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Cette étude présente les premières données sur l'apparition d'un Nématode du genre Anguillicola, parasite de la vessie natatoire de l'anguille, au Maroc Les résultats montrent la présence de ce parasite dans les eaux littorales de l'Atlantique (Loukkos et Sebou). Par contre, les anguilles de la façade méditerranéenne semblent être indemnes (Moulouya).

We report a case of spontaneous bladder rupture due to bladder carcinoma. A 62-year-old man presented to the emergency department with acute urine retention; two days later, the patient presented with abdominal distension and a large intraperitoneal effusion on CT scan, as well as a breccia in the bladder. Exploratory laparotomy confirmed a definitive diagnosis: bladder rupture due to bladder carcinoma. He underwent radical cystectomy. Surgery is recommended to treat carcinomatous bladder rupture. Rapid diagnosis is essential to optimize patient outcomes. The possibility of spontaneous bladder rupture should not be overlooked as a differential diagnosis in cases of acute abdomen., Competing Interests: There is no conflict of interest between the authors of this work., (© 2024 The Authors.)

Introduction: surveillance data on Helicobacter pylori (H. pylori) antibiotic susceptibilities in Morocco are limited, despite resistance being the key factor in treatment failure. Virulence factors of H. pylori are associated with carcinogenesis and may be also associated with the efficacy of treatment. The aim of our study is to determine the prevalence of H. pylori metronidazole resistance in a Moroccan population infected with H. pylori and to study the impact of their virulence factors CagA and VacA on their resistance to metronidazole., Methods: the susceptibility to metronidazole of 185 isolates was determined by PCR. The isolates were also genotyped for CagA and VacA genes by PCR., Results: the metronidazole resistance rate was 62.70%. No association between resistance to metronidazole and social factors was detected. Regarding the virulence factors, we remarked that the moderate virulent strains s1/m2/i1/d1 with a CagA negative were the most resistant to metronidazole with a rate of 84% compared to the less virulent strains bearing the CagA negative VacA s2m2i2d2 genotype with a rate of 58% and the high virulent strains s1/m1/i1/d1-CagA positive with a rate of 47.06%., Conclusion: our study revealed a very high prevalence of resistance to metronidazole in our population. The resistance ability of H. pylori maybe affected by its virulence intensity. H. pylori eradication regimens should therefore be reevaluated in this setting., Competing Interests: The authors declare no competing interests., (Copyright: Essaidi Imane et al.)

Background: H. pylori infection induce atrophic gastritis (AG) and intestinal metaplasia (IM) that can lead to gastric cancer (GC). The severity of gastric lesions is related to H. pylori genetic diversity. The oncogenic potential of H. pylori cagA virulence factor is linked to its high polymorphic EPIYA motifs., Objectives: Our aim was to evaluate the association of EPIYA motifs with the risk of AG and IM in Casablanca population., Methods: A total of 210 patients suffering from gastric lesions (chronic gastritis, AG, and IM) was enrolled. H. pylori infection and the type of lesions were diagnosed by ureC PCR and histological examination, respectively. Detection of the cagA gene, and the type of EPIYA motifs, were carried out by PCR., Results: The prevalence of H. pylori and cagA gene was 95% and 37%, respectively. CagA-positive strains were associated with the risk of IM. The EPIYA motifs detected were: EPIYA-ABC (58%), EPIYA-ABCC (22%), and EPIYA-AB (20%). The EPIYA-ABCC motif was associated with the risk of IM (p-value = 0.007), compared to AG (p-value = 0.28)., Conclusion: The EPIYA-ABCC motif might be a useful marker for the identification of patients at high risk of developing IM that can lead to GC., (© 2022 Jouimyi MR et al.)

