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OBJECTIVE: Major limitation for the use of stent in the treatment of coronary artery disease is development of stent restenosis. The impact of intravascular ultrasound (IVUS) guidance during drug eluting stent (DES) implantation is presently not yet well established. PATIENTS AND METHODS: For the present study, we included 30 patients who received DES with IVUS-guided stenting (Group A) and 30 patients receiving the DES without IVUS-guided stenting (Group B). The patients were evaluated for their ninth month control angiographies and were followed during two years for the development of relevant clinical events after the DES implantations. The angiographic and clinical results were compared between the groups. RESULTS: After the percutaneous intervention, the minimal luminal diameter and net acute gain were significantly increased in Group A in respect to Group B (3.3 ± 0.34 vs. 2.8 ± 0.33, p < 0.01). Moreover, the rate for performing post-dilatation following stent implantation was higher in Group A than in Group B (p = 0.01). By contrast, stent restenosis rates were similar between the groups (p > 0.3). CONCLUSIONS: The present results indicate that the use of IVUS for the implantation of DES can increase the success rate of the intervention. The IVUS guidance during DES implantation can be complementary percutaneous intervention, in particularly by detecting the situations that need for post-dilatation. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The frequency of hypoplastic right coronary artery (HRCA) and its contribution to coronary artery anomalies (CAAs) has not been thoroughly studied. Here we aimed to investigate whether a casual relationship exists between the presence of HRCA and CAAs. MATERIALS AND METHODS: We retrospectively reviewed coronary angiography records of 7500 patients. The images were carefully assessed for coronary artery (CA) anatomy and CAAs. Overall, we compared CAAs at the presence and absence of HRCA and evaluated potential association between HRCA and CAAs. Besides, we grouped HRCA patients according to the presence of CA disease (CAD) into two groups and compared their CAAs. RESULTS: While the percentage of HRCA was 6.2%, it was 3.34% for CAAs. The percentage of CA with anomalous origin (CAAO) at the presence of HRCA was significantly higher than the presence of normal right coronary artery (NRCA) (p < 0.01). Similarly, the percentage of absent left main coronary artery (ALMCA) was also considerable increased in HRCA patients with respect to the patients with NRCA (p < 0.01). The percentage of CAAO was notably higher in the CAD (-) than CAD (+) patients with HRCA (p < 0.01). Likewise, the prevalence of ALMCA was also noticeably higher in the CAD (-) than CAD (+) patients with HRCA (p < 0.01). CONCLUSIONS: HRCA is a clinically significant and frequently encountered congenital variation. The present observations indicate that the presence of HRCA is closely associated with a high prevalence of CAAO, particularly with increased rate of ALMCA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the case of a 53-years-old male patient who was diagnosed with a long left anterior descending coronary artery arising from the distal right coronary artery.

