Role Of Hp Research Articles

Modulation of oxidative stress and Ca2+ mobilization through TRPM2 channels in rat dorsal root ganglion neuron by Hypericum perforatum

A main component of St. John’s Wort (Hypericum perforatum, HP) is hyperforin which has antioxidant properties in dorsal root ganglion (DRG) neurons, due to its ability to modulate NADPH oxidase and protein kinase C. Recent reports indicate that oxidative stress through NADPH oxidase activates TRPM2 channels. HP may be a useful treatment for Ca2+ entry and oxidative stress through modulation of TRPM2 channels in the DRG. We aimed to investigate the protective role of HP on Ca2+ entry and oxidative stress through TRPM2 channels in DRG neurons of rats.The native rat DRG neurons were used in whole-cell patch-clamp, Fura-2 and antioxidant experiments. Appropriate, nontoxic concentrations and incubation times for HP were determined in the DRG neurons by assessing cell viability. The H2O2-induced TRPM2 currents were inhibited by 2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA). TRPM2 current densities and cytosolic free Ca2+ concentration in the neurons were also reduced by HP (2 and 24h). In Fura-2 experiments, cytosolic Ca2+ mobilization was reduced by voltage-gated calcium channel blockers (verapamil+diltiazem, V+D) and HP. Glutathione peroxidase activity and GSH values in the DRG were high in HP, 2-APB and V+D groups although lipid peroxidation level was low in the groups.In conclusion, we observed a protective role for HP on Ca2+ entry through a TRPM2 channel in the DRG neurons. Since over-production of oxidative stress and Ca2+ entry are implicated in the pathophysiology of neuropathic pain and neuronal inflammation, our findings may be relevant to the etiology and treatment of neuropathology in DRG neurons.

Hemopressin an Inverse Agonist of Cb1 Cannabinoid Receptors Reverses Mechanical Sensitivity on Diabetes-Induced Neuropathy in Mice

Peripheral neuropathy is one of the most common complications of diabetes affecting about 50% of patients with the disease. The most prominent symptoms involve the extremities and occur as both an exaggerated response to noxious stimuli (hyperalgesia), mild or non-painful stimuli (allodynia). Hemopressin (Hp) is a non apeptide first found in rat brain extracts, which selectively binds CB1 cannabinoid receptors (CB1R) and exerts antinociceptive actions in experimental inflammatory and neuropathic pain models. However there is no data about its efficacy in neuropathic metabolic-related disease, like diabetes mellitus. The aim of this study was to investigate the role of Hp on mechanical and thermal sensitivity of mice submitted to an experimental model of type 1 diabetes mellitus-induced neuropathy. Mechanical allodynia and thermal sensibility were assessed by von Frey filaments or plantar test, respectively, 7, 14, 21 and 28 days after streptozotocine injection (STZ; 200 mg/kg). Body weight and blood glucose were monitored once a week. Hp was administered orally, once a day (2.5 mg/kg) for 28 days. Hp reversed mechanical allodynia in diabetic mice without changing blood glucose levels or body weight. No effects were observed for thermal sensitivity. These results make hemopressin an attractive approach for the development of cannabinoid-based therapies for the treatment diabetic neuropathic pain.

Haptoglobin inhibits the pro-inflammatory activity of HMGB1 (P4177)

Abstract HMGB1 is a cytokine mediator in the pathogenesis of inflammatory diseases including sepsis (Yang et al, BBA, 2009). Recently we demonstrated that haptoglobin (Hp), a naturally occurring serum protein, binds to HMGB1 and suppresses HMGB1-stimulated TNF and IL-8 release in cultured macrophages. Hp knockout mice subjected to cecal ligation and puncture (CLP)-induced sepsis had significantly higher serum HMGB1 levels and higher mortality rates compared to wild type animals (75% survival in wild type vs. 34% in Hp knockout mice; P<0.05). Wild type mice subjected to CLP and received injections of Hp were twice as likely to survive (63% survival in Hp-treated vs. 33% in vehicle control; P<0.05), suggesting the therapeutic potential of exogenous Hp in sepsis. Hp is composed of alpha and beta subunits in a polymeric form (Yueh, J. Chromat B Life Sci. 2007). Structure-functional analysis revealed that Hp beta subunit alone is sufficient to recapitulate effects of Hp to neutralize HMGB1 in vitro in macrophages. The survival advantage of Hp in CLP-induced sepsis was also fully reproduced by Hp beta. Surface plasmon resonance analysis showed that Hp beta binds HMGB1 with high affinity (Kd = 29 nM). Thus, our data reveal unexpected roles of Hp as an endogenous antagonist of HMGB1, preventing the harmful HMGB1-induced inflammation in sepsis. The essential domain of Hp maps to the beta subunit, making it a target in the design of therapeutics.

