Extremely Low Frequency Electromagnetic Fields impair the Cognitive and Motor Abilities of Honey Bees.

Extremely low frequency electromagnetic field (ELF EMF) pollution from overhead powerlines is known to cause biological effects across many phyla, but these effects are poorly understood. Honey bees are important pollinators across the globe and due to their foraging flights are exposed to relatively high levels of ELF EMF in proximity to powerlines. Here we ask how acute exposure to 50 Hz ELF EMFs at levels ranging from 20-100 µT, found at ground level below powerline conductors, to 1000-7000 µT, found within 1 m of the conductors, affects honey bee olfactory learning, flight, foraging activity and feeding. ELF EMF exposure was found to reduce learning, alter flight dynamics, reduce the success of foraging flights towards food sources, and feeding. The results suggest that 50 Hz ELF EMFs emitted from powerlines may represent a prominent environmental stressor for honey bees, with the potential to impact on their cognitive and motor abilities, which could in turn reduce their ability to pollinate crops.

Membrane skeletal alterations during in vivo mouse red cell aging. Increase in the band 4.1a:4.1b ratio.

We have examined membrane protein profiles for alterations during red blood cell aging. To obtain populations of in vivo-aged red cells, we maintained mice in a state of continuous erythropoietic suppression for up to 8 wk using serial hypertransfusion. The circulating t1/2 of red cells from mice which had been erythropoietically suppressed for 8 wk was less than 1 d compared with a t1/2 of 15 d for red cells from normal animals. The most obvious alteration in membrane proteins was an increase in the ratio of the membrane skeletal components 4.1a:4.1b from 0.3 for the normal red cell population to greater than 1 for these old cells. The 4.1a:4.1b ratio thus appears to be a useful index of red cell age. Analyses of the density profile of cells aged in the hypertransfused mice disclosed that these old cells had a density range similar to that of controls, suggesting that cell density does not increase significantly with red cell age in the mouse.

Platelets of the Wistar Furth rat have reduced levels of alpha-granule proteins. An animal model resembling gray platelet syndrome.

Rats of the Wistar Furth (WF) strain have hereditary macrothrombocytopenia (large mean platelet volume [MPV] with increased platelet size heterogeneity and reduced platelet count). Ultrastructural studies suggest that this anomaly results from erratic subdivision of megakaryocyte cytoplasm into platelets. In this study, we have examined protein profiles of platelets of WF rats for biochemical abnormalities associated with this anomaly. Marked decreases in protein bands with an Mr of 185, 57, 53, 16, 13, and 8 kd were observed in one-dimensional reduced SDS-PAGE gels in WF platelets compared with platelets of Wistar, Long Evans, and Sprague-Dawley rats. These proteins were released into the supernatant when washed platelets were treated with thrombin suggesting that they were alpha-granule proteins. These abnormalities were not present in offspring of crosses between Wistar Furth and Wistar rats; however, they were present in platelets of offspring with large MPV derived from backcrosses of (WF X Wistar) F1 males to WF females, but not in backcross offspring with normal platelet size. Immunoblotting confirmed decreased levels of thrombospondin, fibrinogen, and platelet factor 4 in WF platelets. Electron microscopic examination revealed that platelet alpha granules were usually smaller in Wistar Furth than in Wistar rats. In addition, immunogold electron microscopy demonstrated that the surface connected canalicular system of the large Wistar Furth platelets, contained dense material composed of alpha-granule proteins, not present in Wistar platelets. From these results, we conclude that the Wistar Furth rat platelet phenotype of large mean platelet volume and decreased levels of alpha-granule proteins represents an animal model resembling gray platelet syndrome. The autosomal recessive pattern of inheritance of the large MPV phenotype and platelet alpha-granule protein deficiencies suggests that a component common to both formation of platelet alpha granules, and subdivision of megakaryocyte cytoplasm into platelets, is quantitatively or qualitatively abnormal in Wistar Furth rat megakaryocytes and platelets.

A role for cyclin D3 in the endomitotic cell cycle.