Introduction: Helicobacter pylori (H.pylori) infection is recognized as a worldwide problem, mainly in developing countries where infection reaches 80% of the population. H.pylori is associated with various gastric diseases, mainly, many benign, premalignant and malignant lesions of the gastric mucosa. The aim of our study was to determine the prevalence of H.pylori infection and to highlight the determinants of the infection as well as the gastric lesions associated with this bacterium in a Moroccan population., Patients and Methods: A total of 162 asymptomatic subjects collected from Casablanca blood transfusion, and 254 patients suffering from various gastric lesions collected from gastroenterology and oncology services of the IbnRochd CHU, were targeted typing of gastric lesionsand H.pylori status were performed by Histological examination and ELISA test., Results: Our results showed a high prevalence of H. pylori infection in asymptomatic and gastric diseases patients. We noticed that the worsening of gastric lesions related to H.pylori infection increases with age, and it was influenced bytobacco consumption and the living area., Conclusion: Our study showed that gastric cancer was more occurred in rural areas than in urban areas.It is necessary to update the recommendations regarding diagnosis, treatment of H. pylori infection and follow-up of the patients to avoid the evolution of simple chronic gastritis to gastric cancer.

A moderately thermophilic bacterial strain, Meiothermus ruber H328, can efficiently solubilize intact chicken feathers by aerobic cultivation at 55 °C for 6 days. The keratinolytic proteases extracellularly secreted by the strain were partially purified by an ultrafiltration system and a size-exclusion column chromatography, and thus were found to be two different sizes of macromolecules with an extremely high molecular mass like the sizes of virus and DNA (peak 1 fraction) and with a molecular mass of larger than 500 kDa (peak 2 fraction). They formed protein complex assemblies that were composed of multiple but different proteins. The peak 1 fraction showed more thermophilic characteristics than did the peak 2 fraction in temperature dependence and thermal stability. By contrast, they comparably showed extraordinary resistance to powerful denaturants, SDS at 30 % (w/v) and organic solvents (methanol, ethanol, acetonitrile, acetone, and chloroform) at 40 % (v/v) at 60 °C for 30 min. The extraordinary denaturant tolerance and the large molecular size of the keratinolytic protease complex assemblies suggest the possibility that those may be lipophilic and have the structure of partial membrane fractions, or membrane vesicles, which are exfoliated from the outer membrane of the cells.

The thermophilic bacterium Meiothermus ruber H328 aggressively degrades chicken feathers. When feathers were added to culture medium, the cells significantly exfoliated membrane vesicles from the outer membrane as observed by electron microscopy of ultrathin sections. This is the first report of membrane vesicle production associated with keratinolytic activity by Meiothermus sp.

Aims: The aim of this study was to determine whether serum levels of adipokines, including the ratio of serum adiponectin to leptin (A/L) levels could predict the severity of liver injury in patients with non-alcoholic fatty liver disease (NAFLD)., Patients and Methods: Fifty-seven patients with biopsy-proven non-alcoholic steatohepatitis (NASH) (mean age 51+/-12, sex ratio 1), 17 with simple steatosis (mean age 47+/-12, sex ratio 1.4) and 10 controls without steatosis (mean age 51+/-11, sex ratio 4) were investigated. In all subjects, serum concentrations of triglycerides, ultrasensitive C reactive protein, leptin, adiponectin, soluble tumour necrosis factor receptor 1, interleukin (IL)-6 and Homeostasis Model Assessment Method (HOMA) were measured. Hepatic expression of adiponectin and its two receptors was assessed by quantitative reverse transcriptase polymerase chain reaction., Results: Body mass index (BMI) and HOMA were correlated positively with leptin levels (r=0.44 and 0.28 respectively) and negatively with the A/L ratio (r=0.51 and 0.41 respectively). Independent parameters associated with NASH vs steatosis were HOMA>3 [odds ratio (OR)=6.9] and A/L ratio <1.4 10(3) (OR=5.2). The combination of HOMA with A/L ratio showed an area under the receiver operating characteristic curve of 0.82 for distinguishing between NASH and steatosis. Extensive portal fibrosis was present in 17 (23%) patients with NAFLD. Three independent parameters were associated with fibrosis: age (OR=1.1), BMI (OR=1.3) and high IL-6 levels (OR=1.6). The hepatic expression of adiponectin receptor 2 was significantly higher in patients with NASH compared with controls and was related with necroinflammatory injury., Conclusions: This study shows that in patients with NAFLD, the combination of HOMA with A/L ratio may be a useful non-invasive approach to appreciate the severity of liver damage.

