Relationship between milk constituents from milk testing and health, feeding, and metabolic data of dairy cows.

A new evaluation scheme to assess the nutritional status of dairy cows on the basis of milk constituents was derived from 7.37 million German records of milk testing. The aim of this work was to validate this new scheme. Two data sets with fertility and health information (data set A) and with measured energy and nutrient intake and metabolic characteristics (data set B) were analyzed. Data set A included 32 commercial dairy farms in northeast Germany, with 72,982 records of 43,863 German Holstein cows; data set B included 12 German experimental farms, with 49,275 records of 1,650 German Holstein, Simmental, and Brown Swiss cows. Milk traits were linked to health disorders and metabolic and feeding characteristics. Frequently used limits of milk constituents were compared with ranges of the new "Dummerstorf feeding evaluation." To distinguish an optimal from a deficient energy supply, a milk protein content ≥3.20% (previously used) and a milk fat:protein ratio (FPR) ≤1.4 (new scheme) were chosen and compared with feed energy intake in relation to demand. Energy status was more often correctly assigned by FPR than by milk protein content (80.7 and 68.7%, respectively). Over all data, the new optimum range of milk urea between 150 and 250 mg/L was better suited to dietary crude protein intake in relation to demand than the previously used range of 150 to 300 mg/L (42.4 and 38.0%, respectively). Ketosis or blood values associated with ketosis such as ß-hydroxybutyrate >1.2 mmol/L or nonesterified fatty acids >1,000 µmol/L, as well as strong mobilization of body weight ≥1.5 kg/d, loss of back fat thickness ≥10 mm, and loss of body condition score ≥1 unit in first 60 days in milk were compared with different milk trait thresholds. For the updated scheme FPR >1.4 was used in combination with either milk protein content below the individual statistical lower limit of milk protein content, or milk fat content greater than the individual statistical upper limit of milk fat content; FPR >1.5 was taken as a frequently used threshold. For these ketosis indicators, the new scheme had higher sensitivities. Energy oversupply or the risk of overconditioning could not be identified by milk constituents alone. Urinary acid-base content was not related to milk content. Similarly, milk testing data did not allow a clear distinction to be made between the diagnoses of acidosis and, for example, ketosis. Essential requirements for good herd management are the continuous observation of milk testing data in combination with other established instruments of feeding and animal monitoring.

Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (ΔGFR < 1·5 ml/min/year) or mild (ΔGFR 1·5-5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (ΔGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high-dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (ΔGFR). Mycophenolic acid provided further maintenance in non-randomized trials. Differentiated, precise, larger, randomized, placebo-controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN.

[Influence of routine CT examination on fracture classification and therapy for pelvic ring fractures in patients aged over 65 years old]. / Einfluss der Standard-Computertomografie hinsichtlich Frakturklassifikation und Therapie von Beckenringfrakturen bei Patienten über dem 65. Lebensjahr.

BACKGROUND: The incidence of pelvic ring fractures in elderly patients increases continuously. Several studies showed that the complexity of injury is often underestimated and a fracture of the posterior pelvic ring not visible with conventional X-rays. The aim of this study was to determine the influence of routine CT on incidence, classification of and therapy for pelvic ring fractures in patients aged over 65 years. PATIENTS AND METHODS: Between 2004 and 2010, 310 elderly patients with a pelvic ring fracture were admitted to a German university level 1 trauma centre. Patients of group 1 (2004-2006) were examined with CT only if a pelvic ring fracture was diagnosed by X-ray and pain in the posterior pelvic ring persisted so that mobilisation was impossible. In group 2 (2007-2010) CT was used for routine examination. Demographic data, injury mechanism and severity (ISS) were documented as well as time and type of diagnostic procedure. Also fracture classification (AO), time and type of treatment were investigated in correlation with total hospital stay. RESULTS: 252 (82 %) patients were female, the median age was 81 years (65-100 years). 228 (74 %) had a low energy trauma, 41 (13 %) a traffic accident and 12 (4 %) had fallen from heights over 3 m. Only in 29 (9 %) cases was no trauma evident. 35 (11 %) patients were injured with an ISS over 16 and classified as polytrauma. The mean ISS was 26.8 ± 11.7. In group 2 the incidence of type A fractures decreased from 64 % to 36 %, whereas the incidence of type B fractures increased from 25 % to 49 % as did isolated sacrum fractures from 1 % to 6 %. Also the indication for operative stabilisation changed in type B fractures from 33 % to 40 % and in isolated sacrum fractures to 71 %. Total hospital stay was between eight and ten days in non-operative and between 20 and 22 days in operative treatment. CONCLUSION: A low energy trauma is the major cause of injury for patients of an age over 65 years with a pelvic ring fracture. With the routine CT examination type B fractures and isolated sacrum fractures are seen more often than expected and resulting in a change of treatment procedures.

