 60 years old accounted for 15% of hospitalized patients, most of them were virologically controlled under HIV treatment, and cardiovascular diseases were their leading reason for admission. CONCLUSION: Needs for hospitalization among PLWH remain important, with a wide variety in causes of admission, involving all hospital departments. It is essential to prevent comorbidities to reduce these hospitalizations, and to maintain a link between the management of PLWH, that becomes rightly, increasing ambulatory, and recourse to specialized inpatient services.

Receptor for the fourth component of complement on human B lymphocytes and cultured human lymphoblastoid cells.

This report describes receptors for C4b on human peripheral B lymphocytes. The simultaneous presence of C3b and C4b receptors on the same lymphocytes was demonstrated by the formation of mixed rosettes consisting of the lymphocytes, EAC14 and EAC1423. Furthermore, reduction of the number of EAC1423 rosette-forming lymphocytes in a lymphocyte population by albumin gradient centrifugation concomitantly reduced EAC14 rosette-forming lymphocytes. Binding of EAC14 intermediates to receptors on human lymphocytes and erythrocytes could be inhibited by equal amounts of soluble C3b or C4b, suggesting the presence of a single receptor for both ligands on those cells. In contrast, the results of the rosette assay with Raji cells, cultured human lymphoblastoid cells, EAC14 and EAC1423 suggested that the receptors for C4b and C3b are distinct entities, since Raji cells formed rosettes with EAC1423, but not with EAC14. Moreover, this report demonstrates a cooperation of erythrocyte-bound C4b and C3b in the binding of EAC1423 to B lymphocytes. In contrast to KAF-treated C3b, KAF-treated C4b did not bind to B lymphocytes, indicating that these cells lack a receptor for C4d.

C1q deviation test for the detection of immune complexes, aggregates of IgG, and bacterial products in human serum.

This report describes a new, rapid, sensitive, and quantitative method for the detection of immune complexes, endotoxins, and other complement activating materials in patients sera utilizing the ability of these substances to react with isolated C1q. The procedure is based on the inhibition of radiolabeled C1q binding to sensitized sheep erythrocytes by C1q-reactive substances in pathological sera. The C1q deviation test may be performed on 50 mu1 of serum, using 1 mug of radiolabeled C1q per sample. The procedure may be completed in 1.5-2 h, it is capable of detecting 5 mug of aggregated human IgG per ml of serum, and its coefficient of variation is 4.2%. Application of the test to the study of 193 sera from 43 patients with Dengue hemorrhagic fever showed a positive correlation between degree of C1q deviation and severity of disease.

Consequences of alkaline treatment for the ultrastructure of the acetylcholine-receptor-rich membranes from Torpedo marmorata electric organ.

After fixation with glutaraldehyde and impregnation with tannic acid, the membrane that underlies the nerve terminals in Torpedo marmorata electroplaque presents a typical asymmetric triple-layered structure with an unusual thickness; in addition, it is coated with electron-dense material on its inner, cytoplasmic face. Filamentous structures are frequently found attached to these "subsynaptic densities." The organization of the subsynaptic membrane is partly preserved after homogenization of the electric organ and purification of acetylcholine-receptor (AchR)-rich membrane fragments. In vitro treatment at pH 11 and 4 degrees C of these AchR-rich membranes releases an extrinsic protein of 43,000 mol wt and at the same time causes the complete disappearance of the cytoplasmic condensations. Freeze-etching of native membrane fragments discloses remnants of the ribbonlike organization of the AchR rosettes. This organization disappears ater alkaline treatment and is replaced by a network which is not observed after rapid freezing and, therefore, most likely results from the lateral redistribution of the AchR rosettes during condition of slow freezing. A dispersion of the AchR rosettes in the plane of the membrane also occurs after fusion of the pH 11-treated fragments with phospholipid vesicles. These results are interpreted in terms of a structural stabilization and immobilization of the AchR by the 43,000-Mr protein binding to the inner face of the subsynaptic membrane.