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colony stimulating factor production. Both functions were also recovered when FLFCs cultured in contact with CD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulates FLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes. Disclosure of potential conflicts of interest is found at the end of this article.

Objective: Stavudine (d4T), a nucleoside reverse-transcriptase inhibitor (NRTI), can induce lipoatrophy, fatty liver, hyperlactataemia and abnormal liver tests. NRTI toxicity is usually ascribed to mitochondrial DNA (mtDNA) depletion and impaired mitochondrial respiration. However, NRTIs could have effects unrelated to mtDNA. Recently, we reported that 100 mg/kg/day of d4T stimulated fatty acid oxidation (FAO) in mouse liver, and reduced body fatness without depleting white adipose tissue (WAT) mtDNA. We hypothesized that higher d4T doses could further reduce adiposity, while inhibiting hepatic FAO., Methods: Mice were treated for 2 weeks with d4T (500 mg/kg/day), L-carnitine (200 mg/kg/day) or both drugs concomitantly. Body fatness was assessed by dual energy X-ray absorptiometry, and investigations were performed in plasma, liver, muscle and WAT., Results: D4T reduced the gain of body adiposity, WAT leptin, whole body FAO and plasma ketone bodies, and increased liver triglycerides and plasma aminotransferases with mild ultrastructural abnormalities in hepatocytes. Plasma lactate and respiratory chain activities in tissues were unchanged. Stearoyl-CoA desaturase (SCD-1), an enzyme negatively regulated by leptin, was overexpressed in liver. High doses of beta-aminoisobutyric acid (BAIBA), a d4T catabolite, increased plasma ketone bodies. Although L-carnitine did not correct body adiposity, it prevented d4T-induced impairment of FAO and liver abnormalities., Conclusions: D4T overdosage triggers fat wasting, leptin insufficiency and mild liver damage, without causing respiratory chain dysfunction. Overexpression of SCD-1 reduces fatty acid oxidation and overcomes the stimulating effect of BAIBA on hepatic FAO. L-carnitine does not correct leptin insufficiency but prevents d4T-induced impairment of FAO and liver damage.

Objectives: Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients' insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals., Methods: Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24-48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays., Results: In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1 alpha and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1 beta and tumour necrosis factor-alpha., Conclusions: Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.

Objective: To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART)., Methods: Forty HIV-infected patients on stable effective ART were enrolled, 33 of them completed the study. Patients underwent a physical examination, laboratory tests and needle biopsy of subcutaneous abdominal adipose tissue both at inclusion and at month 6. Changes in fat morphology, mitochondrial DNA (mtDNA) content and gene expression were examined in 29, 23 and 20 patients, respectively., Results: Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor alpha (TNFalpha)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-gamma coreceptor 1alpha) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFalpha- and IL6-expressing cells was lower at month 6 than at month 0, and so was CD68 expression, a macrophage marker. Adipocyte mitochondrial status also improved, with lower mitochondrial density and cytochrome oxidase 4 mRNA levels, and higher mtDNA content. Sterol regulatory element binding protein 1 mRNA levels increased, reflecting better adipocyte differentiation., Conclusions: A 6-month ART interruption markedly improved adipose tissue functions, although fat distribution did not visibly change. Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status. PIs were also associated with altered adipocyte differentiation and mitochondrial status. These data clearly show the detrimental effect of antiretroviral drugs, in particular thymidine analogues, on adipose tissue and argue for switch strategies sparing these drugs.

