Familial and constitutional bleeding disorder due to platelet cyclo-oxygenase deficiency

Three family members from two successive generations had a bleeding tendency. Their template bleeding time was prolonged and platelet aggregation induced by ADP and adrenaline showed no second wave; collagen at low to moderate concentrations failed to aggregate and release ATP, whereas higher amounts aggregated and released. Aggregation and release due to thrombin, ristocetin, and synthetic epoxy derivatives (U 44069 and U 46619) were normal. Arachidonate (AA) was inactive, and was not converted either in thromboxane (TX) A2 activity evaluated on the rabbit aorta strip, nor in TXB2 evaluated by radioimmunoassay and by radiochromatography. The parallel impairment of TXB2 and PGE2 formation by the patient's platelets are compatible with a platelet cyclo-oxygenase deficiency. This study suggests that transmission is autosomal dominant, and confirms that cyclo-oxygenase is not needed for aggregation and ATP release by high amounts of collagen.     

Development of Dietary Patterns Spanning Infancy and Toddlerhood: Relation to Body Size,Composition and Metabolic Risk Markers at Three Years

Little is known about the development of dietary patterns during toddlerhood and the relation to growth and health. The study objective was to characterise the development of dietary patterns from 9–36 mo of age and investigate the association to body size, body composition and metabolic risk markers at 36 mo. Food records were filled out at 9, 18 and 36 mo of age (n = 229). Dietary patterns were identified by principal component analysis (PCA). Three dietary patterns were identified: Transition Food, Healthy Food and Traditional Food. The course of development in dietary patterns from 9–36 mo indicated tracking for a relatively large group of participants in the three patterns. Transition Food and Healthy Food were associated with some of the investigated outcomes. Children with lower adherence to the Transition Food pattern than average at 18 and 36 mo irrespectively of intake at 9 mo had higher BMI z-scores at 36 mo. Similar trend was identified for higher fat mass indices. Children with lower adherence to the Healthy Food pattern than average at all three ages compared to children with higher adherence to the Healthy Food pattern at the first two registrations, 9 and 18 mo had higher total cholesterol and LDL. Hence, this could represent undesirable development of dietary patterns in toddlers. In conclusion, development of dietary patterns can be exploratory characterised by PCA and related to potential cardiovascular risk markers in toddlers even within a relatively homogeneous population with a high socioeconomic status. The tracking of dietary patterns from 9 mo of age indicates a need for early and sustained promotion of healthy diets.     

运动障碍疾病与脑内金属铜、铁、钙沉积

在过去的20年,金属及其代谢过程对神经疾病的影响引起了神经科学家的极大兴趣。近年来大量文献报道,铁、铜、锰和锌作为重要的神经化学因子与目的蛋白相互作用导致了与疾病病理生理密切相关的反应。     

Murine myeloid progenitor responses to GM-CSF and eosinophil precursor responses to IL-5 represent distinct targets for downmodulation by prostaglandin E(2)

1. Because Prostaglandin E(2) (PGE(2)) and dibutiryl cyclic AMP (dbcAMP) modulate the production and effects of haemopoietic cytokines in allergy, we examined their ability to modulate responses of myeloid progenitors to GM-CSF, and of eosinophil precursors to IL-5. 2. The ability of PGE(2), dbcAMP, rolipram, forskolin, dbcGMP and PGD(2), to modulate the responses to GM-CSF and IL-5 in colony formation (progenitor) and eosinophil differentiation (precursor) assays using bone-marrow from nonsensitized or from intranasally-challenged, ovalbumin-sensitized mice of five strains was studied. 3. PGE(2) (10(-7) M) inhibited GM-CSF-stimulated colony formation in bone-marrow from BP-2 mice. This effect was duplicated by dbcAMP (0.3 - 1x10(-6) M), Rolipram (10(-5) M) and forskolin (3x10(-5) M), but not Prostaglandin D(2) (10(-6) M). Inhibition affected similarly all myeloid colony types. Progenitors from sensitized and challenged BP-2 mice were also inhibited by PGE(2) and cyclic AMP. PGE(2) inhibited progenitors from C57BL/10, CBA/J and A/J, but not BALB/c mice. However, BALB/c progenitors were sensitive to dbcAMP and Forskolin (10(-4) M). In contrast, in precursor assays, PGE(2) (10(-7) - 10(-9) M) blocked responses to IL-5 in bone-marrow from BP-2 and BALB/c mice, either na?ve or sensitized and challenged, to a similar extent. PGD(2) (10(-6) M) was ineffective, as was PGE(2) (10(-7) M), if added after 48 h of culture. 4. In conclusion, PGE(2) inhibits the responses of bone-marrow myeloid progenitors to GM-CSF and of eosinophil precursors to IL-5, in na?ve or ovalbumin sensitized and challenged mice. These effects are duplicated by cyclic AMP-elevating agents. In the BALB/c strain, the resistance of progenitors, but not precursors, to PGE(2) inhibition, indicates these developmental stages are separate targets for PGE(2) modulation.     