Dopaminergic terminals in the rat cortex.

The destruction of ascending noradreniergic pathways by bilateral microinjections of 6-hydroxydopamnine made laterally to the pedunculus cerebellaris superior completely abolished the in vitro synthesis of [(3)H]norepinephrine from L-[(3)H]tyrosine in slices and in synaptosomes of the rat cortex. However, normal [(3)H]dopamine synthesis could still be observed in both cortical preparations from animals with lesions. These results provide the first biochemical support for the existence of dopaminergic terminals independent of noradrenergic terminals in the rat cortex.

Stathmin: a relay phosphoprotein for multiple signal transduction?

Stathmin is a ubiquitous, phylogenetically conserved protein present in the cytoplasm of cells in a variety of unphosphorylated and phosphorylated forms. Its expression and phosphorylation are regulated throughout development and in response to extracellular signals regulating cell proliferation, differentiation and functions. The overall pattern of its molecular forms reflects the activation of corresponding second messenger pathways. This phosphoprotein is therefore a good candidate as a general relay in signal transduction, possibly integrating diverse signals of the cell's environment.

Stathmin/Op18 phosphorylation is regulated by microtubule assembly.

Stathmin/Op 18 is a microtubule (MT) dynamics-regulating protein that has been shown to have both catastrophe-promoting and tubulin-sequestering activities. The level of stathmin/Op18 phosphorylation was proved both in vitro and in vivo to be important in modulating its MT-destabilizing activity. To understand the in vivo regulation of stathmin/Op18 activity, we investigated whether MT assembly itself could control phosphorylation of stathmin/Op18 and thus its MT-destabilizing activity. We found that MT nucleation by centrosomes from Xenopus sperm or somatic cells and MT assembly promoted by dimethyl sulfoxide or paclitaxel induced stathmin/Op18 hyperphosphorylation in Xenopus egg extracts, leading to new stathmin/Op18 isoforms phosphorylated on Ser 16. The MT-dependent phosphorylation of stathmin/Op18 took place in interphase extracts as well, and was also observed in somatic cells. We show that the MT-dependent phosphorylation of stathmin/Op18 on Ser 16 is mediated by an activity associated to the MTs, and that it is responsible for the stathmin/Op18 hyperphosphorylation reported to be induced by the addition of "mitotic chromatin." Our results suggest the existence of a positive feedback loop, which could represent a novel mechanism contributing to MT network control.

Intercomparison of methods of coupling between convection and large-scale circulation: 2. Comparison over nonuniform surface conditions.

As part of an international intercomparison project, the weak temperature gradient (WTG) and damped gravity wave (DGW) methods are used to parameterize large-scale dynamics in a set of cloud-resolving models (CRMs) and single column models (SCMs). The WTG or DGW method is implemented using a configuration that couples a model to a reference state defined with profiles obtained from the same model in radiative-convective equilibrium. We investigated the sensitivity of each model to changes in SST, given a fixed reference state. We performed a systematic comparison of the WTG and DGW methods in different models, and a systematic comparison of the behavior of those models using the WTG method and the DGW method. The sensitivity to the SST depends on both the large-scale parameterization method and the choice of the cloud model. In general, SCMs display a wider range of behaviors than CRMs. All CRMs using either the WTG or DGW method show an increase of precipitation with SST, while SCMs show sensitivities which are not always monotonic. CRMs using either the WTG or DGW method show a similar relationship between mean precipitation rate and column-relative humidity, while SCMs exhibit a much wider range of behaviors. DGW simulations produce large-scale velocity profiles which are smoother and less top-heavy compared to those produced by the WTG simulations. These large-scale parameterization methods provide a useful tool to identify the impact of parameterization differences on model behavior in the presence of two-way feedback between convection and the large-scale circulation.

Beneficial effect of highly active antiretroviral therapy on the prognosis of AIDS-related systemic non-Hodgkin lymphomas.