In order to test the accuracy of glycated hemoglobin (HbA1c) in predicting mean glycemia in HIV-infected patients, we recorded consecutive HbA1c measurements from 1238 non-HIV-infected and 112 HIV-infected patients, all devoid of any hemoglobinopathy, in a retrospective, transversal study. Mean fasting glycemia from the six previous weeks (measured-Gly) and HbA1c-estimated glycemia [HbA1c-Gly (1.85x%HbA1c-4.78) mM] were compared. Mean hemoglobin, red cell volume, serum creatinine, CD4 count, and HIV viral load from the same period were collected in HIV-infected patients. Although measured-Gly was not significantly different between non-HIV-infected (6.95+/-3.23 mM) and HIV-infected patients (6.62+/-2.42 mM), HbA1c underestimated the mean fasting glycemia by 12.3% in HIV-infected as compared to non-HIV-infected patients (p=0.0001). The difference "measured-Gly-HbA1c-Gly" was correlated with the red cell volume (p<0.0001) in HIV-infected patients. We then searched for the presence of subclinical hemolysis, a cause of both macrocytosis and reduced HbA1c levels, in HIV-infected patients. To this end, we prospectively measured serum haptoglobin in 249 consecutive samples from HIV-infected subjects without any known cause of hemolysis. A very low haptoglobin level, a marker of hemolysis, was frequent and negatively correlated with the red cell volume in these patients. Treatment with nucleoside analogues was significantly associated with macrocytosis and low haptoglobin. In conclusion, HbA1c could be inappropriately low in HIV-infected patients. Its underestimation of mean fasting glycemia could be due to an antiretroviral-induced subclinical hemolysis, but further studies are needed to explore this hypothesis. Self-monitoring of blood glucose and search for latent hemolysis should be promoted in diabetic HIV-infected patients.

106 consecutive patients with Alzheimer's disease living in the community were examined in a memory clinic from a neurological department. They were screened for weight loss over the last 2 years. Age, duration of the disease, behavioral disorders, mini mental status examination, body mass index were recorded. Tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), interleukin 6 (IL-6) and interleukin 2 (IL-2) blood levels were measured. Weight loss was reported in 42.5% of the patients. TNFalpha levels were significantly higher in these patients (18.8 versus 15.8 pg/mL; p=0.04) than in patients without weight loss. Weight loss was also associated with a lower MMSE score (16.9 versus 19.3; p=0.03), current pacing (20% versus 1.6%; p=0.002), and hallucinations (20.0% versus 3.3%; p=0.008). The levels of the other cytokines did not differ between the patients with and without weight loss. Our findings suggest an association between high levels of circulating TNFalpha and unexplained weight loss in Alzheimer's disease.

HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFalpha, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue.

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.

We have compared the levels of immunoglobulins G (IgG) and G4 (IgG4) in extreme seropositive patients from the GRIV cohort consisting of 168 patients with slow progression (SP) and 60 with rapid progression (RP) as well as in 173 healthy controls. IgG levels were significantly higher in SP patients than in RP patients (P = 0.008), both higher than in seronegative individuals. IgG4 levels were significantly lower in SP patients than in RP patients (P = 0.001), both lower than in seronegative individuals. We tried to correlate these levels with biological parameters (CD4(+) and CD8(+) cells, total lymphocytes, white blood cell counts, percentage of CD4(+) cells, and viral load) as well as with genetic markers from Th1/Th2 cytokines (IL2, IL4, IL6, IL10, IL13, and IFNgamma). IgG levels were correlated with the percentage of CD4(+) cells in SP while IgG4 levels were correlated with CD8(+) cell count in SP and with percentage of CD4(+) cells in RP patients. Among the parameters measured in SP patients at the time of inclusion in the study, the best predictor of progression towards AIDS was the viral load, the best predictor for stability was CD4(+) cell count, but overall, the best predictor for SP evolution (stability vs. progression) appeared to be the percentage of CD4(+) cells. Interestingly, correlations between the levels of IgG or IgG4 and the cytokine gene polymorphisms were found, notably in the IL10 gene.