In vivo data are rare but essential for establishing the clinical potential of ruthenium-based photoactivated chemotherapy (PACT) compounds, a new family of phototherapeutic drugs that are activated via ligand photosubstitution. Here a novel trisheteroleptic ruthenium complex [Ru(dpp)(bpy)(mtmp)](PF 6 ) 2 ([2](PF 6 ) 2 , dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2'-bipyridine, mtmp = 2-methylthiomethylpyridine) was synthesized and its light-activated anticancer properties were validated in cancer cell monolayers, 3D tumor spheroids, and in embryonic zebrafish cancer models. Upon green light irradiation, the non-toxic mtmp ligand is selectively cleaved off, thereby releasing a phototoxic ruthenium-based photoproduct capable notably of binding to nuclear DNA and triggering DNA damage and apoptosis within 24-48 h. In vitro , fifteen minutes of green light irradiation (21 mW cm -2 , 19 J cm -2 , 520 nm) were sufficient to generate high phototherapeutic indexes (PI) for this compound in a range of cancer cell lines including lung (A549), prostate (PC3Pro4), conjunctival melanoma (CRMM1, CRMM2, CM2005.1) and uveal melanoma (OMM1, OMM2.5, Mel270) cancer cell lines. The therapeutic potential of [2](PF 6 ) 2 was further evaluated in zebrafish embryo ectopic (PC3Pro4) or orthotopic (CRMM1, CRMM2) tumour models. The ectopic model consisted of red fluorescent PC3Pro4-mCherry cells injected intravenously (IV) into zebrafish, that formed perivascular metastatic lesions at the posterior ventral end of caudal hematopoietic tissue (CHT). By contrast, in the orthotopic model, CRMM1- and CRMM2-mCherry cells were injected behind the eye where they developed primary lesions. The maximally-tolerated dose (MTD) of [2](PF 6 ) 2 was first determined for three different modes of compound administration: (i) incubating the fish in prodrug-containing water (WA); (ii) injecting the prodrug intravenously (IV) into the fish; or (iii) injecting the prodrug retro-orbitally (RO) into the fish. To test the anticancer efficiency of [2](PF 6 ) 2 , the embryos were treated 24 h after engraftment at the MTD. Optimally, four consecutive PACT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW cm -2 , 114 J cm -2 , 520 nm). Most importantly, this PACT protocol was not toxic to the zebrafish. In the ectopic prostate tumour models, where [2](PF 6 ) 2 showed the highest photoindex in vitro (PI > 31), the PACT treatment did not significantly diminish the growth of primary lesions, while in both conjunctival melanoma orthotopic tumour models, where [2](PF 6 ) 2 showed more modest photoindexes (PI ∼ 9), retro-orbitally administered PACT treatment significantly inhibited growth of the engrafted tumors. Overall, this study represents the first demonstration in zebrafish cancer models of the clinical potential of ruthenium-based PACT, here against conjunctival melanoma., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Heart injuries usually occur due to penetrating or blunt traumas. High mortality rates are seen in heart injuries, owing to firearms and cutting/piercing tools. Factors such as the degree of injury, its localization, and the length of time to reach the hospital influence mortality rates. Despite the increase in imaging facilities and improvements in hospital transportation in today's conditions, high mortality rates are still observed, owing to causes such as sudden blood loss, cardiac arrest, or cardiac tamponade. The present study aimed to present the successful treatment of a 46-year-old male patient with injuries to the left atrium and posterior wall of the left ventricle due to a gunshot wound using the approach of median sternotomy and peripheral cannulation.

In classical textbooks of Anatomy, the mental nerve is considered to be the terminal or main branch of the inferior alveolar nerve, especially trifurcate with no designated names as soon as it emerges from the mental foramen. The textbooks define the innervation area of the mental nerve regionally without naming its terminal branches. Nomina Anatomica designates 3 terminal branches of mental nerve as "labial, gingival, and mental branch" but offers no description about their distribution on the mandible. In the present study, bilateral dissections were performed on the lower lip specimens of 20 newborns for 40 mental nerves to determine the branching types of mental nerve. Although anatomy textbooks indicate that mental nerve divides into 3 branches, the authors noted that mental nerve branched into 1, 2, or 3 branches at or right after its exit from the mental foramen. Branching patterns were typed in 13 different subclasses under 3 main groups (Form I-II-III). Moreover, the branching patterns that could not be included in one of these 3 main groups were defined as "Complex Form." The most common type of branching that the authors observed was Form II, which had 2 terminal branches with an incidence of 41.9% (16 specimens). The next frequently encountered type was Form III, having 3 terminal branches, and it was detected in 32.0% of patients (12 specimens). The least common form was Form I, which had 1 terminal branch with a frequency of 15.8% (6 specimens). The unclassified group, Complex Form, was found 10.5% (4 specimens).