The influence of HAART on the survival of patients with AIDS-related lymphoma (ARL) was evaluated. A retrospective analysis of 73 HIV-1-infected patients with proven ARL diagnosed between 1992 and 2000 was conducted. Patients received uniformly the same chemotherapy regimen according to CD4 cell counts at NHL diagnosis:, patients with CD4 cells below or above 100 cells x 10(6)/liter received CHOP or ACVBP regimens, respectively. Event-free survival (EFS) and survival were estimated by the Kaplan-Meir method and a Cox model was used to evaluate the effect of different variables on survival. At diagnosis of ARL, the median age was 37 years and 22 patients (30%) had prior AIDS-defining events. Median CD4 cell count was 99 x 10(6)/liter. The median follow-up was 60 months. Ann Arbor stage 3-4 was noted in 60 patients (82%) and bone marrow or meningeal involvement was present in 13 (17%) and 12 (16%) patients, respectively. Two groups were identified: group 1 (n = 38) included patients who had never received HAART and group 2 (n = 35) included those who received HAART either before the diagnosis or following ARL. There was no statistical significant differences in lymphoma extensive stage, presence of B symptoms, meningeal involvement, CD4 cell count at diagnosis, prior AIDS events, or chemotherapy regimens between the two groups. Median survival (MS) of the whole cohort of patients was 8 months. Estimated EFS was significantly higher (30 months) in group 2 compared to group 1 (6.1 months) (p = 0.03). In the multivariate Cox model HAART has an independent significant effect on EFS (p = 0.0085). No influence on outcome was found for other variables except for prior AIDS and bone marrow involvement. HAART has significantly improved the survival and EFS in patients with ARL, independently of chemotherapy regimen.

Incidence of IDDM in the province of Rzeszów, Poland, 0- to 29-year-old age-group, 1980-1992.

OBJECTIVE: To study the incidence of insulin-dependent diabetes mellitus (IDDM) in the province of Rzeszów, Poland, and to test for differences in incidence by age at diagnosis, time cluster, sex, urban-rural population, and season. RESEARCH DESIGN AND METHODS: A registry was established in 1990 to collect new IDDM cases among people 0-29 years of age, from 1980 to 1992. Data were collected according to the Diabetes Epidemiology Research International Group recommendations. RESULTS: The average age-standardized incidence of IDDM was 5.31/100,000 population (95% confidence interval [CI] 4.67-6.04) for those 0-29 years of age. Among males, it was 5.68/100,000 (CI 4.77-6.77), and among females it was 4.93/100,000 (CI 4.07-5.97). The incidence for children 0-14 years old was 5.11/100,000 (CI 4.27-6.11) and for those 15-29 years old, 5.55/100,000 (CI 4.60-6.68). The incidence of IDDM in autumn (September through November) was the highest (87 of 243 cases) and differed statistically from each of the other seasons. The incidence of IDDM among the urban and rural populations did not differ. There were also no differences between the sexes and the groups divided by 5-year age intervals. CONCLUSIONS: This study documents the low incidence rate and seasonal dependence of IDDM among people 0-29 years of age in the province of Rzeszów, Poland.

Intercomparison of methods of coupling between convection and large-scale circulation: 1. Comparison over uniform surface conditions.

