Emerging roles for the FCRL family members in lymphocyte biology and disease.

Members of the extended Fc receptor-like (FCRL) family in humans and mice are preferentially expressed by B cells and possess tyrosine-based immunoregulatory function. Although the majority of these proteins repress B cell receptor-mediated activation, there is an emerging evidence for their bifunctionality and capacity to counter-regulate adaptive and innate signaling pathways. In light of these findings, the recent discovery of ligands for several of these molecules has begun to reveal exciting potential for them in normal lymphocyte biology and is launching a new phase of FCRL investigation. Importantly, these fundamental developments are also setting the stage for defining their altered roles in the pathogenesis of a growing number of immune-mediated diseases. Here we review recent advances in the FCRL field and highlight the significance of these intriguing receptors in normal and perturbed immunobiology.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

[Orbital metastasis of a previously unknown lung carcinoma mimicking posterior ischemic optic neuropathy]. / Orbitale Metastase eines bis dato unbekannten Lungenkarzinoms mit klinischem Aspekt einer posterioren ischämischen Optikusneuropathie.

A 65-year-old patient presented with increasing loss of vision in the right eye. A relative afferent pupillary defect as well as visual field perimetry deficits in an otherwise unremarkable eye led to the presumed diagnosis of ischemia of the optic nerve; however, further imaging revealed an extensive necrotic bronchial carcinoma in the left upper lobe metastasizing to the orbit with compression of the optic nerve. The clinical and histological features are discussed with respect to possible primary origins of orbital metastases.

The direct vascular relaxing action of betaxolol, carteolol and timolol in porcine long posterior ciliary artery.

The vascular relaxing properties of three beta adrenoceptor antagonists, betaxolol, carteolol and timolol, currently used in the treatment of glaucoma, were characterized, compared and contrasted in the porcine long posterior ciliary artery. Isolated arterial ring segments precontracted with increased extracellular KCl (plus 40 mM) or the thromboxane analog, U-46619 (3 x 10(-7) M), were relaxed in a concentration-dependent fashion by betaxolol, carteolol, timolol or nitroprusside. In vessel segments depolarized with increased extracellular KCl, EC50 values indicated that the intrinsic relaxant sensitivity to betaxolol was equal to that of nitroprusside, six-fold greater than that of carteolol, and ten-fold greater than that of timolol. Similarly, the maximum relaxation occurring at equimolar concentrations (10(-4) M) for the beta adrenoceptor antagonists was betaxolol > carteolol = timolol. Qualitatively similar results were noted in ring segments of the rabbit external iliac artery precontracted with increased extracellular KCl (plus 30 mM). Under conditions in which specific receptor-linked events are absent and voltage-gated Ca++ entry is maximized, the Ca++ concentration response relationship in porcine long posterior ciliary artery was shifted to the right in an apparent competitive manner by betaxolol, reflecting a 5.6-fold reduction in the sensitivity to Ca++. Conversely, nitroprusside reduced the Ca++ sensitivity three-fold in a noncompetitive fashion; not only shifting the Ca++ concentration response relationship to the right, but also depressing the maximum by 57%. Porcine long posterior ciliary arterial segments precontracted to a similar degree with U-46619, in which voltage-gated Ca++ entry is only one component of many specific cell signalling transduction mechanisms contributing to the precontraction, exhibited a sensitivity to betaxolol that was six-fold less than to nitroprusside, but two-fold greater than to timolol and 20-fold greater than to carteolol. These results are consistent with an obvious direct vascular relaxing capacity for beta adrenoceptor antagonists that primarily represents a capacity for inhibiting voltage-gated Ca++ entry in vascular smooth muscle. Additionally, the differential potencies of these three beta adrenoceptor antagonists characterized in this study suggests that this property is much more likely to contribute to any potentially beneficial effects of betaxolol than carteolol or timolol.

Endocrine and exocrine effects of testicular torsion in the prepubertal and adult rat.