The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer. The efficacy of TLD1433 was tested on several cell lines from CM (CRMM1, CRMM2 and CM2005), uveal melanoma (OMM1, OMM2.5, MEL270), epidermoid carcinoma (A431) and cutaneous melanoma (A375). Using 15 min green light irradiation (21 mW/cm 2 , 19 J.cm -2 , 520 nm), the highest phototherapeutic index (PI) was reached in CM cells, with cell death occurring via apoptosis and necrosis. The therapeutic potential of TLD1433 was hence further validated in zebrafish ectopic and newly-developed orthotopic CM models. Fluorescent CRMM1 and CRMM2 cells were injected into the circulation of zebrafish (ectopic model) or behind the eye (orthotopic model) and 24 h later, the engrafted embryos were treated with the maximally-tolerated dose of TLD1433. The drug was administrated in three ways, either by (i) incubating the fish in drug-containing water (WA), or (ii) injecting the drug intravenously into the fish (IV), or (iii) injecting the drug retro-orbitally (RO) into the fish. Optimally, four consecutive PDT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW/cm 2 , 114 J.cm -2 , 520 nm). This PDT protocol was not toxic to the fish. In the ectopic tumour model, both systemic administration by IV injection and RO injection of TLD1433 significantly inhibited growth of engrafted CRMM1 and CRMM2 cells. However, in the orthotopic model, tumour growth was only attenuated by localized RO injection of TLD1433. These data unequivocally prove that the zebrafish provides a fast vertebrate cancer model that can be used to test the administration regimen, host toxicity and anti-cancer efficacy of PDT drugs against CM. Based on our results, we suggest repurposing of TLD1433 for treatment of incurable CM and further testing in alternative pre-clinical models.

Objectives: The incidence of obesity and obesity-assosiated pathologies continues to increase with profound adverse effects on health status in the developed countries., Background: We aimed to investigate the effect of high fat diet on the adrenal gland morphology., Methods: We fed the mice with either high-fat diet (60 % kcal from fat) or low-fat diet (10 % kcal from fat) for nine weeks. Unbiased stereological methods were used to evaluate the adrenal gland morphology. The sections were evaluated using Cavalieri's method and volume fraction approach. We calculated mean volume of adrenal gland, mean volume of adrenal medulla, VVadrenal medulla/adrenal gland, mean diameter of cromaffin cells, number of chromaffin cells in per unit volume (NVcc mm‒3), total number of cromaffin cells, VVzona glomerulosa/adrenal cortex, VVzona fasciculata/adrenal cortex , VVzona reticulosa/adrenal cortex., Results: The weight of adrenal gland, body weight intraperitoneal adipose tissue and adrenal gland weight in the obese mice significantly increased when compared with the control group. No changes were observed in the mean volume of adrenal gland, mean volume of adrenal medulla, VVzona glomerulosa/adrenal cortex, VVzona fasciculata/adrenal cortex, total number of cromaffin cells and diameter of cromaffin cells. However, NVcc mm-3 and VVzona reticulosa/adrenal cortex in the obese mice considerably increased compared with the control group., Conclusion: The present results suggest that high fat diet adversely affects the adrenal gland morphology (Tab. 2, Fig. 6, Ref. 28).

This study aimed to evaluate the role of gender in types and frequency of coronary artery aneurysm and ectasia.We assessed retrospectively the angiography records of 6100 patients. At first, we mainly reviewed angiographic movies for the presence of coronary ectasia and/or aneurysm. Consequently, based on the number of the coronary artery involvement, the coronary ectasia and aneurysm were graded as mild if 1 coronary artery was involved and severe if 2 or more coronary arteries were involved. The location of ectasia and aneurysm was analyzed with respect to their isolated or combined location on various coronary arteries. The patients included in the present study were divided into 2 groups based on their gender as male and female. Then, we evaluated the impact of gender on severity and the location of the ectasia and aneurysm.The incidence of the aneurysm and ectasia was 3.5%. Among the patients with aneurysm and ectasia, 6.9% were male and 4.5% were female. Aneurysm and ectasia were evaluated together; their frequency was significantly higher in the male than female patients (P < 0.01). However, when their incidence was evaluated separately, coronary artery ectasia was markedly greater in male patients with regard to female patients (P < 0.01). Incidence of CAE presence on the RCA was significantly greater in males than females (2.7% vs 1.9%, P < 0.05).This study showed that incidence of CAE is more common in males than females. Particularly, frequency for the involvement of CAE on RCA and concurrently on 3 vessels is greater in male patients than female patients.