Upregulation by glucocorticoids of responses to eosinopoietic cytokines in bone-marrow from normal and allergic mice

Since the production of eosinopoietic cytokines (GM-CSF, IL-3, IL-5) is inhibited by glucocorticoids, while responsiveness to these cytokines is enhanced in bone-marrow of allergic mice, we studied the ability of glucocorticoids to modulate murine bone-marrow eosinopoiesis. Progenitor (semi-solid) and/or precursor (liquid) cultures were established from bone-marrow of: (a) normal mice; (b) ovalbumin-sensitized and challenged mice or (c) dexamethasone (1-5 mg kg(-1)) injected mice. Cultures were established with GM-CSF (2 ng ml(-1)) or IL-5 (1 ng ml(-1)), respectively, alone or associated with dexamethasone, hydrocortisone or corticosterone. Total myeloid colony numbers, frequency and size of eosinophil colonies, and numbers of eosinophil-peroxidase-positive cells were determined at day 7. In BALB/c mice, dexamethasone (10(-7) M) increased GM-CSF-stimulated myeloid colony formation (P = 0.01), as well as the frequency (P=0.01) and size (P<0.01) of eosinophil colonies. Dexamethasone (10(-7) M) alone had no effect. Dexamethasone (10(-7)-10(-10) M) increased (P<0.002) eosinophil precursor responses to IL-5. Potentiation by dexamethasone was still detectable: (a) on low density, immature, nonadherent BALB/c bone-marrow cells, (b) on bone-marrow from other strains, and (c) on cells from allergic mice. Hydrocortisone and corticosterone had similar effects. Dexamethasone administered in vivo, 24 h before bone-marrow harvest, increased subsequent progenitor responses to GM-CSF (P = 0.001) and precursor responses to IL-5 (P<0.001). These effects were blocked by RU 486 (20 mg kg(-1), orally, 2 h before dexamethasone, or added in vitro at 10 microM, P<0.001). Glucocorticoids, acting in vivo or in vitro, through glucocorticoid receptors, enhance bone-marrow eosinopoiesis in na?ve and allergic mice.     

Initial Management of Burns

Burns is a preventable tragedy, which is unfortunately still common in India. The possibility of disfigurement, death and emotional trauma as a result of burns is a shattering experience to the victim as well as his/her family. Proper initial management can salvage many such unfortunate victims. Burns patients require close monitoring, barrier nursing and sympathetic attitude of medical and paramedical staff in a burns ICU to have a reasonable chance of survival.Key Words: Burns, Inhalation injury, Resuscitation, Wound management     

High-resolution real-time ultrasonography of thyroid nodules

High-resolution real-time ultrasonography was used to evaluate 98 patients with palpable abnormalities of the thyroid and positive isotopic studies. It confirmed 37 of 73 (51%) suspected solitary nodules. Of 25 patients thought to have multinodular goiter, sonography was supportive in 21 (84%). In patients with adenoma or adenomatous nodules, characteristic features included a sonolucent "halo". Colloid nodules tended to be more sonolucent than normal thyroid tissue, whereas Hashimoto thyroiditis was characterized by an enlarged gland and decreased echogenicity.     

Involvement of leukotrienes and PAF-acether in the increased microvascular permeability of the rabbit retina

The effects of intravenous injection of PAF-acether and of leukotrienes LTB₄ and LTD₄ on rabbit retina were determinedin vivo in the unanaesthetized animal. PAF-acether induced an intense ischemia accompanied by a marked plasma leakage. The extravasation remained both in the platelet-depleted rabbit where a sludge phenomenon appeared and in the reserpine-treated animal. Prostacyclin injected after PAF-acether restored only partially the normal retinal appearance.The effect of LTC₄ and LTD₄ was markedly less intense than PAF-acether which is not too surprising in this species, given the previous results.     