HIV-1-infected patients on antiretroviral therapy frequently develop a lipodystrophy syndrome, characterized by peripheral lipoatrophy and visceral fat redistribution associated with metabolic alterations including dyslipidemia and insulin resistance. Its pathophysiology remains unclear but the antiretroviral treatment, associating protease inhibitors (PIs) and nucleoside analogue inhibitors of the viral reverse transcriptase (NRTIs), plays a major role. Some antiretroviral molecules inhibit differentiation and induce insulin resistance and apoptosis in adipose cells both in vitro and in vivo. In vitro, PIs and NRTIs increase the expression and secretion of pro-inflammatory cytokines such as TNF alpha, IL-6 and L-1beta, which are involved in altered adipocyte functions and decrease that of adiponectin, a positive modulator of insulin sensitivity. Similar alterations are observed in fat and serum from HIV-1-infected lipodystrophic patients under antiviral treatment associating PIs and NRTIs. Altered adipokine secretion could result from patients' exposure to PIs and NRTIs and lead to altered adipocyte differentiation, insulin resistance and apoptosis, ultimately resulting in lipoatrophy. These disorders probably result in a decreased secretion of adiponectin and an increased release of free fatty acids by insulin-resistant adipose tissue. Therefore, they could be involved in whole body insulin resistance and metabolic alterations in lipodystrophic HIV-1-infected patients.

Objective: The lipodystrophy syndrome is a major adverse effect of highly active antiretroviral therapy (HAART), associated with altered circulating levels and adipose tissue mRNA expression of proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF)alpha, and adiponectin. Proinflammatory cytokines and adiponectin, which are secreted by adipose tissue, regulate fat metabolism, insulin sensitivity and adipose cell apoptosis. We examined the direct effects of individual antiretrovirals on lipid metabolism and cytokine and adiponectin production by cultured adipocytes., Methods: Differentiating 3T3-F442A cells and differentiated 3T3-L1 adipocytes were treated for 12 or 4 days, respectively, with protease inhibitors (PIs) indinavir, nelfinavir, amprenavir, lopinavir and ritonavir, or nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine, at near-Cmax concentrations. Lipid metabolism was estimated by Oil Red O staining of intracellular lipids, mRNA expression of fatty acid synthase and adipocyte lipid binding protein 2, and insulin activation of lipogenesis. Apoptosis was estimated by flow cytometry. The expression and secretion of proinflammatory cytokines (IL-6, TNFalpha and IL-1beta) and adiponectin were evaluated by real-time reverse transcription PCR and ELISA., Results: Chronic treatment of 3T3-F442A differentiating adipocytes and differentiated 3T3-L1 adipocytes with PIs and NRTIs reduced lipid accumulation, mRNA expression of lipid markers and insulin-induced lipogenesis. IL-6, TNFalpha, IL-1beta and adiponectin expression and secretion were markedly altered in differentiating 3T3-F442A adipocytes. PIs had either no effect on differentiated 3T3-L1 adipocytes (TNFalpha expression and sucretion) or their effect was less marked than in 3T3-F442A cells. Indinavir and amprenavir did not alter cytokine secretion and expression by mature adipocytes. The effects of stavudine and zidovudine on differentiating and mature adipocytes were similar, despite the difference in treatment procedure. The drugs with the strongest effect on TNFalpha expression also increased adipocyte apoptosis, in contrast to the drugs that only moderately increased TNFalpha expression., Conclusions: These results suggest that increased cytokine and decreased adiponectin secretion and expression induced by some PIs and NRTIs may contribute to the adipose tissue loss (via apoptosis and lipid leakage) and insulin resistance associated with the lipodystrophy syndrome.