Objectives: We planned to compare the impact of two beta blockers, metoprolol and nebivolol, on arterial blood pressure during exercise in patients with mild hypertension., Methods: A total of 60 patients (13 males, 47 females; mean age: 54.3 ± 10.7 years) were enrolled in the present study. The patients were randomly selected to receive either nebivolol 5 mg/day (n = 30) or metoprolol 50 mg/day (n = 30) for 8 weeks. At the end of the 8th week, each of the patients received exercise stress test according to Bruce protocol and their blood pressures were remeasured after rest, exercise, and recovery., Results: Blood pressures were determined to be similar between metoprolol and nebivolol groups during rest, exercise, and recovery periods. Metoprolol and nebivolol achieved similar reductions in blood pressures during rest and exercise. However, five patients in nebivolol group and four patients in metoprolol group developed exaggerated BP response to exercise but the difference between metoprolol and nebivolol was not meaningful (P = 0.37)., Conclusion: The results of the present study showed that metoprolol and nebivolol established comparable effects on the control of blood pressures during exercise in the patients with mild hypertensions.

Background: Cardiac simulators have been developed as an alternative training model in order to improve the cardiac auscultation skills of medical students. The effectiveness of the cardiac simulator's use in cardiac auscultatory training is presently not yet well established., Objectives: The authors aimed to investigate whether the use of a cardiac simulator can improve the auscultation skills of medical students., Material and Methods: The students taking the auscultation training on the cardiac simulator were grouped as Group A and the students not taking the auscultation training on the cardiac simulator were grouped as Group B (before). The students in Group B (before) were grouped as Group B (after) after receiving the auscultation training on the cardiac simulator. The percentages of accurate diagnoses for the tested heart murmurs were compared between Group A and Group B (before), and between Group B (before) and Group B (after)., Results: The rate of making correct diagnoses of normal heart sounds was similar in all the groups (Group A, Group B (before), and Group B (after)). By contrast, the percentage of accurate diagnoses for the tested heart murmurs was notably improved among the students in Group A with respect to Group B (before) (p < 0.01). Similarly, the rate of correct diagnoses for the tested heart murmurs was markedly higher among the students in Group B (after) than in Group B (before) (p < 0.01)., Conclusions: The use of a cardiac simulator as a training tool can improve the auscultation skills of medical students quickly and efficiently.

Purpose: The purpose of this study was to evaluate whether a association exits among overweight and obesity and left ventricular systolic and diastolic functions in patients admitted with first ST-elevation myocardial infarction (STEMI)., Methods: The present study was performed on 451 consecutive patients diagnosed with first STEMI (376 men, 75 women; mean age 56.1 ± 10.8 years). The patients were classified into three groups based on their body mass index (BMI) as normal weight (BMI < 25 kg/m2), overweight (BMI: 25-29.9 kg/m2) and obese (BMI > 30 kg/m2). Echocardiographic features were evaluated and compared among the three groups., Results: Mitral annulus E velocities were higher in obese individuals than normal weight group (p < 0.01). In contrast, mitral A velocities were lower (p =0.03); consequently, E\A and E'\A' ratios were lower (both p = 0.01) in the obese group with respect to normal weight group. When the correction of entire variations existing among the groups were performed using multivariate linear regressions analyses, it turned out that BMI was independently associated with E/A (β = -0.19, p = 0.044) and with E'/A' (β = -0.016, p = 0.021). Ejection fraction, wall motion score index and myocardial S velocities were comparable among the study groups (p > 0.05)., Conclusion: These results suggest that while obesity has no adverse effect on the left ventricular systolic function, it has unfavorable consequences on the left ventricular diastolic function in the patients with first STEMI. In contrast, no unfavorable effects of overweight on the left ventricular systolic and diastolic function were detected.

