Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients

Initial studies have shown that recombinant human interleukin-6 (rhIL- 6) induces anemia. Until now, the pathophysiologic mechanism of this induced anemia has been unknown. To unravel the underlying mechanism, we examined 15 cancer patients receiving rhIL-6 as an antitumor immunotherapy in a phase II study. rhIL-6 was administered subcutaneously at 150 micrograms once daily for 6 consecutive weeks. Various hematologic and biochemical parameters were measured weekly during rhIL-6 treatment and 4 weeks after rhIL-6 discontinuation. To determine plasma volume and red blood cell (RBC) volume, radioisotope dilution assays with labeled autologous RBCs and with human serum albumin were performed before rhIL-6 administration and on day 8 of rhIL-6 therapy. Hemoglobin levels decreased (mean change +/- SE) 7% +/- 1.5% within 3 days after the start of rhIL-6 therapy (P < .0001) and 19% +/- 2% at week 4. Levels had normalized at follow-up. The plasma volume increased 18% +/- 5% during the first week of rhIL-6 administration (P < .003), whereas RBC volume remained unaffected. The mean RBC corpuscular volume remained unchanged for 2 weeks and then began to decrease slowly, reaching its nadir at week 6 (5% +/- 1%; P < .01). Serum iron levels decreased 65% +/- 12% at week 4 (P < .002) and then returned to initial baseline values. Erythropoietin levels increased rapidly up to 68% at week 3 (P < .0001) and had normalized 4 weeks after rhIL-6 therapy. Levels of serum albumin, prealbumin, and transferrin decreased (P < .0001, P < .003, and P < .0001, respectively), whereas levels of serum amyloid A (P < .003), C-reactive protein, haptoglobin, and alpha-1-antitrypsin (P < .0001) increased during rhIL-6 treatment. All levels returned to pretreatment values after discontinuation of rhIL-6. No alterations in reticulocyte counts, serum lactic dehydrogenase levels, and bilirubin levels were observed. A 6-week regimen of subcutaneous rhIL-6 results in a rapid dilution anemia, caused by an acute and significant increase in plasma volume and followed by hypoferremia. This anemia is reversible after the cessation of rhIL-6 treatment.     

Prevention of mother‐to‐child transmission of HIV in Denmark, 1994–2008

Objectives

The aim of this study was to describe trends in the management of pregnancies in HIV‐infected women and their outcomes over a 14‐year period in Denmark on a national basis.

Methods

The study was a retrospective cohort study of all HIV‐infected women in Denmark giving birth to one or more children between 1 June 1994 and 30 June 2008.

Results

We identified 210 HIV‐infected women with 255 pregnancies, ranging from 7 per year in 1995 to 39 per year in 2006. Thirty per cent of the women were Caucasian and 51% were Black African. Knowledge of HIV status before pregnancy increased from 8% (four of 49) in 1994–1999 to 80% (164 of 206) in 2000–2008. Only 29% (53 of 183) of the women chose to consult an infectious disease specialist when planning pregnancy, while 14% (27 of 199) received assistance with fertility. The proportion of women on antiretroviral therapy (ART) increased from 76% (37 of 49) in 1994–1999 to 98% (201 of 206) in 2000–2008. Vaginal deliveries ranged from 0 in 2003 to 35% of pregnancies in 2007. Mother‐to‐child transmission (MTCT) of HIV decreased from 10.4% in 1994–1999 to 0.5% in 2000–2008. All women giving birth to an HIV‐positive child were diagnosed with HIV during or after delivery and did not receive prophylactic ART.

Conclusions

The annual number of HIV pregnancies increased fivefold during this 14‐year period and substantial changes in pregnancy management were seen. No woman treated according to the national guidelines, i.e. ART before week 22, intravenous zidovudine (ZDV) during labour, neonatal ZDV for 4 to 6 weeks and no breastfeeding, transmitted HIV to her child.     