Previous studies of experimental torsion have suggested that there may be important differences between the adult testis and the prepubertal testis in their responses to torsion, especially with regard to the potential for contralateral damage following unilateral testicular torsion. In the present study, adult Sprague-Dawley rats and prepubertal Sprague-Dawley rats (35 days of age) were subjected to unilateral 1-, 2-, and 4-hour periods of 720 degrees or 360 degrees testicular torsion. Ipsilateral and contralateral testes were examined 30 and 60 days after torsion repair for effects on testis weight, histology, and daily sperm production (DSP). Other animals were subjected to 1-/or 4-hour 720 degrees torsion, and testicular vein testosterone concentrations were determined 30 days later. In adult animals, 1-, 2-, and 4-hour 720 degrees torsion resulted in a significant decline in ipsilateral testis weight within 30 days. Endocrine and exocrine function were also clearly disrupted. In prepubertal animals, 1-hour 720 degrees torsion significantly reduced testis weight 60 days after surgery. Also, prepubertal DSP values and testicular vein testosterone concentrations were not significantly reduced from control values by 1-hour 720 degrees torsion when examined 30 days after surgery. Longer periods of 720 degrees torsion resulted in damage similar to that seen in the adult animals. Neither adult nor prepubertal animals regained any lost function when examined 60 days after insult. Torsion of 360 degrees induced no testicular injury in adult or prepubertal animals. Contralateral testes were not affected by degree or duration of torsion in either adult or prepubertal animals. These results suggest that the prepubertal testis may be more refractory to the effects of short periods of torsion than the adult. More importantly, these results demonstrate that ipsilateral torsion does not result in contralateral testicular damage in either adult or prepubertal animals.

Pulmonary artery vasoactivity in broiler and Leghorn chickens: an age profile.

Vascular function plays a preponderant role in the pulmonary changes that occur with maturation, during birth, and in the development of pulmonary hypertension. This study was designed to characterize the changes in vasoactivity occurring in broiler and Leghorn chickens from late embryonic life to 5 wk of age. Pulmonary arteries were isolated from 19- and 20-d-old embryos, hatchlings, and 1-, 2-, 3-, 4- and 5-wk-old chickens of both lines and subjected to KCl (45.4 mM)- and endothelin-1 (10(-7.5) M)-induced vasoconstrictions followed by acetylcholine (ACh; 10(-5), 10(-6) and 10(-7) M)- and papaverine (10(-4) M)-induced vasodilations. Vasoconstrictions were greatest at hatch and rapidly declined thereafter, whereas vasodilations were greatest in 20-d-old embryos except with 10(-7) M ACh. Broilers grew faster than Leghorns and had lower vasodilation responses to all concentrations of ACh at 2 and 5 wk of age. Broilers also had greater right-to-total ventricular weight ratios at 5 wk of age, whereas ratios were greater in Leghorn embryos at 20 d of incubation and at hatch. Thus, for a brief period before hatch there is a significant increase in pulmonary endothelium-dependent vasodilation capacity in the chicken embryo, which may aid in the transition from chorioallantoic to pulmonary respiration. The absence of differences in vasodilator capacity between broilers and Leghorns before hatch suggests that the differences in pulmonary artery relaxation capacity and pulmonary hypertension observed after hatch in broilers are not necessarily acquired during incubation but may be related to rapid growth of the broiler chicken.

In vitro hypoxia differentially affects constriction and relaxation responses of isolated pulmonary arteries from broiler and leghorn chickens.

Under normoxic conditions in vitro, isolated pulmonary arteries from broilers exhibit reduced endothelium-dependent relaxation responses when compared with Leghorns. In vivo, hypoxia increases the susceptibility of broiler chickens to pulmonary hypertension syndrome (PHS), whereas Leghorns are considered resistant to PHS. Because L-arginine supplementation decreases the incidence of PHS in vivo and improves the relaxation responses of broiler isolated pulmonary arteries in vitro, we hypothesized that in vitro hypoxia would further reduce the relaxation responses of broilers to endothelium-derived nitric oxide (EDNO)-dependent vasodilators and that L-arginine supplementation would alleviate this impairment. As a test of this hypothesis, pulmonary arteries from broiler and Leghorn chickens were isolated and exposed to normoxia or hypoxia in the presence or absence of L-arginine while their constriction and relaxation responses to vasoactive compounds were recorded. In broilers, hypoxia did not affect the constriction responses of isolated pulmonary arteries but decreased EDNO-dependent acetylcholine-induced relaxation responses. In contrast, in Leghorns hypoxia increased endothelin-1-induced vasoconstriction responses and reduced the EDNO-dependent relaxation responses only to the lowest concentration of acetylcholine used. L-Arginine supplementation augmented the relaxation responses to acetylcholine in broilers and Leghorns under normoxia but failed to augment them under hypoxia. Relaxation responses to the NO donor, sodium nitroprusside, were not affected by hypoxia in Leghorns but were increased by hypoxia in broilers. These results suggest that the increased incidence of PHS in broiler chickens reared under hypoxia may be associated with a hypoxia-induced reduction in the synthesis or activity of EDNO in the pulmonary circulation.

Diffuse skeletal hyperostosis in idiopathic hypoparathyroidism.

A case of idiopathic hypoparathyroidism (IHP) is reported with extensive ligamentous and tendinous ossification and soft tissue calcification. The pertinent radiological features of IHP and the unusual findings in this case are reviewed together with similar previously reported cases. Whether IHP is a causative or aggravating factor in the aetiology of the skeletal changes is discussed with particular reference to their similarity to diffuse idiopathic skeletal hyperostosis (DISH). We conclude that, in patients with an ossifying diathesis, IHP acts as a stimulant resulting in exuberant skeletal hyperostosis that is indistinguishable from DISH.