Coronary artery anomalies are rarely encountered in general population. Gender may play a role in the types and incidence of coronary artery anomalies, although the effect of gender is not well established. In the present study, we therefore aimed to investigate the frequency and location of various types of coronary artery anomalies and their correlation with gender. We assessed retrospectively the coronary angiography movies of 7,810 patients (2,214 females and 5,596 males), the method of which is distinct from the earlier studies with angiographic archive records. We defined and classified the coronary artery anomalies according to their origin, course (myocardial bridge), and termination (fistula). The incidence of coronary artery anomalies was 3.35% (262 of 7,810): 130 individuals with anomalous origin (1.66%), 105 individuals with myocardial bridges (1.34%), and 27 with fistulas (0.35%). The frequency of the coronary artery anomalies was significantly higher in the females than the males (p = 0.001). Of the coronary artery origin anomalies, the circumflex and the left anterior descending artery originating from separate ostia in the left aortic sinus were higher in the females compared to the males (P < 0.001). In contrast, the frequency of myocardial bridges was higher in the males (P = 0.01). No gender difference was detected in fistulas. Thus, gender affects the types of coronary artery anomalies, except for fistulas. The determination of the presence of the coronary artery anomalies during the coronary angiography is critical for the planning of the treatment and for the proper clinical follow-up of patients.

Objective: To study the effect of 2,3,5-Trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861) on intercellular adhesion molecule 1 (ICAM-1) and P-selectin expression, leukotriene B4 (LTB4) level, and myeloperoxidase (MPO) activity 24 hours after traumatic brain injury (TBI)., Methods: This study was carried out in the laboratory of the Department of Clinical Pharmacology, Osmangazi University, Eskisehir, Turkey in 2006. Traumatic brain injury was induced in 2 sets of animals using Feeney`s weight-drop method. The first set was used to study the expression of ICAM-1, P-selectin, CD11a, and mouse anti-rat granulocyte monoclonal antibody (HIS48). The second was used to study tissue changes in LTB4 level, and MPO activity. The rats were sacrificed at 0.5, 4, 24, 48, and 72 hours post-injury., Results: Intercellular adhesion molecule (p=0.000001) and P-selectin expression (p=0.00002) peaked at 24 hours, remained high at 48 hours (p=0.00012 for ICAM-1, and p=0.00002 for P-selectin), and 72 hours (p=0.000008 for ICAM-1, p=0.0011 for P-selectin). The HIS48 intensity was significantly increased at 24-72 hours (p=0.022), while the intensity of CD11a became significant only at 72 hours (p=0.040). Myeloperoxidase activity increased notably at 24 hours (p=0.00077), and peaked at 48 hours (p=0.00001). The LTB4 increased markedly at 4 hours (p=0.000004), and peaked at 24 hours (p=0.000001). Pretreatment with AA-861 considerably suppressed the expression of ICAM-1 (p=0.0053), and P-selectin (p=0.0018) on microvascular endothelium, and lowered MPO activity (p=0.0007), and LTB4 level (p=0.008) at 24 hours., Conclusion: The present results suggest that AA-861 might be a potential mediator in the treatment of brain inflammation in TBI.

Extracorporeal shockwave lithotripsy (SWL) has remained the preferred method of treatment of urinary stones since its introduction in 1980. Although SWL is classified as a potential first-line treatment for renal stones smaller than 2 cm and its overall success rate is higher than 85% for stone clearance, not all renal calculi are successfully fragmented after SWL. Among the urinary stones, calcium oxalate monohydrate (COM) stone is one of the hardest stones to fragment. Several factors interfering with stone fragility are known to exist. In addition to technical properties for SWL to increase the quality and rate of stone disintegration, the composition of stones such as trace element levels may also interfere with the efficacy of SWL. Therefore, in the present study, we aimed to elucidate the correlation, if it exists, between fragmentation of renal stones and their trace element (Cu, Zn, Mg, Fe, Pb, Mn, Cr) concentrations. For this purpose, the patients admitted to our department who were identified with urinary stones (740 patients) and underwent SWL sessions were evaluated prospectively. Patients having 5-20 mm of solitary COM stone in the renal pelvis were included in this study. The trace element concentrations of renal stones that were successfully fragmented with SWL (SWL-S) were compared with those that were unsuccessfully fragmented after three SWL sessions (SWL-US) and removed surgically. Our measurements showed that the concentrations of Cu, Fe, Pb, and Cr were similar in both groups; by contrast, the concentration of Zn, Mg and Mn was significantly lower in SWL-US renal stones. The present results suggest that low concentrations of Zn, Mg and Mn in COM stones appear to make them resistant to SWL fragmentation and may offer a critical distinction for the choice of a treatment program.