Platelets, essential for thrombosis and hemostasis, develop from polyploid megakaryocytes which undergo endomitosis. During this cell cycle, cells experience abrogated mitosis and reenter a phase of DNA synthesis, thus leading to endomitosis. In the search for regulators of the endomitotic cell cycle, we have identified cyclin D3 as an important regulatory factor. Of the D-type cyclins, cyclin D3 is present at high levels in megakaryocytes undergoing endomitosis and is markedly upregulated following exposure to the proliferation-, maturation-, and ploidy-promoting factor, Mpl ligand. Transgenic mice in which cyclin D3 is overexpressed in the platelet lineage display a striking increase in endomitosis, similar to changes seen following Mpl ligand administration to normal mice. Electron microscopy analysis revealed that unlike such treated mice, however, D3 transgenic mice show a poor development of demarcation membranes, from which platelets are believed to fragment, and no increase in platelets. Thus, while our model supports a key role for cyclin D3 in the endomitotic cell cycle, it also points to the unique role of Mpl ligand in priming megakaryocytes towards platelet fragmentation. The role of cyclin D3 in promoting endomitosis in other lineages programmed to abrogate mitosis will need further exploration.

Role of the distal half of the c-Mpl intracellular domain in control of platelet production by thrombopoietin in vivo.

The cytokine thrombopoietin (TPO) controls the formation of megakaryocytes and platelets from hematopoietic stem cells. TPO exerts its effect through activation of the c-Mpl receptor and of multiple downstream signal transduction pathways. While the membrane-proximal half of the cytoplasmic domain appears to be required for the activation of signaling molecules that drive proliferation, the distal half and activation of the mitogen-activated protein kinase pathway have been implicated in mediating megakaryocyte maturation in vitro. To investigate the contribution of these two regions of c-Mpl and the signaling pathways they direct in mediating the function of TPO in vivo, we used a knock-in (KI) approach to delete the carboxy-terminal 60 amino acids of the c-Mpl receptor intracellular domain. Mice lacking the C-terminal 60 amino acids of c-Mpl (Delta60 mice) have normal platelet and megakaryocyte counts compared to wild-type mice. Furthermore, platelets in the KI mice are functionally normal, indicating that activation of signaling pathways connected to the C-terminal half of the receptor is not required for megakaryocyte differentiation or platelet production. However, Delta60 mice have an impaired response to exogenous TPO stimulation and display slower recovery from myelosuppressive treatment, suggesting that combinatorial signaling by both ends of the receptor intracellular domain is necessary for an appropriate acute response to TPO.

Shortened platelet survival as a cause of thrombocytopenia in mice with L1210 leukemia.

Thrombocytopenia is a frequent complication of acute leukemias of humans and animals. To define the possible causes of this decrease in platelets, we have studied platelet kinetics in mice after transplantation of 10(6) ascites cells from mice bearing L1210 leukemia. The circulating half-time of 51Cr-labeled platelets was reduced to approximately one-half that of controls when studied 1 or 3 days posttransplantation. Recovery of transfused 51Cr-labeled platelets was reduced to approximately one-half that in controls when studied 3 days after introduction of L1210 cells. Megakaryocyte concentration showed no change during the 5-day survival after i.v. infusion of leukemic cells but was increased on Day 5 and i.p. inoculation with an average host survival of 7 days. Megakaryocyte diameter distributions were significantly shifted toward larger sizes beginning on Day 2 after i.v. inoculation and on Day 3 after i.p. inoculation. Twenty-four-hr [3H]thymidine labeling indices of megakaryocytes were significantly increased beginning on Day 3 after i.v. inoculation but were significantly decreased on Days 5 and 6 after i.p. introduction of L1210 cells. We conclude that the decrease in platelets in mice transplanted with L1210 leukemia results primarily from shortened platelet survival and organ pooling. Megakaryocytes remain normal in concentration but increase in size, a usual response to decreases in platelet count.

Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia.

Eleven consecutive leukemia patients with thrombosis induced by asparaginase-prednisone-vincristine therapy were studied to gain insight into the pathogenesis of this complication. Measurement of anti-thrombin III, plasminogen, factor V, and fibrin degradation products as well as platelet aggregation sensitivity to adenosine diphosphate disclosed no consistent abnormalities that would explain pathologic thrombus formation. A decrease in platelet counts observed in nine of 11 patients, prompted us to investigate the possible involvement of factor VIII in this disorder. Levels of factor VIII procoagulant activity, von Willebrand factor (vWF) and ristocetin cofactor were similar to findings for an identically treated comparison group who remained free of thrombotic complications. However, qualitative examination of vWF by crossed immunoelectrophoresis (CIE) revealed a distinct right shift of the immunoprecipitin lines in each of three thrombotic patients tested, whereas a normal profile was found in three similarly treated patients without the complication. This altered pattern had reverted to normal when CIE was repeated 2 to 7 months later. We postulate that the abnormal vWF is related to the development of thrombosis.