Multiplex sequence-specific polymerase chain reaction reveals new MASP2 haplotypes associated with MASP-2 and MAp19 serum levels.

Deficiency of mannan-binding lectin-associated serine protease 2 (MASP-2) has been associated with infections, whereas high levels appear to increase the risk of inflammatory disorders. Nevertheless, MASP2 haplotypes have been poorly investigated. To overcome haplotyping cost and time consumption, we developed multiplex polymerase chain reactions with sequence-specific primers (PCR-SSP) for 8 single nucleotide polymorphisms (SNPs), reducing the number of necessary reactions from 18 to 7. SNPs were distributed from the promoter to the last exon, and a single PCR-SSP was used for p.D120G. We evaluated the phylogenetic relationships and global distribution of 10 identified haplotypes in 338 Danish individuals with known MASP-2 and MAp19 levels and 309 South Brazilians. Four haplotypes were associated with reduced MASP-2 levels in plasma (lower than 200 ng/mL). Simultaneous association with the highest MASP-2 (over 600 ng/mL) and lowest MAp19 levels (lower than 200 ng/mL) was demonstrated with the intron 9 mutation (Kruskal-Wallis p < 0.0001). Cumulative genotype frequencies predict approximately 0.4% severely deficient and 25% overproducing individuals in both populations. Rapid and low-cost screening of patients with multiplex MASP2 PCR-SSP could be used to identify clinical conditions where MASP-2 (or MAp19) levels may be disease modifying, possibly improving disease outcome through early therapeutic and preventive measures.

Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation.

BACKGROUND AND PURPOSE: We investigated the influence of metoprolol on gap junction proteins connexin43 (Cx43) and connexin40 (Cx40) in atrial tissue from patients with/without atrial fibrillation (AF). EXPERIMENTAL APPROACH: Left atrial tissue samples from 160 patients with AF or sinus rhythm (SR) with or without metoprolol (mean daily dose: 65.2 ± 9.1 mg·day⁻¹) were analysed for Cx43 and Cx40 by Western blot and immunohistology. Transverse and longitudinal conduction velocities were determined by 64 multi-electrode mapping. KEY RESULTS: Both Cx43 and Cx40 expression were significantly increased in patients with AF versus SR. Cx43-expression in AF was significantly higher in patients receiving metoprolol, while Cx40 expression was unaffected by metoprolol treatment. In AF, the ratio of lateral/polar expression of Cx43 and Cx40 was enhanced due to increased expression at the sides of the cells (lateral) and a loss at the cell poles. This AF-induced increase in lateral/polar expression of Cx43, but not of Cx40, was significantly antagonized by metoprolol treatment. Functionally, in AF patients, transverse conduction velocity in atrial samples was significantly enhanced and this change was also significantly antagonized by metoprolol. CONCLUSIONS AND IMPLICATIONS: AF induced enhanced lateral expression of Cx43 and Cx40 together with enhanced transverse conduction velocity in left atrial tissue. Alterations in localization of Cx43 and conduction changes were both antagonized by metoprolol, showing that pharmacological modulation of gap junction remodelling seems, in principle, possible. This finding may open new approaches to the development of anti-arrythmic drugs.

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy.

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

A new role for extracellular Ca2+ in gap-junction remodeling: studies in humans and rats.

We wanted to elucidate whether extracellular calcium may regulate the expression of the cardiac gap-junction proteins connexin 40 and connexin43. In the free wall of the left atria of 126 cardiac surgery patients with either sinus rhythm (SR) or chronic atrial fibrillation (AF), we determined the expression of the cardiac gap-junction proteins Cx43 and Cx40 by Western blot and immunohistology. For deeper investigation, we incubated cultured neonatal rat cardiomyocytes at 2 or 4 mM Ca(++) for 24 h and determined intercellular coupling, Cx40, Cx43 protein and mRNA expression, protein trafficking and sensitivity to verapamil (10-100 nM), cyclosporin A (1 microM),and BMS605401 (100 nM), a specific inhibitor of Ca(2+)-sensing receptor (CaSR). We found in patients that both Cx are up-regulated in AF in the left atrium (by 100-200%). Interestingly, Cx40 was mainly up-regulated, if total serum calcium was >or=2.2 mM, while Cx43 was independent from extracellular [Ca(++)]. In cultured cells, 4 mM Ca(++)-exposure lead to up-regulation of Cx40, but not Cx43. We found enhanced Cx40 in the plasma membrane and reduced Cx40 in the Golgi apparatus. The membrane Cx40 up-regulation resulted in enhanced gap-junction intercellular coupling with a shift in the Boltzmann fit of voltage-dependent inactivation indicating a higher contribution of Cx40 as revealed by dual whole cell voltage clamp experiments. BMS605401 could prevent all Ca(2+)-induced changes. Moreover, cyclosporin A completely abolished the Ca(2+)-induced changes, while verapamil was ineffective. We conclude that extracellular calcium (24 h exposure) seems to up-regulate Cx40 but not Cx43.