Objective: To investigate the incidence of the asymptomatic thyroglossal duct anomalies and to review the literature and make comments on the significance of this condition., Methods: A total of 80 cadavers were dissected in the present study. This study was carried out during 2005, where the cadavers were randomly included from the criminal laboratories of the Ministry of Justice, Republic of Turkey in Istanbul. None of the cadavers had laryngeal and cervical injuries resulting from a trauma or the cause of their death. The examined cadavers included 59 men and 21 females, and their age were ranged from 35-80 years old. The larynges were removed and fixed in 10% formalin and then dissected. The sections were examined using surgical SMZ 10 Nikon stereomicroscope. We evaluated the presence, localization, and diameter of the cysts with regard to age and sex of the cadavers., Results: We observed a total of 12 different localization of thyroglossal ducts and cysts among the dissected 80 cadavers. Ten of these ducts cysts were found in males with an age range of 35-68 years and 2 in female cadavers aged 46-65 years. In 6 cases, the thyroglossal ducts and cysts were located in the left of the midline of the neck, while 3 cases were from the right of the midline, and the remaining was located on the midline of the neck. In all cases, thyroglossal ducts and cysts were complete and restricted to the infrahyoid region; all of them had connection with the hyoid bone, but not with the perichondrium of the cartilage. In addition, the thyroglossal ducts had connection with the left lobe of the thyroid glands in 3 cases, one case in the right lobe, and 2 cases with the isthmus of the thyroid gland. Finally, in 5 cases thyroglossal ducts were complete and had well-developed cysts., Conclusion: Thyroglossal duct remnants are one of the most often seen congenital asymptomatic masses of the neck region (7%). The presence of these duct remnants may lead to abnormal phonation and epithelial carcinomas. Therefore, correlation of the rate of thyroglossal duct remnants in a population together with the related clinical symptoms can lead to an early diagnosis and better treatment chances for these problems.

It is believed that Ag in immune complexes (ICs) on follicular dendritic cells (FDCs) selects high affinity B cells and promotes affinity maturation. However, selection has been documented in the absence of readily detectable ICs on FDCs, suggesting that FDC-ICs may not be important. These results prompted experiments to test the hypothesis that IC-bearing murine FDCs can promote high affinity IgG responses by selecting B cells after stimulating naive IgM(+) cells to mature and class switch. Coculturing naive lambda(+) B cells, FDCs, (4-hydroxy-3-nitrophenyl)acetyl-chicken gamma-globulin (CGG) + anti-CGG ICs, and CGG-primed T cells resulted in FDC-lymphocyte clusters and production of anti-4-hydroxy-5-iodo-3-nitrophenyl acetyl. Class switching was indicated by a shift from IgM to IgG, and affinity maturation was indicated by a change from mostly low affinity IgM and IgG in the first week to virtually all high affinity IgG anti-4-hydroxy-5-iodo-3-nitrophenyl acetyl in the second week. Class switching and affinity maturation were easily detectable in the presence of FDCs bearing appropriate ICs, but not in the absence of FDCs. Free Ag plus FDCs resulted in low affinity IgG, but affinity maturation was only apparent when FDCs bore ICs. Class switching is activation-induced cytidine deaminase (AID) dependent, and blocking FDC-CD21 ligand-B cell CD21 interactions inhibited FDC-IC-mediated enhancement of AID production and the IgG response. In short, these data support the concept that ICs on FDCs can promote AID production, class switching, and maturation of naive IgM(+) B cells, and further suggest that the IC-bearing FDCs help select high affinity B cells that produce high affinity IgG.