Microvascular blood flow is altered after repair of testicular torsion in the rat.

PURPOSE: Previous studies have shown that experimental testicular torsion with a duration of 1 hr. or longer causes irreversible damage to the rat testis, but that testicular blood flow values are normal 24 hrs. after repair of torsion. More acute evaluation of return blood flow after repair of torsion has not been performed and was the topic of this study. MATERIALS AND METHODS: Laser-Doppler flowmetry was used to evaluate testicular microvascular blood flow before application of 1, 2, or 4 hr., 720 degrees torsion, during torsion, and at several time points after repair of torsion. Experiments were performed in both adult and prepubertal rats. RESULTS: Testicular torsion essentially eliminated blood flow in both adult and prepubertal testes. Considering all the flow data within each group after torsion repair, increasing time of torsion was associated with significantly less return blood flow in both adult and prepubertal animals. Interestingly, only the four hour torsion data was associated with reduced return flow in prepubertal animals while both two and four hour torsion were associated with poor return flow in adult animals. Vasomotion, or pulsatile microvascular flow, often seen before torsion in both adult and prepubertal animals, was never seen after torsion repair. CONCLUSIONS: Increasing times of torsion are associated with lower microvascular blood flow values during the hour following the relief of torsion. Vasomotion is eliminated by torsion during the period studied. Whether vasomotion returns is unknown, but altering this flow pattern might be involved in the mechanism of injury caused by acute torsion.

Effects of nicorandil on receptor-mediated Ca2+ release and Ca2+ entry in vascular smooth muscle.

In a solution containing La3+, or one without Ca2+ (Ca2+-free) and containing 1.0 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), norepinephrine (NE)-induced transient contractions in rabbit aorta attributed to Ca2+ release are depressed 31 and 38%, respectively, by an approximate ED60 relaxing concentration of nicorandil (SG-75). In addition, after 15 min in a Ca2+-free, low-EGTA (0.01 mM) solution, plus D600 to eliminate any potential-dependent Ca2+ entry, NE elicits a similar phasic response that is attenuated 34% by SG-75. Apparently, this is primarily due to inhibition of Ca2+ release rather than to stimulation of rebinding, uptake, and/or extrusion of Ca2+ following release. For, when tissues initially exposed to a Ca2+-free, low-EGTA plus D600 solution with or without SG-75 and NE are then rinsed with the same solution for 20 min to remove SG-75 and/or NE and again exposed to NE there is only a small residual maintained response in tissues not exposed to SG-75. However, in tissues that have been exposed to SG-75 prior to NE, a measurable phasic response is elicited that is approximately 50% of control NE responses. When Ca2+ is added to a Ca2+-free, low-EGTA plus D600 solution after NE-induced Ca2+ release, a rapid and significant increase in tension ensues that is well maintained and is proposed to represent specific alpha-adrenoceptor-mediated Ca2+ entry. This NE-mediated, D600-insensitive Ca2+ entry is readily inhibited or relaxed by SG-75.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary artery endothelium-dependent vasodilation is impaired in a chicken model of pulmonary hypertension.

Among chicken strains, broilers are prone to pulmonary hypertension, whereas Leghorns are not. Relaxations to endothelium-dependent (ACh, A23187) and endothelium-independent [sodium nitroprusside (SNP), papaverine (PPV)] vasodilators were compared in preconstricted pulmonary artery (PA) rings from these chicken strains. ACh (10(-7), 10(-6), and 10(-5) M)- and A23187 (10(-6) and 10(-5.5) M)-induced relaxations were smaller (P < 0.05) in broilers than Leghorns. N(G)-nitro-L-arginine methyl ester (10(-3.5) M) caused similar reductions in ACh-induced relaxations in both strains. L-Arginine (10(-4) M) enhanced ACh-induced relaxations more in broilers than Leghorns. Relaxations to 10(-10)-10(-6) M SNP did not differ between strains, but were greater (P < 0.05) in broilers than Leghorns at higher concentrations (10(-5) and 10(-4) M). PPV (10(-4) M)- and SNP (10(-4) M)-induced maximal relaxations were greater in broilers than in Leghorns (176.2 +/- 14.7 vs. 120.9 +/- 14.7% and 201.3 +/- 7.8 vs. 171.2 +/- 10.7%, respectively, P < 0.05). Broiler PA rings appear to have increased intrinsic tone and reduced endothelium-derived nitric oxide activity, both of which may contribute to the susceptibility of broiler chickens to pulmonary hypertension.