GNAS1 T393C polymorphism and disease progression in patients with malignant melanoma

Background: Once metastasized, despite a variety of therapeutic options, the prognosis of patients with malignant melanoma (MM) is still poor. Therefore, the search for reliable markers to identify patients with high risk of disease progression is of high clinical importance. We have recently shown that TT genotypes of the single-nucleotide polymorphism (SNP) T393C in the gene GNAS1 are significantly associated with better outcome in a variety of carcinomas. - Patients: In the present study we assessed whether the T393C SNP is also related to the clinical course in MM. 328 patients with MM were retrospectively genotyped and genotypes were correlated with clinical outcome. - Results: While the allele frequency in the MM group (fC 0.52) did not significantly differ from that of healthy blood donors, the T393C SNP was associated with tumor progression of MM. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). - Conclusions: In summary, the GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression also in patients with MM; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy.     

The patient cohort of the German competence network for HIV/AIDS (KompNet):a profile

Objective

In this paper, we describe the main objectives, the study design and the onset of the patient cohort of the German Competence Network for HIV/AIDS (KompNet). Furthermore, we depict sociodemographic and clinical baseline characteristics and an estimation of the coverage and representativity as to the composition of persons living with HIV/AIDS (PLWHA) in Germany.

Methods

The KompNet cohort is an open, retrospective and prospective, multicenter, disease-specific and nationwide cohort study that started gathering data in June 2004. Semi-annually, follow up visits of the patients are documented, covering clinical and sociodemographic data. At enrolment and three years afterwards, an EDTA-sample is taken; a serum-sample is taken at every follow up visit.

Results

As of 14.9.2008, a total of 15,541 patients were enrolled by 44 documenting sites. In September 2007, the cohort size was reduced to 10 outpatient clinics and fifteen private practitioners, covering a total of 9,410 patients. The documentation of these patients comprises 24,117 years of follow up-time since enrolment (mean: 2.6 years), 62,862 person years inclusive data documented retrospectively on course of HIV-infection and combined antiretroviral therapy (cART, mean: 6.7 years). 1,008 patients (10.7%) were lost to follow up and 175 (1.9%) died since enrolment. 84.9% of patients were men. Main risks of transmission were sex between men (MSM: 62.9%), heterosexual contacts (18.4%), intravenous drug use (IVDU: 7.0%) and origin from a high prevalence country (HPL: 5.2%). Mean age was 45 years.

Conclusion

The KompNet cohort covers about a quarter of all patients being under treatment in Germany. The composition of the cohort represents well the most important risks of transmission in Germany. The cohort contains a high proportion of patients being older than 49 years (28.1%). On basis of its comprehensive database and its biomaterials banks, the KompNet cohort serves as an important instrument to monitor and analyse the effects of combined antiretroviral therapy (cART) in Germany, interdigidating basis, clinical and psychosocial research in view to translational research.     

Lower limb and back pain in Guillain-Barré syndrome and associated contrast enhancement in MRI of the cauda equina

This study assesses the frequency of lower limb and back pain in children with Guillain-Barré syndrome and reviews the magnetic resonance imaging results of those undergoing spinal imaging. Over an 8-y period, nine children presented with various combinations of severe back pain, leg pains, impairment of gait and bladder dysfunction. Guillain-Barré syndrome was confirmed on clinical examination and peripheral electrophysiology ( n = 8). Magnetic resonance imaging in four patients, following contrast injection, showed enhancement of the cauda equine and, additionally, of the cervical nerve roots in one of the patients. A further patient, who was not scanned with contrast, had abnormal thickening of the lumbar roots. Carbamazepine and steroids were effectively used for analgesia in three cases. All the patients recovered.
Conclusion: Guillain-Barré syndrome should be considered in the differential diagnosis of children presenting with back and/or leg pain. Early diagnosis ensures prompt monitoring for autonomic dysfunction and respiratory compromise.     