Senescence leads to the appearance of atrophic follicular dendritic cells (FDCs) that trap and retain little immune complexes (IC), generate few memory B cells, and induce a reduced number of germinal centers (GC). Deficiencies in antibody responses to T cell dependent exogenous antigens such as pneumonia and influenza vaccines may reflect intrinsic FDC defects or altered FDC-B cell interactions. We recently studied antigen handling capacity and co-stimulatory activity of old FDCs and determined age-related changes in the expression or function of FcgammaRII or CR1 and 2 on FDCs. Here, we present an overview of FDC function in recall responses with known deficiencies in FDCs and GC development. Then, we review our recent work on aged FDCs and discuss age-related changes in molecular interactions between FDCs and B cells. We also discuss the causes underlying the impaired humoral immune response with respect to age-related molecular changes in FDC and B cell interactions. In vitro evidence suggests that FcgammaRII on aged FDCs is regulated abnormally and this in turn might cause the development of a defective FDC-network (reticulum) that retains few ICs, promotes ITIM signaling, prevents B cell proliferation and GC formation, and antibody production.

Immune complexes (IC) initiate immunoreceptor tyrosine-based inhibition motif (ITIM) signaling and inhibit B cell activation by coligating B cell receptor for antigen (BCR) and FcgammaRII. Nevertheless, IC on follicular dendritic cells (FDC) stimulate rapid germinal center (GC) B cell proliferation suggesting that interactions between IC and FDC render IC capable of B cell activation. To understand this, we studied the kinetics of FDC FcgammaRII and complement receptors 1 and 2 (CR1&2) expressions during the GC reaction and determined whether FDC FcgammaRII could bind Fc in IC and block ITIM signaling. Mice were immunized with sheep red blood cells (SRBC), and CR1&2 and FcgammaRII levels in FDC reticula were monitored. The role of FDC FcgammaRII was studied using anti-BCR-stimulated A20 cells. Levels of FDC FcgammaRII in spleens of SRBC-injected mice increased within 24 h and were dramatically increased (approximately 50-fold) on days 3 and 5. In contrast, CR1&2 levels increased less than twofold. Addition of normal FDC, but not FDC lacking FcgammaRII, reduced and reversed anti-BCR-induced SH2 domain-containing inositol phosphatase (SHIP)-1 phosphorylation in A20 cells. FDC were able to induce normal recall responses even after overnight incubation of the lymphocytes with IC to stimulate ITIM signaling. Engagement of Ig Fc with numerous FcgammaRII on FDC appears to minimize IC-induced ITIM signaling. Thus, rapid up-regulation of FDC FcgammaRII may explain why poorly immunogenic IC are rendered highly immunogenic when presented by FDC in GC.

Aging is associated with reduced trapping of Ag in the form of in immune complexes (ICs) by follicular dendritic cells (FDCs). We postulated that this defect was due to altered regulation of IC trapping receptors. The level of FDC-M1, complement receptors 1 and 2, FcgammaRII, and FDC-M2 on FDCs was immunohistochemically quantitated in draining lymph nodes of actively immunized mice for 10 days after Ag challenge. Initially, FDC FcgammaRII levels were similar but by day 3 a drastic reduction in FDC-FcgammaRII expression was apparent in old mice. FDC-M2 labeling, reflecting IC trapping, was also reduced and correlated with a dramatic reduction in germinal center (GC) B cells as indicated by reduced GC size and number. Nevertheless, labeling of FDC reticula with FDC-M1 and anti-complement receptors 1 and 2 was preserved, indicating that FDCs were present. FDCs in active GCs normally express high levels of FcRs that are thought to bind Fc portions of Abs in ICs and minimize their binding to FcRs on B cells. Thus, cross-linking of B cell receptor and FcR via IC is minimized, thereby reducing signaling via the immunoreceptor tyrosine-based inhibition motif. Old FDCs taken at day 3, when they lack FcgammaRII, were incapable of preventing immunoreceptor tyrosine-based inhibition motif signaling in wild-type B cells but old FDCs stimulated B cells from FcgammaRIIB(-/-) mice to produce near normal levels of specific Ab. The present data support the concept that FcR are regulated abnormally on old FDCs. This abnormality correlates with a reduced IC retention and with a reduced capacity of FDCs to present ICs in a way that will activate GC B cells.