Objective: To achieve a better understand of the pathophysiology of HIV-related lipoatrophy, we compared the mRNA expression of adipocytokines in fat samples from patients and healthy HIV-seronegative controls together with fat morphology and we studied the relationship between changes in fat morphology, adipocytokine expression, markers of adipose tissue differentiation and whole body insulin sensitivity., Design: Cross-sectional analytical study., Subjects and Methods: The mRNA expression of adipocytokines and transcriptional factors in fat samples from 26 patients with peripheral lipoatrophy (all under anti-retroviral therapy associating protease inhibitor and nucleoside-analogue reverse transcriptase inhibitors) and from 16 non-HIV-infected controls was measured by real time quantitative RT-PCR. Fat morphology was assessed histologically on a subgroup of 10 patients and six controls: collagen fibres by Sirius Red staining, apoptosis by the TUNEL technique, vessels by smooth muscle alpha-actin staining and macrophages by CD68 staining. Insulin resistance was assessed by using the homeostasis model assessment., Results: The patients' fat showed higher values of apoptosis (P=0.005), fibrosis (P<0.05), vessel density (P=0.001) and macrophage infiltration (P<0.05) than the controls' fat, together with lower adiponectin and leptin mRNA levels and higher interleukin (IL)-6 and tumour necrosis factor (TNF)alpha mRNA levels. TNFa and IL-6 expression correlated positively with the level of apoptosis (P=0.05 and P<0.05, respectively) and negatively with CCAAT-enhancer binding protein (C/EBP)alpha (P<0.001 and P<0.05, respectively). Apoptosis correlated negatively with the expression level of sterol-regulatory-element-binding-protein-1c (SREBP1c) (P=0.01) and C/EBPalpha (P=0.01) whilst the vessel density correlated negatively with SREBP1c (P<0.005), C/EBPalpha (P=0.001) and beta (P=0.001). Adiponectin and leptin expression correlated positively with each other, and also with adipogenic marker expression and overall insulin sensitivity. These relationships were also present when the patient group was studied separately. Finally, fat morphological abnormalities correlated positively with whole body insulin resistance., Conclusions: Adipose tissue from patients with HIV-1-related lipoatrophy shows increased apoptosis, together with decreased adipocyte differentiation. Increased TNFalpha and IL-6 expression could be a major phenomenon linking these alterations. Decreased adiponectin and leptin expression, which may result from decreased adipocyte differentiation, could be involved in the observed whole body insulin resistance.

IL-6 has emerged as an important cytokine upregulated in states of insulin resistance such as type 2 diabetes. We evaluated the chronic effect of IL-6 on insulin signaling in 3T3-F442A and 3T3-L1 adipocytes. First, cells responded to a chronic treatment with IL-6 by initiating an autoactivation process that increased IL-6 secretion. Second, IL-6-treated adipocytes showed a decreased protein expression of IR-beta subunit and IRS-1 but also an inhibition of the insulin-induced activation of IR-beta, Akt/PKB, and ERK1/2. Moreover, IL-6 suppressed the insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4. IL-6-treated adipocytes failed to maintain their adipocyte phenotype as shown by the downregulation of the adipogenic markers FAS, GAPDH, aP2, PPAR-gamma, and C/EBP-alpha. IL-6 also induced the expression of SOCS-3, a potential inhibitor of insulin signaling. Finally, the effects of IL-6 could be prevented by rosiglitazone, an insulin-sensitizing agent. Thus, IL-6 may play an important role in the set-up of insulin resistance in adipose cell.

Objectives: Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART)., Methods: We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index., Results: The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease., Conclusions: These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

Immunoglobulin D (IgD) multiple myeloma is rare, accounting for less than 2% of all patients with multiple myeloma. The main presenting features are bone pain in 70% of patients. Extramedullary involvement is less common. We report a case of Ig D lambda multiple myeloma in a 74-year-old man that was revealed by pleural effusion and dyspnea. This effusion was found to be caused by multiple myeloma after electrophoretic and cytologic assays. The patient received a course of chemotherapy with melphalan and prednisone. The patient died one month later with signs of septic shock. Pleural effusion as a first sign of Ig D multiple myeloma is rarely described and the prognosis associated with such a localisation is very poor.

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.