Engineering strategies to control vascular endothelial growth factor stability and levels in a collagen matrix for angiogenesis: The role of heparin sodium salt and the PLGA-based microsphere approach

New vessel formation is the result of the complex orchestration of various elements, such as cells, signalling molecules and extracellular matrix (ECM). In order to establish the suitable conditions for an effective cell response, the influence of vascular endothelial growth factor (VEGF) complexation with heparin sodium salt (Hp) on its pro-angiogenic activity has been evaluated by an in vitro capillary-like tube formation assay. VEGF with or without Hp was embedded into collagen gels, and the activated matrices were characterized in terms of VEGF activity and release kinetics. Taking into account the crucial role of Hp in VEGF stability and activity, VEGF/Hp complex was then encapsulated into microspheres based on poly(lactide-co-glycolide) (PLGA), and microsphere properties, VEGF/Hp release kinetics and VEGF in vitro activity over time were evaluated. Integrated microsphere/collagen matrices were developed in order to provide a continuous release of active VEGF/Hp inside the matrix but also a VEGF gradient at the boundary, which is an essential condition for endothelial cell attraction and scaffold invasion. The results confirmed a strong influence of Hp on VEGF configuration and, consequently, on its activity, while the encapsulation of VEGF/Hp complex in PLGA-microspheres guaranteed a sustained release of active VEGF for more than 30days. This paper confirms the importance of VEGF stability and signal presentation to cells for an effective proangiogenic activity and highlights how the combination of two stabilizing approaches, namely VEGF/Hp complexation and entrapment within PLGA-based microspheres, may be a very effective strategy to achieve this goal.

Helicobacter pylori infection and colorectal carcinoma: pathologic aspects.

Helicobacter pylori infection and colorectal carcinoma: pathologic aspects.

Exploratory Study of Haptoglobin Levels by Genotype in Adult Sickle Cell Patients