Morphological and kinetic studies of immune complex (IC) trapping by follicular dendritic cells (FDC) show marked age-related deficits. We postulated that a reduction in trapped IC, which generate CD21 ligands (L) on FDC, would lead to inadequate FDC-Ag-B cell interactions resulting in depressed Ab responses. To determine whether the age-related defect was the result of the aging of FDC or changes in the in vivo microenvironment of FDC (i.e. aging B and T cells), FDC-B cell-T cell-Ag interactions were studied in in vitro germinal centers where various combinations of old and young cells could be compared. Since we reasoned that reduced IC on FDC would generate less CD21L needed to stimulate the B cell co-receptor via CD21, we also examined the role of complement (C'). The hypothesis that aging reduces the accessory activity of FDC was tested with increasing numbers of FDC from young (12 weeks) or old (20 months) mice in the presence of young (12 weeks) B and T lymphocytes. The Ag-specific stimulatory activity of FDC was studied using the OVA-specific Ab response which was reduced by 40-50% in the presence of old FDC. Antigen-independent FDC-mediated co-stimulation was studied by using LPS to stimulate B-lymphocytes to produce immunoglobulin (Ig). In the presence of old FDC, co-stimulation was decreased by 70-80% in the LPS system. Incubation of aged FDC with IC and C' to provide FDC with CD21L restored co-stimulatory activity to near normal levels. In marked contrast, no defects in old B and T cells were apparent. The data suggest that the Ag handling capacity and co-stimulatory activity of old FDC become defective with aging and this appears to be a consequence of reduced trapping and presentation FDC-Ag and CD21L to B cells.

Follicular dendritic cells (FDCs), as accessory cells to B cells, promote germinal center (GC) development. Age-related defects in the role of FDCs are well documented in vivo. In old mice, FDCs bind fewer immune complexes (ICs) and produce few iccosomes for endocytosis by B cells, antigen processing, and presentation to T cells. We recently studied whether these defects are due to changes in the FDC microenvironment or to changes in FDCs and their surface molecules. In vitro evidence suggests that age-related defects in both B cell stimulation via the BCR and co-stimulation via CD21/CD21L are related to IC-trapping by FDCs in vivo-a defect which is repairable, at least, in vitro.

Follicular dendritic cells (FDCs) represent a unique cell population of antigen trapping cells restricted to follicles within the secondary lymphoid tissues. FDCs appear to be involved in the formation of primary follicles during the ontogeny of lymphoid tissue. We sought to determine the kinetics and tissue distribution of cells in the spleen of newborn mice expressing various differentiation antigens restricted to FDCs using immunohistochemistry with monoclonal antibodies (mAb) against FDCs and in vivo immune complex binding and retention. The earliest FDC-specific marker displayed was the antigenic determinant recognized by the FDC-M1 mAb, which was detectable by Day 3 prior to follicle formation on cells located around the peripheral part of the developing white pulp. The appearance of CD21/35 (complement receptor Type 2 and 1, CR1.2) was observed at the end of the first week, revealing a focal pattern in B-cell-rich areas. In addition, at that time there were some FDC-M1-positive cells in the nonfollicular part of the periarteriolar region. The administration of anti-horseradish peroxidase antibody followed by soluble antigen HRP into 7-day-old newborn mice resulted in the trapping and retention of immune complexes onto FDCs even in the absence of Fcgamma receptors. The appearance of another FDC-specific marker, FDC-M2, was observed during the second week after birth and was restricted on the cells located in the same area as CR1.2 cells. The Fcgamma receptor Type II appeared on FDCs after the second postnatal week. The above sequence of phenotypic maturation could also be observed in newborns after lethal irradiation at Day 3. This indicates that not only mature FDCs but also their precursors are highly radioresistant, and their phenotypic maturation follows a programmed path that requires only a small number of mature B cells.