Airway administration of Escherichia coli endotoxin to mice induces glucocorticosteroid-resistant bronchoconstriction and vasopermeation

The effects of the administration of Escherichia coli endotoxin (lipopolysaccharide, LPS) into the airways of C57Bl/6 mice were studied. Neutrophil sequestration in the lungs and their enrichment, together with tumor necrosis factor (TNF)-alpha, in bronchoalveolar lavage fluid (BALF) were associated with bronchoconstriction and bronchopulmonary hyperreactivity (BHR) to methacholine and alveolocapillary dysfunction. Granulocyte depletion by the myelotoxic drug vinblastine failed to modify TNF-alpha production and prevented LPS-induced neutrophil recruitment to lungs and BALF, bronchoconstriction, and BHR. Neutrophils were again sequestered in the lungs when LPS was administered 4 to 5 d after vinblastine, whereas inhibition of their passage to BALF persisted. Under those conditions, bronchoconstriction and BHR by LPS also recovered, showing that these functional effects are independent from BALF neutrophil enrichment but require lung sequestration. Administration of granulocyte colony-stimulating factor after vinblastine counteracted its effects and allowed the recovery of lung neutrophil sequestration by LPS and a partial recovery of bronchoconstriction under conditions where neutrophils still failed to migrate to BALF. Dexamethasone (the phosphate salt and its free base) suppressed LPS-induced TNF-alpha generation in BALF and its neutrophil enrichment, whereas neutrophil lung sequestration, bronchoconstriction, BHR, and alveolocapillary dysfunction were marginally reduced and only so at low doses of dexamethasone, higher doses being inactive or aggravating. In situ neutrophil activation could account for LPS-induced bronchoconstriction and BHR, both of which are refractory to steroids and appear to be mediated by unrelated mechanisms, which may be relevant for acute respiratory distress syndrome, a condition for which LPS administration is used as a model.     

The pharmacology of slow reacting substance C and of arachidonic acid

Administration of nonsteroid anti-inflammatory drugs (AID) inhibits hypotension and bronchoconstriction induced by the polyunsaturated prostaglandin (PG) precursor arachidonic acid (AA) and by slow reacting substance C (SRS-C, a mixture of unsaturated fatty acids split from lecithin by snake venom phospholipase A₂). AID also prevent bronchoconstriction and secondary blood pressure fall due to bradykinin. We have studied the pharmacology of SRS-C and of AA, in order to find whether similar basic mechanisms would explain the anti-inflammatory and the anti-SRS-C/AA properties of AID. It was initially shown that SRS-C and AA released from isolated guinea-pig lungs a new putative mediator, described previously during anaphylaxis and bradykinin administration to the lungs, and named rabbit aorta contracting substance (RCS). Generation of RCS was accompanied by that of PG and both were inhibited by AID. Substances similar to RCS and to PG were also formed when SRS-C or AA were injected into blood provided by an anaesthetized dog and superfusing a cascade of isolated organs. Formation of these substances was suppressed after treatment of the dogs with AID. Further experiments demonstrated that RCS and PG were released from blood and from platelet rich plasma (PRP) incubated with AA or with SRS-C (Ferreira and Vargaftig [17], Vargaftig and Zirinis [19]), this release being equally blocked by AID. Furthermore, formation of mediators in PRP by AA was accompanied by a calcium dependent and serum independent platelet aggregation, liable as well to blockade by AID. As PGs do not induce platelet aggregation, this effect might well be due to an intermediate substance generated during the formation of PG from AA. Recent results show that in vivo and in vitro AA or SRS-C induced release of PG-like mediators, as well as AA induced platelet aggregation, are also blocked by SH agents, the most effective and specific being thioglycerol and sodium diethyldithio-carbamate. These agents have been shown to inhibit bronchoconstriction and hypotension due to AA and to SRS-C, as well as bronchoconstriction and the secondary hypotension due to bradykinin. A similar pattern of activities is displayed by AID. The hypothesized roles of phospholipase A₂, PG and PG precursors will be discussed and integrated in a general picture based on successive steps of release of mediators during inflammation.