Abstract 2145Patients with sickle cell disease (SCD) have both extravascular and intravascular hemolysis; it is estimated that 1/3 of the hemolytic process in SCD is intravascular. Hemoglobin (Hb) released from hemolyzed red blood cells is bound by haptoglobin (Hp) in a 1:1 stochiometric complex, which is then taken up by macrophages through the scavenger receptor, CD163. When the binding capacity of haptoglobin is exceeded, concentration of cell free Hb in plasma increases, excess cell free Hb is a nitric oxide (NO) scavenger and leads to a NO depletion state. This, in turn, leads to endothelial dysfunction with increased expression of adhesion molecules and inflammatory markers, platelet activation, and an inflammatory state. This process has been incriminated in the pathogenesis of certain complications of SCD and other chronic hemolytic states with a significant intravascular hemolytic component. These include increased pulmonary artery pressure (PASP), priapism, leg ulcers, and renal dysfunction. In addition to these deleterious effects of excess cell free Hb, the fate of Hb—Hp complexes may play a significant role in the pathogenesis of the inflammatory state. Hp is a polymorphic protein with two well characterized alleles, Hp-1 and Hp-2. A large body of evidence suggests that Hp-2 allele si a major susceptibility gene for the development of vascular complications (coronary artery restenosisand cardiovascular disease). This has been attributed to the generation of a more potent inflammatory response after the binding of the larger Hp-2/Hb complexes to the CD163 receptor. We previously reported on the distribution of Hp genotypes in our pediatric and adult populations [Hughes et al, Blood 106(11), 3805 30(b), December 2005] and more recently have shown that binding of Hp-2-Hb complexes to mononuclear cell cultures from SCD patients resulted in a 3–12 fold higher inflammatory cytokine release (GM-CSF, IL1, IL-10, and TNF) compared to that observed with Hb-Hp1 complexes [Bora et al, Blood 112(11):513(1441), 2008]. We studied the haptoglobin levels in the plasma of SCD patients on and off hydroxyurea (HU) and in relation to their Hp genotype. Since clinical assays for haptoglobin are rather insensitive below 6 mg/dl, we used a sensitive ELISA (Genway Biotech) technique to quantify Hp. Hp genotypes are determined by a previously published PCR procedure, which resulted in a 3245 bp product for Hp-1 and 4945 bp for Hp-2 (Fig. 1).The distribution of Hp genotypes showed a paucity of the Hp-2-2 (17%) in this adult SCD population with 31% Hp-1-1 and 52% Hp-1-2 genotypes, confirming our previous observations. Hp concentration was strikingly lower in the SCD population (N-48) compared to normal controls (N=3); 2.31 mg/dL vs.45.58 mg/dL, p=0.01. There was no significant difference in Hp concentration among SCD patients with different Hp genotypes (Fig. 2). Similarly Hp levels between patients on and off HU did not differ significantly. Our findings are confirmatory of the data reported recently by Moller et al (Brit. J. Haematol, 153, 105–11, 2011) in 41 children with SCD, who did not find a significant difference in Hp levels in patients on and off HU. To our knowledge this is the first study of Hp levels in adult patients with SCD and different Hp genotypes. A larger study in this patient population looking at Hp levels in relation to both Hp genotype and HU usage is underway. We anticipate that this will provide insights into the role of Hp and its polymorphisms and its contribution to the phenotypic heterogeneity of SCD. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The haptoglobin phenotype influences the risk of cutaneous squamous cell carcinoma in kidney transplant patients

Cutaneous squamous cell carcinoma (SCC) is the most frequent skin cancer after organ transplantation. Currently, the pre-identification of transplant patients at increased risk for non-melanoma skin cancer remains difficult. To investigate the Hp polymorphism as a marker for the identification of a subset of patients with an increased susceptibility to develop SCC/Bowen's disease. Haptoglobin phenotyping was performed with haemoglobin-supplemented starch gel electrophoresis in 300 kidney transplant patients. High-performance gel permeation chromatography was used in case of low serum haptoglobin concentration. Cox regression analysis (adjusted for age, gender and Mediterranean origin) showed a significant association of the Hp 1-1 phenotype with a higher risk of SCC/Bowen's disease (P = 0.035) and multiple primary SCCs (P = 0.002). No significant difference between the Hp phenotypes was found for the development of Bowen's disease and SCCs in the first 10 years following renal transplantation. However, after a follow-up of >10 years, a significant association between the Hp 1-1 phenotype and the occurrence of Bowen's disease and SCC was reported (P = 0.002 and P = 0.001 respectively). This study shows an increased risk for the development of (multiple) SCCs in kidney transplant patients with the Hp 1-1 phenotype. This finding points to the role of Hp 1-1 phenotype as an important predictor in identifying a subset of patients with an increased need for preventive measures and is in agreement with the decreased anti-inflammatory capacity of this phenotype.

Hesperetin, a citrus flavonone, attenuates cadmium-induced nephrotoxicity in rat

The present study has been designed to investigate the possible attenuative role of hesperetin (Hp), a citrus flavonone on cadmium (Cd) induced nephrotoxicity in rat using biochemical and histopathological approaches. Administration of Cd subcutaneously at a dose of 3 mg/kg b.w for 21 days significantly induced the renal damage, which was evident from the increased levels of serum urea, uric acid and creatinine with a significant decrease in creatinine clearance. Cd significantly decreased the levels of urea, uric acid and creatinine in urine. The levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and protein carbonyl content (PCC) also significantly increased while the activities of vitamin C, vitamin E, reduced glutathione (GSH), total sulphydryl group (TSH) and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) significantly decreased in the kidney of Cd intoxicated rats. Hp administrated orally along with Cd for 21 days, significantly revert the status of renal markers, urine markers, lipid peroxidation markers and antioxidant defence system of the kidney tissue to near normal level in a dose dependent manner. Hp at a dose of 40 mg/kg b.w exhibited significant ( P < 0.05) nephroprotection when compared with the other two doses. Histological studies on the ultrastructural changes of kidney supported the attenuative role of Hp. Thus, the results suggest that Hp acts as a potent nephroprotective agent against Cd induced nephrotoxicity in rats.