Subcellular localization of neuronal nitric oxide synthase in rat small intestine

The subcellular localization of neuronal nitric oxide synthase (NOS I, EC 1.14.13.39) was investigated in the longitudinal muscle/myenteric plexus (LM/MP) preparation of rat small intestine. The presence of NOS I, inducible nitric oxide synthase (NOS II), and endothelial nitric oxide synthase (NOS III) was assessed after homogenization and low-speed centrifugation in a postnuclear supernatant by immunological detection after PAGE and Western blotting. Only NOS I was clearly present, whereas NOS II and NOS III were below detection limits. After high-speed centrifugation of the postnuclear supernatant, soluble and particulate fractions were obtained, and the presence of NOS I in these fractions was investigated by measurement of NOS I immunoreactivity and enzyme activity. We found that 90 +/- 1% of NOS I immunoreactivity and 97 +/- 1% of NOS enzyme activity were confined to the soluble fraction of the tissue. Further immunological analysis demonstrated that washing the particulate fraction revealed detectable amounts of NOS I only after concentration of the washing supernatant. Most particulate NOS I remained in the pellet and therefore represents cell organelle-associated enzyme. No NOS I immunoreactivity could be detected as a soluble protein within organelles of the cell. Particulate NOS I could in part be solubilized by Triton X-100 treatment, and the detection of Triton X-100-soluble NOS I was dependent on the antibody used. In conclusion, our results indicate that NOS I in the LM/MP preparation of rat small intestine is mainly soluble and that the particulate NOS I is partly an intrinsic membrane protein and can partly be solubilized by detergent treatment.     

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT1 receptors

1. CHO-K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO-AT1 cells) were used for pharmacological studies of non-peptide AT1 receptor antagonists. 2. In the presence of 10 mM LiCl, angiotensin II caused a concentration-dependent and long-lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild-type CHO-K1 cells. 3. [3H]-Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization. 4. Non-peptide selective AT1 antagonists inhibited the angiotensin II (0.1 microM) induced IP accumulation and the binding of [3H]-angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin. 5. Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half-maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 microM losartan indicating a syntopic action of both antagonists. 6. Losartan caused a parallel rightward shift of the angiotensin II concentration-response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed-type behavior in both functional and binding studies. 7. Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long-lasting inhibition.     

The beta-adrenergic transduction system in kidneys from young and senescent rats

beta-Adrenoceptor density, ligand affinity, high-affinity agonist binding, basal adenylate cyclase activity and cAMP synthesis upon stimulation with either forskolin, F-, guanine nucleotides (GTP or GppNHp) or isoproterenol in the presence of the nucleotides were studied in membranes prepared from kidneys of young (2-3 month) and old (24-25 month) male Wistar rats. There is a significant (P less than 0.01) 62% increase in beta-receptor density, a significant (P less than 0.05) 115% decrease in ligand affinity, a significant (P less than 0.05) 33% decrease of high-affinity binding sites for (-)-isoproterenol and a significant (P less than 0.01) 151% decrease of the affinity of the high-affinity agonist binding site. Basal adenylate cyclase activity and the activity after stimulation with guanine nucleotides and forskolin were significantly higher in old animals as compared to young (P less than 0.01). Stimulation of the system with isoproterenol in the presence of GTP was more effective in old animals, although the P less than 0.05 level of significance was barely reached. It is suggested that age-dependent changes of the beta-adrenoceptors in rat kidney are similar to those described for lungs: changes at the different levels of the beta-adrenergic transduction chain associated with age are compensatory so as to ensure equal cAMP synthesis for a given agonist stimulation.     

"Covert toxocariasis" in a child treated with low-dose diethylcarbamazine

A girl aged 2.5 years with "covert toxocariasis" was treated with low-dose diethylcarbamazine because of supposed noticeable disseminated Toxocara canis infection without ocular or visceral manifestations. There was marked blood and bone marrow eosinophilia, significant increased Toxocara canis antibody (ELISA) and immunoglobulins E, G and M, leucocytosis and an increased sedimentation rate. She had no geophagia, but often sucked small stones, probably contaminated with faeces from puppies. Symptoms were fever, inactivity, weakness, tiredness and loss of appetite. She was followed clinically and with blood samples throughout a period of three years and four months.