Diversity of the MBL2 gene in various Brazilian populations and the case of selection at the mannose-binding lectin locus.

The mannose binding lectin (MBL2) polymorphism is responsible for a common immunodeficiency in the human species. There were suggestions that the MBL2 polymorphism has been under balancing selection, based on the high global frequency of alleles generating MBL deficiency and on the worldwide distribution of diseases negatively associated with them. To describe the distribution of MBL2 allelic haplotypes in Brazilian populations and to discuss the evolution of this polymorphism, we analyzed six South Brazilian populations (152 Guarani Amerindian, 239 Kaingang Amerindian, 107 admixed, Brazilian 32 Afro-Brazilian, 202 Euro-Brazilian and 16 Oriental-Brazilian). Eight haplotypes were observed: MBL2*HYPA, LYQA, LYPA, LXPA, LYPB, LYQC, HYPD, and LYPD. In addition, through sequencing of the promoter and exon 1 from Amerindian and Oriental individuals, three new single-nucleotide polymorphisms (SNPs) were found in the MBL2 promoter region in the Kaingang. Analysis of the sequencing data by neutrality tests (Tajima's D and Fu and Li's D* and F*) revealed no deviation from selective neutrality equilibrium in the Guarani and Kaingang. Significant Fay and Wu's H results are explained by the recent gene flow in these populations. Contrarily to previous thoughts, stochastic evolutionary factors seem therefore to have had a predominant role in shaping the MBL2 polymorphism, at least in the Amerindians.

Association of a new mannose-binding lectin variant with severe malaria in Gabonese children.

Mannose-binding lectin (MBL2) variants that decrease the plasma level of the protein or encode dysfunctional proteins are frequently associated with the severity of a number of infections and autoimmune disorders. The high frequencies of these variants in most populations of the world are probably maintained by some selective advantage against widespread diseases. We found 14 new MBL2 allelic haplotypes, two of them with non-synonymous variants, by screening 136 children with uncomplicated malaria, 131 children with severe malaria and 39 older healthy schoolchildren. We also found a significant association of a novel variant with susceptibility to severe malaria (P=0.010). Increased MBL plasma levels and corresponding MBL2 genotypes were associated with lower concentration of several cytokines and chemokines in plasma of malaria patients. We suggest that malaria could have been one of the evolutionary driving forces shaping the MBL2 polymorphism in the African population.

Subchronic alpha- and beta-adrenergic regulation of cardiac gap junction protein expression.

Gap junction channels are essential for intercellular electrical communication in the heart. The most important cardiac gap junction proteins are connexin43 (predominantly) (Cx43), connexin40 (Cx40), and in early developmental stages connexin45. Since catecholamines play an important role in cardiac (patho)physiology, we wanted to elucidate whether catecholamines may affect expression of Cx43 and Cx40. Cultured neonatal rat cardiomyocytes were exposed for 24 h to increasing concentrations of noradrenaline (1-10000 nM) (physiological agonist at alpha and beta-adrenoceptors), resulting in significantly increased Cx43-expression, while Cx40 was unaffected. In further experiments cells were incubated with either phenylephrine (alpha-adrenergic agonist) or isoproterenol (beta-adrenergic agonist) (0.1-1000 nM) for 24 h. Both catecholamines lead to a concentration-dependent increase in Cx43 protein and mRNA expression (EC50: 10-20 nM). Inhibition experiments showed that the phenylephrine effect was transduced via PKC, while the isoproterenol effect was mediated by PKA. Dual whole-cell voltage clamp demonstrated that increased Cx43-expression was accompanied by significant increases in gap junction current. In additional in vivo experiments, adult rats were subjected to 24-h infusion of isoproterenol or phenylephrine showing again significant increase in Cx43 but not Cx40. Adrenergic stimulation of cardiomyocytes can enhance Cx43 expression thereby increasing cellular coupling, indicating a possible role for catecholamines in the regulation of cardiac gap junction expression in cardiac disease.