As part of an international intercomparison project, a set of single-column models (SCMs) and cloud-resolving models (CRMs) are run under the weak-temperature gradient (WTG) method and the damped gravity wave (DGW) method. For each model, the implementation of the WTG or DGW method involves a simulated column which is coupled to a reference state defined with profiles obtained from the same model in radiative-convective equilibrium. The simulated column has the same surface conditions as the reference state and is initialized with profiles from the reference state. We performed systematic comparison of the behavior of different models under a consistent implementation of the WTG method and the DGW method and systematic comparison of the WTG and DGW methods in models with different physics and numerics. CRMs and SCMs produce a variety of behaviors under both WTG and DGW methods. Some of the models reproduce the reference state while others sustain a large-scale circulation which results in either substantially lower or higher precipitation compared to the value of the reference state. CRMs show a fairly linear relationship between precipitation and circulation strength. SCMs display a wider range of behaviors than CRMs. Some SCMs under the WTG method produce zero precipitation. Within an individual SCM, a DGW simulation and a corresponding WTG simulation can produce different signed circulation. When initialized with a dry troposphere, DGW simulations always result in a precipitating equilibrium state. The greatest sensitivities to the initial moisture conditions occur for multiple stable equilibria in some WTG simulations, corresponding to either a dry equilibrium state when initialized as dry or a precipitating equilibrium state when initialized as moist. Multiple equilibria are seen in more WTG simulations for higher SST. In some models, the existence of multiple equilibria is sensitive to some parameters in the WTG calculations.

Zidovudine therapy and HIV encephalitis: a 10-year neuropathological survey.

OBJECTIVE: To assess the effect of zidovudine on productive HIV infection of the brain. DESIGN: To correlate the incidence of HIV-specific neuropathology with zidovudine therapy. PATIENTS: We examined 192 AIDS cases neuropathologically; 97 had never been treated with zidovudine, 72 had received zidovudine for over 3 months and until death, 23 had their treatment terminated more than 1 month before death. RESULTS: The incidence of HIV encephalitis/HIV leukoencephalopathy (HIVE/HIVL) and of multinucleated giant cells (MGC) was significantly lower in patients who had received zidovudine than in those who had never received zidovudine. The yearly incidence of HIVE/HIVL increased between 1982 and 1987 probably because of improved survival, and decreased between 1987 and 1990 although the percentage of patients treated with zidovudine increased. Since 1991 the incidence of HIVE/HIVL and of MGC increased slightly. The percentage of patients treated with zidovudine until death decreased and that of patients whose treatment was terminated increased concomitantly. In 1989 and 1990, most patients whose treatment was terminated had MGC and HIVE/HIVL. In 1991 and 1992 this incidence decreased markedly, coinciding with the introduction of dideoxyinosine therapy. CONCLUSION: Zidovudine treatment significantly reduces the occurrence of productive HIV infection of the brain in AIDS. Discontinuing zidovudine therapy may favour the occurrence of HIV encephalitis. Substitution therapy with dideoxyinosine also appears to protect against HIV-specific brain pathology.

Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy.

In a sample of 277 patients included in the French APROCO cohort study who were initially adherent at follow-up visit 4 months after initiation of a protease inhibitor-containing regimen, 76.4% self-reported at least one lipodystrophy-related symptom and 30.0% failed to maintain adherence behaviour 20 months after enrolment. After multiple adjustment for other related factors, such as younger age, alcohol consumption and poor housing conditions, the number of self-reported lipodystrophy symptoms was independently associated with adherence failure.

Phosphorylation of intracellular proteins related to the multihormonal regulation of prolactin: comparison of normal anterior pituitary cells in culture with the tumor-derived GH cell lines.

We have previously identified a group of cytoplasmic phosphoproteins (proteins 1-11) whose phosphorylation could be related, on a pharmacological basis, to the multihormonal regulation of PRL synthesis and release in the anterior pituitary tumor-derived GH cell lines. Phosphoproteins with identical migration properties on two-dimensional electrophoresis gels were also detectable in normal rat anterior pituitary cells in culture. We designed appropriate culture and [32P] phosphate-labeling conditions allowing to analyze the regulation of the phosphorylation of these proteins in normal pituitary cells. TRH, 12-O-tetradecanoylphorbol-13-acetate, and vasoactive intestinal peptide induced the same qualitative changes in phosphorylation of proteins 1-11 in normal as in GH cells. Quantitative differences observed are most likely due to the heterogeneity of primary pituitary cultures. Phosphorylation changes affecting proteins 14-16, not previously detected in GH cells, were also observed with normal anterior pituitary cells. GH cell lines have lost the sensitivity of pituitary lactotrophs for dopamine, an important physiological inhibitor of PRL synthesis and release. In normal anterior pituitary cells in culture, dopamine inhibited also the TRH-stimulated phosphorylation of proteins 1-10, thus strengthening the correlation between phosphorylation of these proteins and multihormonal regulation of pituitary cell functions. Our results indicate: 1) that the same phosphoproteins as in GH cells are related to the multihormonal regulation of nontumoral, normal anterior pituitary cells in culture; 2) that dopamine acts by interfering with the phosphorylation of these proteins. The phosphoproteins described here are therefore likely to be part, in normal anterior pituitary cells and possibly in other cell types, of the intracellular machinery involved in the cascade of transducing events leading from the binding of extracellular signals to the regulation of their target biological functions.