Background: Lipodystrophy is a major side-effect of antiretroviral therapy but its pathophysiology remains elusive. In-vitro studies show that HIV-1-protease inhibitors affect adipocyte differentiation at an early step involving sterol-regulatory-element-binding-protein-1 (SREBP1), but in-vivo studies are lacking., Methods: We compared fat morphology and mRNA and protein expression of major adipocyte differentiation markers and cytokines in subcutaneous abdominal adipose tissue from 26 HIV-1-infected patients who developed peripheral lipoatrophy while on protease inhibitors and from 18 HIV-1-seronegative healthy controls., Findings: Patients' fat contained a higher proportion of small adipocytes than control fat, together with lower mRNA concentrations of the adipogenic differentiation factors CCAAT-enhancer binding protein (C/EBP) beta and alpha, peroxisome proliferator-activated receptor (PPAR) gamma, and the 1c isoform of SREBP1, with a median decrease of 93% in the latter. The SREBP1 protein concentration was increased 2.6-fold, whereas the PPARgamma protein concentration was decreased by 70%. The expression of adipocyte-specific markers, including leptin, was lower in fat from patients than in fat from controls, whereas expression of tumour necrosis factor (TNF) alpha was higher and correlated negatively with the expression of SREBP1c and downstream adipogenic factors. SREBP1c mRNA concentrations correlated negatively, and TNFalpha mRNA concentrations positively, with glycaemia and insulin resistance, but did not correlate with lipid variables., Interpretation: The altered differentiation status of peripheral adipocytes in HIV-1-infected patients with antiretroviral-induced lipoatrophy is associated with greatly reduced SREBP1c expression. Since the differentiation factor SREBP1 is rapidly targeted by protease inhibitors in vitro, our results suggest that SREBP1c could be an important mediator of peripheral lipoatrophy in this setting, leading to metabolic alterations such as insulin resistance.

Coronary artery disease is a leading cause of death in France. Some of its risk factors are well identified such as age, smoking, high blood pressure and dyslipidemia, but some others such as lipoprotein (a) (Lp(a)) are still under investigation. Lp(a) is an LDL-like particle to which is linked an apolipoprotein (a). The latter shows a high sequence homology with plasminogen that gives Lp(a) thrombogenic properties in addition to its atherogenic capacity. Many epidemiological studies have shown that a high plasma level of Lp(a) is a risk factor for coronary, cerebral and peripheral atherosclerosis. Out of thirteen prospective studies, ten have confirmed this result. The negative results from the three remaining studies were probably due to either the inadequate storage of the samples or the preventive drug treatment given to the patients during the studies and to the lack of standardization of Lp(a) assays. More over it has been shown that beside high plasma Lp(a) level, the presence of a low molecular weight Apo(a) isoform is also related to a higher incidence of coronary artery disease. This review of the literature clearly demonstrates the relationship between Lp(a) and atherosclerosis, and the need to measure Lp(a) in order to better evaluate the risk of atherosclerotic vascular disease especially in patients with a hyper LDLemia an early cardio- or cerebrovascular disease or a family history of atherosclerosis. Management of patients with high Lp(a) concentrations should be directed at minimizing all other risk factors for atherosclerotic disease.

Lipoprotein (a) [Lp(a)] is a LDL-like particle linked to an apo-lipoprotein (a) which has high sequence homology with plasminogen that gives Lp(a) thrombogenic properties in addition to atherogenic capacity. Many epidemiological studies have shown that a high plasma level of Lp(a) is a risk factor for coronary, cerebral and peripheral atherosclerosis. Out of thirteen prospective studies, ten have confirmed this result. The negative results from the three remaining studies were probably due to either inadequate storage of the samples or preventive drug treatment given to the patients during the studies. This review of the literature clearly demonstrates the relationship between Lp(a) and atherosclerosis and the need to measure Lp(a) in order to better evaluate the risk of atherosclerotic vascular disease especially in patients with a hyper LDLemia, an early cardio- or cerebrovascular disease or a family history of atherosclerosis.