3T3-L1 지방전구세포에서 합토글로빈에 의한 염증성 cytokine 발현 조절

백색지방조직(white adipose tissue)은 에너지 저장뿐만 아니라 다양한 adipokines을 분비하는 중요한 내분비 기관이다. 급성기반응 단백질로 알려져 있는 합토글로빈(haptoglobin)도 adipokine의 한 종류로서 지방세포에서 합성되고 분비된다. 그러나 adipokine으로서의 기능과 지방조직에서의 역할은 아직까지 규명되지 않았다. 본 연구에서는 3T3-L1 지방전구세포를 합토글로빈 유전자로 transfection 시켜 합토글로빈을 과발현하는 세포를 만들고 세포증식, 염증관련 인자들의 발현조절 및 단구세포의 유인성을 조사하였다. 그 결과, 합토글로빈은 3T3-L1 세포의 성장에는 별 영향을 미치지 않았으나 IL-6와 COX-2 발현을 저해하고 HO-1 합성을 증가하였다. 또한 THP-1 단구세포를 이용한 invasion assay에서는 합토글로빈이 단구세포의 이동을 저해하였다. 이러한 결과들은 합토글로빈이 지방조직에서 항염증 반응에 관여함을 시사한다. 만성적 염증상태(chronic low-grade inflammatory state)로 인식되고 있는 비만은 염증관련 인자들에 의한 인슐린저항성이 유도되는 바, 합토글로빈은 비만 관련 인슐린저항성을 방지하고 인슐린민감성을 향상시키는 데에도 기여할 것으로 생각된다. White adipose tissue is now recognized as an important endocrine organ which secretes various signal factors and proteins termed 'adipokine'. Haptoglobin (Hp), which has been known as an acute phase protein, belongs to the adipokine. However, the function of Hp in adipose tissue remains unclear. To verify the role of Hp in preadipocytes, in this study, 3T3-L1 preadipocyte cells were stably transfected with human Hp gene and Hp-overexpressing cells were made. The Hp had no effect on cell growth of preadipocytes. By RT-PCR and Western blot analysis, the Hp inhibited gene expression of IL-6 and COX-2 and enhanced HO-1 synthesis in preadipocytes. Moreover, invasion assay showed the Hp suppressed migration of monocytes to preadipocytes. These findings suggest that the Hp may inhibit an inflammatory reaction in adipose tissue by regulating the expressions of pro-inflammatory and anti-inflammatory mediators, and by repressing monocytes/macrophages infiltration.

A549 폐 상피세포에서 합토글로빈에 의한 염증반응 조절

Haptoglobin (Hp) is an acute phase protein, and its plasma level increases consistently in response to inflammation. To investigate the biological role of Hp in lung epithelial cells, the gene expressions of cyclooxygenase-2 (COX-2) and inflammatory cytokines were analyzed using human Hp gene-transfected A549 cells. Western blot analysis showed that COX-2 expression was markedly increased in Hp DNA-transfected cells (stable transfection and transient transfection) compared with that in vehicle DNA-transfected cells. When the Hp-expressing cells were treated with of LPS or 100 U/ml of for 24 hr, the COX-2 expression was synergistically up-regulated. ACP-based PCR data demonstrated the Hp decreased SPARC expression, but increased IL-4 and S100AI expressions. These findings suggest that the Hp acts as a pro-inflammatory mediator in lung inflammation.

Antioxidant role of human haptoglobin.