Luteinizing hormone-releasing hormone-signal transduction and stathmin phosphorylation in the gonadotrope alphaT3-1 cell line.

We have investigated the effects of GnRH (LHRH) and of the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate on stathmin phosphorylation in the gonadotrope alphaT3-1 cell line. Stathmin expression and its phosphorylation were maximal during the exponential phase of cell growth. LHRH stimulated stathmin phosphorylation through a specific receptor in a dose- and time-dependent manner, and TPA induced a similar extensive stathmin phosphorylation. Their effects were inhibited either in PKC-depleted alphaT3-1 cells, or by the PKC inhibitor staurosporine. In the context of the known implication of PKC in LHRH-induced signal transduction, our results show that stathmin phosphorylation is involved in LHRH transduction, either as a result of direct activation of specific PKC isoforms or through a pathway involving kinases downstream to PKC activation.

Phosphorylation of a group of proteins related to the physiological, multihormonal regulations of the various cell types in the anterior pituitary gland.

We previously identified a group of cytoplasmic phosphoproteins whose phosphorylation could be related to the multihormonal regulation of PRL in the homogeneous tumor-derived GH cell lines (set of proteins 1-11) and in heterogeneous normal anterior pituitary cells in culture (set of proteins 1-15). In normal cells, a mixture of hypothalamic hormones induced, like the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, stronger phosphorylation changes than TRH alone. Proteins of the set 1-15 are therefore likely to be present also in the nonmammotrophic anterior pituitary cell types, where their phosphorylation can be regulated by the hormones specific of the cell type considered. This interpretation is confirmed by the presence of the same proteins in cells of the corticotroph-like AtT-20/D16 cell line and the regulation of their phosphorylation by CRF. The same phosphoproteins were also detected in non dissociated anterior pituitary tissue from ovariectomized rats. Their phosphorylation was regulated by various hormones and other extracellular agents in a way similar to their regulation in anterior pituitary cells in culture. A 5-day estradiol implant pretreatment of the ovariectomized rats, which stimulates the anterior pituitary gland both directly and indirectly, resulted in a very high level of basal phosphorylation of proteins 1-15. Only very little further stimulation was achieved by the addition of exogenous hypothalamic hormones, indicating that the actual physiological regulatory pathways are the same as those unraveled in the various cell culture model systems. In conclusion, phosphorylation of proteins 1-15 1) can be related to the multihormonal regulation of the various anterior pituitary cell types in culture and 2) corresponds to intracellular molecular mechanisms actually involved in the physiological regulations of pituitary functions in the intact anterior pituitary gland.

Combining insulin-like growth factor-I and mean spontaneous nighttime growth hormone levels for the diagnosis of growth hormone deficiency.