ACE-inhibitor treatment attenuates atrial structural remodeling in patients with lone chronic atrial fibrillation.

OBJECTIVE: Chronic atrial fibrillation (AF) is characterized by a remodeling process which involves the development of fibrosis. Since angiotensin II has been suspected to be involved in this process, the aim of our study was to investigate a possible influence of an ACE-I therapy in patients with chronic AF regarding the occurrence of left atrial structural remodeling. METHODS: Atrial tissue samples were obtained from patients with lone chronic AF or sinus rhythm (SR). Collagen I, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) protein expression were measured by quantitative Western Blotting techniques and calculated as mean +/- SEM. Histological tissue samples were used for calculating microvessel density (microvessel/mm(2) +/- SEM). RESULTS: In AF, the collagen amount was higher (1.78 +/- 0.21; p = 0.01) vs. SR (0.37 +/- 0.07) accompanied by declining microcapillary density (AF: 145 +/- 13 vs. SR: 202 +/- 9; p = 0.01). Additionally, a negative correlation (p = 0.01) between collagen content and microcapillary density was observed. To investigate the influence of an ACE-I therapy on this remodeling process, patient groups were divided into AF and SR both with or without ACE-I. Interestingly, there was a significantly lower expression of collagen I in AF with ACE-I (1.04 +/- 0.26) vs. AF without ACE-I treatment (2.07 +/- 0.24, p = 0.02). The microcapillaries were not diminished in AF with ACE-I (180 +/- 15) vs. SR with ACE-I (196 +/- 9), but there was a significant rarification in AF without ACE-I (123 +/- 18; p = 0.03). The expression of VEGF and bFGF did not reveal any significant differences. CONCLUSION: In patients undergoing ACE-I treatment: atrial structural remodeling was attenuated and the loss of atrial microcapillaries was prevented.

Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies.

OBJECTIVE: To test the hypothesis that atrial fibrillation (AF) is associated with changes in the expression of connexins 40 and 43 in the left atrium with more pronounced changes in mitral valve disease than in lone AF. METHODS: Protein concentrations of connexin 40 and connexin 43 were analysed in left atrial tissue of patients undergoing cardiac surgery. One group of patients had lone AF (n = 41), one group had AF and mitral valve repair (n = 36), and one group in sinus rhythm served as controls (n = 15). RESULTS: Western blot analysis of connexin 40 and connexin 43 expression showed an increase of both gap junctional proteins (connexin 43 > connexin 40) in patients with AF of all forms compared with patients in sinus rhythm (p = 0.01 and p = 0.011, respectively). Subgroup analysis showed increased concentrations of connexin 40 in lone AF and AF with mitral valve disease compared with sinus rhythm (p = 0.06 and p = 0.029, respectively), whereas the same analysis for connexin 43 reached significance only in the mitral valve disease group (p = 0.031). No differences in connexin 40 and connexin 43 expression were detectable between lone AF and AF with mitral valve disease. Within the groups connexin 40 and connexin 43 expression did not differ between patients with paroxysmal AF and patients with chronic AF. CONCLUSION: The present study shows for the first time that AF can induce changes in the left atrium with increased connexin expression. Furthermore, no systematic differences between patients with paroxysmal and chronic AF were detected.

Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease.

OBJECTIVE: To examine the hypothesis that major extracellular matrix (ECM) proteins are expressed differently in the left atrial tissue of patients in sinus rhythm (SR), lone atrial fibrillation (AF), and AF with underlying mitral valve disease (MVD). DESIGN: Case-control study. PATIENTS: 118 patients with lone AF, MVD+AF, and SR. MAIN OUTCOME MEASURES: Collagen I, collagen III, and fibronectin protein expression measured by quantitative western blotting techniques and immunohistochemical methods. RESULTS: Protein concentrations increased in patients with AF (all forms) compared with those in SR (all forms): collagen I (1.15 (0.11) v 0.45 (0.28), respectively; p = 0.002), collagen III (0.74 (0.05) v 0.46 (0.11); p = 0.002, and fibronectin (0.88 (0.06) v 0.62 (0.13); p = 0.08). Especially, collagen I was similarly enhanced in both lone AF (1.49 (0.15) and MVD+AF (1.53 (0.16) compared with SR (0.56 (0.28); both p = 0.01). Collagen III was not significantly increased in lone AF but was significantly increased in AF combined with MVD (0.84 (0.07) both compared with SR (0.46 (0.11); p = 0.01). The concentration of fibronectin was not significantly increased in lone AF and MVD+AF (both compared with SR). Furthermore, there was a similar degree of enhanced collagen expression in paroxysmal AF and chronic AF. CONCLUSIONS: AF is associated with fibrosis. Forms of AF differ from each other in collagen III expression. However, there was no systematic difference in ECM expression between paroxysmal AF and chronic AF. Enhanced concentrations of ECM proteins may have a role in structural remodelling and the pathogenesis of AF as a result of separation of the cells by fibrotic depositions.