Human plasma haptoglobin (Hp) is classified according to three phenotypes: Hp 1-1, 2-1, and 2-2 attributed by their two common alleles 1 and 2. Clinically, the 2-2 phenotype is associated with the risk of cardiovascular diseases and diabetes mellitus in patients. In this study, we demonstrate that Hp is an extremely potent antioxidant, which directly protects low density lipoprotein from Cu(2+)-induced oxidation. Its potency was markedly superior to probucol (one of the most potent antioxidants). Ranking of the IC(50) of antioxidant activity was as follows: Hp 1-1 greater, similar Hp 2-1 greater, similar Hp 2-2 greater, similar probucol greater, similar vitamin E. Blockage of disulfide linkages between Hp subunits, not only abolished the alpha-helical content but also diminished the ability of Hp to form a complex with hemoglobin. The modified Hp subunits exerted almost 4 times greater antioxidant activity than that of native Hp. To investigate the antioxidant role of Hp on the cellular level, the cDNA of Hp 1-1 was cloned, introduced into the pcDNA3.0 vector which contains the cytomega lovirus promoter and transfected into chinese hamster ovary (CHO)-K1 cells. Following transfection, CHO cells were able to express Hp 1-1 protein and significantly (p < 0.001) elevated cell tolerance against oxidative stress. Transfected cells showed 2-fold higher resistance to hydrogen peroxide exposure for 24 h compared to control cells. Thus, Hp plays a provocative antioxidant role as demonstrated by our in vitro and ex vivo studies.

Reversibility of heterotopic proliferative glands in glandular stomach of Helicobacter pylori-infected Mongolian gerbils on eradication.

Helicobacter pylori (Hp) infection is an important factor in human gastric disorders. Mongolian gerbils can be easily infected with Hp and represent excellent experimental models to clarify the role of Hp in chronic active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. We have proved the enhancing effects of Hp infection on all histological types of gastric cancers in Mongolian gerbils exposed to chemical carcinogens. Heterotopic proliferative glands (HPGs) also frequently develop with Hp infection in the glandular stomach of infected gerbils, with a slightly dysplastic change of constituent cells. Distinguishing reversible inflammatory lesions from true neoplasms upon eradication is necessary for further biological or histochemical investigations using this model. We employed an experimental model of long‐term Hp infection and eradication in gerbils. HPGs finally developed with a phenotypic shift of intestinalization with Paneth cells. After eradication, HPGs were obviously reduced, and gastric lesions in mucosa also improved with few remnants of the former injury. This shows that reversible HPGs are frequently induced solely by Hp infection in this annual species, and are related to severe gastritis, rather than being malignant in character. Thus, distinguishing reversible lesions from true neoplasms is necessary to investigate the relationship of Hp infection and gastric carcinogenesis in this animal model.

ROLE OF HELICOBACTER PYLORI INFECTION ON INFLAMMATION PATTERN OF GASTRITIS AMONG FUNCTIONAL DYSPEPTIC PATIENTS

BackgroundThe presence of Helicobacter pylori (Hp) is closely related with inflammation of gastric mucosa associated with functional dyspepsia and peptic ulcer disease. While the correlation between Helicobacter pylori and peptic ulcer is accepted worldwide, the role of Hp in functional dyspepsia is still a debatable issue.AimsTo describe the histological features and to determine if there are significant differences on the level of severity and activity of these histological findings compare to the gross endoscopic findings.MethodsThe histopathologic characteristic of gastric biopsy specimens taken from antrum and stained with Giemsa and Hematoxiline‐Eosin stain were investigated among 237 patients (M=122, F=115) diagnosed as dyspepsia. Grade and activity of gastritis was examined according to the Sydney System (chronic inflammation, neutrophilic infiltration, intestinal metaplasia and glandular atrophy). The presence of Hp was determined by histology. All the patients were from the private hospital in Jakarta.ResultClinical and histological data of 237 patients with dyspepsia was analyzed. Average age was 44.14 years (SD 13.69), male 51.5% (122/237), and female 48.5 % (115/237). One hundred and forty four (60.8%) patients with dyspepsia were Hp positive on histology and were significantly older than Hp negatives (46.77 +13.99 and 40.07+12.19). Peptic ulcer was diagnosed for 3.8 % (9/237) and being excluded. The density of Hp in the antrum and corpus were mild 56.5%/5.1%, moderate 3.8%/0.0%, and severe 0.4%/0.0%, consecutively. There were significant different in density of Hp infection in both sites. The present of Hp has a good correlation with the severity and activity of chronic inflammation, neutrophilic infiltration, intestinal metaplasia and glandular atrophy in the antrum and corpus as well (p&lt;0.05).ConclusionThe present of Hp has a good correlation with the severity and activity of chronic inflammation, neutrophilic infiltration, intestinal metaplasia and glandular atrophy in the antrum and corpus as well.