There is no gold standard for the diagnosis of GH deficiency. Recent data show that spontaneous GH levels may lack sensitivity, and that GH stimulation tests lack specificity as currently performed. Serum insulin-like growth factor-I (IGF-I) measurements lack both sensitivity and specificity. Some of these problems may be explained by nutritional effects. In children, overnutrition decreases GH and increases IGF-I, while undernutrition decreases IGF-I and increases GH. To overcome these difficulties and improve diagnostic accuracy, we combined mean spontaneous nighttime GH levels with IGF-I levels in a statistically based bivariate model. On a two-dimensional plot of mean spontaneous nighttime GH level (in SD units) vs. IGF-I level (in SD units), we defined a new variable, S (sum) score, where S = (1/square root of 2) x (nighttime mean GH SD+IGF-I SD). While IGF-I (SD) and the mean spontaneous nighttime GH (SD) showed a significant correlation with body mass index, the S score was independent of body mass. We, therefore, used the S score to define a new test for GH deficiency. A child failed this bivariate test if his S score was less than -2 SD. We applied this model to 47 normal children and 48 short or slowly growing children (all prepubertal). We measured spontaneous nighttime GH levels and IGF-I levels in all children. In addition, the short children underwent 3 GH stimulation tests. Forty-six of the 47 normal children passed the bivariate test for GH sufficiency. Twenty-three of the 48 short or slowly growing children failed the bivariate test, whereas only 11 children had an abnormally low mean spontaneous nighttime GH measurement alone. Sixteen of 23 children who were GH deficient by the bivariate test were also GH deficient by the stimulation tests. In summary, the bivariate test for GH deficiency appears 1) to be independent of body mass, unlike either IGF-I or GH individually; 2) to identify more children than the mean spontaneous nighttime GH level alone; and 3) to be highly specific in the normal population, unlike stimulation tests.

Neurofibrillary tangle-associated alteration of stathmin in Alzheimer's disease.

Stathmin (p19), a 19-kDa cytosolic phosphorotein, plays a key role in converting extracellular signals into intracellular biochemical changes. Antibodies and cDNA specific for stathmin were used to study its levels and localization in normal and Alzheimer's disease (AD) brain tissue. The stathmin protein concentration was reduced in AD neocortex as assessed by Western blotting, whereas the concentration of its mRNA detected by both in situ hybridization and slot blot were increased in AD. The alteration of the stathmin protein concentration was negatively correlated with neurofibrillary tangle numbers but not with plaque numbers. Immunoreactivity was evenly localized to the cytoplasm of neurons in control cortical sections, whereas in AD it was preferentially localized to some of the neurofibrillary tangle-bearing neurons. Numbers of stathmin-positive neurons were inversely correlated with tangle numbers but not with plaque numbers in the frontal cortex of AD patients.

A single amino acid difference distinguishes the human and the rat sequences of stathmin, a ubiquitous intracellular phosphoprotein associated with cell regulations.

Stathmin is a ubiquitous phosphoprotein proposed to play a general role as an intracellular relay integrating diverse regulatory signals of the cell's environment. We used a rat stathmin probe to isolate two classes of cDNAs coding for the human protein and corresponding to the usage of different polyadenylation sites. Compared to the rat sequences, they displayed a very high conservation both at the nucleic acid and the deduced protein sequence levels, with a single conservative amino acid difference. Further analysis of the protein sequence revealed novel putative phosphorylation sites, as well as internal repeated sequences which might reflect structural features involved in the molecular mechanisms by which stathmin fulfills its biological functions. The extreme conservation of the entire stathmin sequence further stresses the essential and general role of stathmin in cell regulations.

Stathmin overexpression in 293 cells affects signal transduction and cell growth.

Stathmin is a ubiquitous cytoplasmic protein whose phosphorylation state changes markedly in response to extracellular signals, and during the cell cycle. To clarify the function of stathmin, its four phosphorylation sites were mutated to either alanines (4A-stathmin) or glutamates (4E-stathmin). In transfected cells, 4A-stathmin caused a strong G2/M block and also inhibited the responsiveness of a co-transfected fos promoter/ luciferase reporter plasmid to serum stimulation, whereas wild type and 4E-stathmin had relatively minor effects. These results support the idea that stathmin plays a role in multiple cellular processes and indicate that the regulation of the phosphorylation state of stathmin is likely to determine its action.