[A comparison of high resolution computerized tomography and magnetic resonance imaging in the evaluation of allergic bronchopulmonary aspergillosis]. / Bildgebende Diagnostik der allergischen bronchopulmonalen Aspergillose: Vergleich von hochauflösender Computertomographie und Kernspintomographie.

Apart from serologic markers structural changes of bronchi and adjacent lung tissue are key factors determining the diagnosis and course of allergic bronchopulmonary aspergillosis (ABPA). Due to problems relating to procedural hazards and radiation exposure using bronchography and computerized tomography we evaluated the efficacy of magnetic resonance imaging of the lung in ABPA. Direct comparison of high resolution computerized tomography (HR-CT) and magnetic resonance imaging (MR) in 5 patients with ABPA revealed that image resolution and data acquisition of present MR technique are insufficient to accurately delineate the extent and activity of structural damage of bronchi and adjacent lung tissue. Although major bronchiectasis may be identified, MR was unable to demonstrate even extensive patchy infiltrates seen in high resolution computerized tomography. At present, magnetic resonance imaging cannot be recommended for determining diagnosis or course of ABPA.

The perceptions of Lutheran pastors toward prenatal genetic counseling and pastoral care.

The purpose of this study is to explore a theological perspective toward genetic counseling. A survey was sent to 207 ministers within the Evangelical Lutheran Church of America (ELCA), to determine their perspectives toward four different scenarios in a prenatal genetic counseling setting. The four different scenarios included situations involving Huntington disease, Down syndrome, trisomy 18, and anencephaly. Nearly all ELCA Lutheran pastors perceived genetic counseling as beneficial and useful and wanted to be involved in the decision-making process for whether or not to terminate pregnancy. Their views toward termination of pregnancy varied depending on the severity of the genetic abnormality. Severity in this study was based upon life compatibility. As the severity of the genetic abnormality increased, the percentage of Lutheran pastors who viewed termination as an option increased from 23% (Down syndrome) to 62% (anencephaly). A better understanding of how spiritual leaders view genetic counseling would provide an insight into how genetics and religious beliefs together play a significant role in shaping the decisions of those faced with abnormal pregnancies.

HLA-DQA1 and HLA-DQB1 alleles and haplotypes in two Brazilian Indian tribes: evidence of conservative evolution of HLA-DQ.

Nucleotide sequence polymorphism of the HLA-DQA1 and HLA-DQB1 class II genes was analyzed in the Kaingang and Guarani Amerindians from southern Brazil using PCR sequence-specific oligonucleotide typing methods. Four different DQA1-DQB1 haplotypes were found: DQA1*0401-DQB1*0402 (associated with DRB1*0802, DRB1*08041, and DRB1*0807), DQA1*0501-DQB1*0301 (associated with DRB1*1602, DRB1*1413, and DRB1*1402), DQA1*03-DQB1*0302 (associated with DRB1*0404 and DRB1*0411), and DQA1*03-DQB1*03032 (associated with DRB1*09012). These HLA-DQA1 and HLA-DQB1 alleles and haplotypes are common in many other populations of all major ethnic groups. Alleles and haplotypes introduced into the populations by post-Columbian admixture were seen at low frequency both in the Kaingang (3.2%) and in the Guarani (3.8%). No novel HLA-DQA1 and HLA-DQB1 alleles have thus far been identified in Amerindians. This differs from previous results for HLA-DRB1, another class II locus presenting novel alleles (i.e., alleles not found in other ethnic groups and probably generated after migration of paleo-Indians to the Americas) in the Guarani and in other South American Indian populations. The distribution of the HLA-DQ alleles and haplotypes in Amerindians indicates a weaker diversifying selective pressure on the HLA-DQ genes compared with HLA-DRB1 and HLA-B. The more conservative evolution of HLA-DQA1 and HLA-DQB1 compared with HLA-DRB1 is strong evidence of (still not well-defined) functional differences of these class II genes.