Ｈ．ｐｙｌｏｒｉ感染スナネズミ実験胃癌の抑制

Helicobacter pylori (Hp) has been classified as a stomach carcinogen on the basis of epidemiological findings. For detailed analysis of the role of Hp in stomach carcinogenesis, it is essential to establish a small animal model. Hirayama et al. first demonstrated that Mongolian gerbils (MGs) can be infected with Hp. We have established experimental models of stomach carcinogenesis in MGs using the chemical carcinogens, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). In the present study, male MGs were infected with Hp before or after MNU administration. Glandular stomach adenocarcinomas not only of well-differentiated but also poorly differentiated and signet-ring cell types were induced. The incidence of adenocarcinomas was significantly higher in animals treated with before or after MNU administration than in the controls. Hp infection also enhances glandular stomach carcinogenesis in MGs treated with MNNG. To further assess this latter possibility, male MGs were treated with MNU followed by inoculation with Hp, or infected with Hp followed by MNU administration, then Hp was eradicated in half of the infected animals. The incidence of tumor development in infected animals was significantly higher than in Hp eradicated animals. The incidence was significantly suppressed by the eradication procedure. Our studies have shown that Hp enhances glandular stomach carcinogenesis of MGs treated with chemical carcinogens. Moreover, Hp eradication may be useful as a prevention approach.

Effect of haptoglobin phenotypes on growth of Streptococcus pyogenes.

The haptoglobin (Hp) 2-1 and 2-2 phenotypes have been shown to agglutinate Streptococcus pyogenes carrying the membrane antigen T4. In this study, the growth rate of two strains of Streptococcus pyogenes (T1 and T4) in human serum was compared among haptoglobin phenotypes in vitro. During incubation for 16 hours in serum of different haptoglobin types, only Hp 2-1 and Hp 2-2 sera showed an inhibitory effect on growth, Hp 2-2 being 1.85 times more potent than Hp 2-1. Growth of Streptococcus pyogenes T4 negatively correlated with the serum concentration of Hp 2-1 (r = -0.908) and Hp 2-2 (r = -0.953). Haptoglobin-depleted serum had no inhibitory effect on bacterial growth. Addition of haemoglobin and ferric citrate to the serum accelerated the growth of Streptococcus pyogenes T4 (P <0.05) but not in Hp 2-2 serum. Haptoglobin types 2-1 and 2-2 can be regarded as inhibitors of Streptococcus pyogenes growth in vitro. These data point towards a potential protective role of Hp 2-2 in Streptococcus pyogenes infection in vivo, independently of iron uptake.

Inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients

AIM: Recent studies have shown that Helicobacter pylori (Hp) infection is etiologically associated with gastric cancer. However, the role of Hp in carcinogenesis is unknown. Hp infection leads to a sustained production of the reactive nitrogen species which cause DNA damage. In this study, we examined the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine in human non-cancerous gastric mucosa. MATERIALS and METHODS: A total of 93 archival gastric biopsy specimens were used. The 34 biopsy specimens from gastric cancer patients were obtained two years or more before diagnosis of gastric cancer (Group A). The other 59 specimens were from the patients who had no evidence of gastric cancer during long term follow-up (Group B). These two groups were age and gender matched. Immunohistochemical analysis was performed to examine the expression of iNOS and nitrotyrosine. RESULTS:

Haptoglobin polymorphism and chronic hepatitis C

Background/Aims: Haptoglobin (Hp) is a hemoglobin-binding acute phase protein characterized by a genetic polymorphism due to the existence of two different alleles encoding for the alpha chain of the protein. Three phenotypes have been described: Hp 1-1, Hp 2-1 and Hp 2-2. The latter two forms are known to possess immunoglobulin-like properties and play a role in the immune response. Recently, it has been shown that in subjects suffering from hepatitis C, serum Hp concentrations were lower than in the reference population. In the present study we examined whether the haptoglobin phenotype distribution in chronic HCV patients was different from the reference population. We also looked for possible relationships between Hp phenotypes and hepatitis C virus types and response to interferon α therapy. Moreover, Hp concentrations were determined. Methods: The study population consisted of 239 Caucasian patients with proven hepatitis C. Hp phenotypes were determined using starch gel electrophoresis of hemoglobin-supplemented serum, followed by peroxidase staining. Serum Hp concentrations were assayed with an immunonephelometric method. Hepatitis C virus was genotyped and classified according to an internationally accepted system. Two hundred and twenty healthy Caucasian blood-donors served as the reference population. Results: In the reference population, 35 individuals (15.9%) had Hp 1-1, 106 persons (48.2%) had Hp 2-1 and 79 had Hp 2-2 (35.9%), resulting in an Hp 1 allele frequency of 0.400, which is in agreement with the Hardy-Weinberg equilibrium. Hp phenotype distributions and Hp allele frequencies in the chronic hepatitis C virus patient group differed significantly from those obtained in the reference population. In the patient population, 59 individuals (24.7%) had Hp 1-1, 112 persons (46.9%) had Hp 2-1 and 68 had Hp 2-2 (28.5%). This resulted in an Hp 1 allele frequency of 0.481, which is in agreement with the Hardy-Weinberg equilibrium. No statistically significant differences were found between Hp phenotype distribution and hepatitis C virus types or response to interferon α therapy. Conclusions: The observed shift in Hp phenotype distribution in chronic hepatitis C may point to a role of Hp in the natural evolution of hepatitis C.

Purification of haptoglobin and its effects on lymphocyte and alveolar macrophage responses.

Clinical observations made on a patient with acute hypersensitivity pneumonitis revealed that the patient's serum contained a mitogenic inhibitor and an extremely high haptoglobin (Hp) level; this led to an investigation of the role of Hp in lymphocyte function. Hp was isolated and purified from acute phase rabbit serum by a new method using DE-52 anion exchange chromatography and preparative isoelectric focusing in a range of pH 3.0-5.0. This technique produced a homogenous, biologically active product in fewer steps and in higher yields than existing techniques. Purified rabbit Hp significantly inhibited polyclonal lymphocyte mitogenic responses to PHA or Con A in a dose-response fashion. Hp also significantly inhibited B-cell mitogenesis at a high concentration (200 mg/100 ml) in response to LPS while it enhanced B-cell mitogenesis at lower concentrations (50 and 100 mg/100 ml). Purified Hp had no effect on monoclonal, antigen-specific (BSA) mitogenesis. Rabbit alveolar macrophages produced significant amounts of prostaglandin E in vitro in response to LPS but Hp had no effect on this production. However, Hp alone caused approximately the same amount of stimulation of PGE production by alveolar macrophages as did LPS alone. The ability of Hp to modulate lymphocyte as well as macrophage function seems to indicate that Hp plays a role in the moderation of inflammation. This ability to moderate inflammation, especially in the lungs, may play an important role in regulating tissue damage and disease following inhalation of inflammatory aerosols.

Die genetische Markierung atypisch-phasischer Psychosen

The 93 patients of the present study resemble each other in their psychosis by phasic course and complete recovery. Frequently the attacks showed an anxious and paranoid syndrome in monopolar repetition or in bipolar change with ecstatic symptoms. Rarely an incoherent state of agitation or stupor could be observed. Considering the distribution of simple inherited serum groups, there is a significant increase of Gc 1-1 and Hp 2-2 in the patient collective. Evidently these serum groups are risk components in a multifactorial hereditary system possessing with Gc 1-1 a marker of the schizophrenic disposition and with Hp 2-2 a determinating trait for affective psychoses. A selective interaction is discussed for both serum groups regarding the vitamin D transport of the Gc fraction with their relation to neuronal function and the possible role of Hp 2-2 in a transport or regulatory system.