Sequential changes in platelet function and coagulation in leukemic children treated with L-asparaginase, prednisone, and vincristine.

Coagulation and platelet function in 13 children with acute lymphoblastic leukemia were studied sequentially during a remission induction with L-asparaginase, prednisone, and vincristine. In the first weeks of therapy, which included four doses of L-asparaginase coagulation was characterized by significant decreases in plasma concentrations of plasminogen, antithrombin III alpha 2-macroglobulin, and fibrinogen. All measures gradually returned to normal after complication of L-asparaginase therapy. In the latter part of induction treatment, clotting times, especially partial Thromboplastin time, decreased significantly, while levels of factors V and VIII increased with recovery of platelet counts. At this time, 6 patients had an increased in vitro platelet aggregation response to adenosine diphosphate, and their partial thromboplastin times were significantly shorter than those of patients without increased aggregation. Concurrent abnormalities in coagulation and platelet function may account for the thrombotic complications that develop in some children receiving induction therapy with these agents.

Normal platelet function after therapy for acute lymphocytic leukemia.

The aggregation responses of platelets from 19 patients who had completed treatment of acute lymphocytic leukemia (ALL) and had remained in remission for two months to 4.8 years were studied both in vitro and in vivo. Responses to 0.5 micro M adenosine diphosphate (ADP), epinephrine, and collagen were all normal. One child had irreversible platelet aggregation to 0.1 micro M ADP, a concentration that only elicited a primary aggregation response from control platelets. The mean platelet-aggregate ratio was normal. We conclude that platelet defects, although a possible late effect of ALL or its chemotherapy, do not occur with any appreciable frequency in long-term survivors.

The role of genotype, genomic imprinting, and sex hormones in platelet and megakaryocyte production.

Our previous data suggested that the higher average ploidy of C3H mouse megakaryocytes is the result of interaction of multiple alleles that act in an additive fashion. Average megakaryocyte DNA content increased with the proportion of C3H genotype. Other factors also influence megakaryocyte ploidy; male mice had megakaryocytes of higher ploidy than did female mice, and the genes that determine megakaryocyte ploidy had a differential expression, depending on the sex of the parent, a finding that suggests genomic imprinting. The role of genotype (and, thus, megakaryocyte DNA content) on other parameters of platelet production and megakaryocytopoiesis has not been examined. Therefore, we report the effects of genotype on platelet counts, platelet sizes, percent 35S incorporation into platelets, total circulating platelet counts (TCPC), total circulating platelet masses (TCPM), megakaryocyte size and number, and total megakaryocyte masses (TMM). Platelet counts of male mice were inversely related to the proportion of C3H genotype. In other words, male mice with a higher proportion of C3H genotype had lower platelet counts than did male mice with predominantly C57BL genotype (p = 0.04). None of the other platelet production indices were significantly correlated with the C3H genotype content of the offspring. However, a significantly positive correlation (p < 0.0001 for males and p < 0.003 for females) was found between megakaryocyte size and megakaryocyte ploidy. Although no significant difference in megakaryocyte numbers was noted, TMM of male mice was positively correlated (p < 0.05) with megakaryocyte ploidy. Male mice had higher platelet counts, percent 35S incorporation into platelet values, TCPC, and TCPM than did female mice, but platelet sizes were the same for both sexes. Megakaryocyte sizes, numbers, and TMM were higher in male than female offspring of some matings, but in several cases, sex did not appear to affect these parameters. Previous work has shown that this difference in platelet production capabilities due to sex of the mouse is most likely caused by male sex hormones. Evidence of different genetic expression (genomic imprinting), depending on the sex of the parent, was found in platelet counts and TCPC of certain backcrosses of female mice and in platelet sizes of male mice (p < 0.05). Therefore, we show that genotype, male sex hormones, and genomic imprinting influence platelet production in mice, but platelet counts of male mice were negatively correlated with size and DNA content of megakaryocytes.

Thrombopoietin derived from human embryonic kidney cells stimulates an increase in DNA content of murine megakaryocytes in vivo.

A thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) is known to increase the size and number of mouse bone marrow megakaryocytes, to increase the proportion of megakaryocytes in endomitosis, and to increase the number of small acetylcholinesterase-positive cells. Megakaryocyte ploidy values have not previously been measured in mice treated with TSF from human embryonic kidney (HEK) cells. Therefore, in the present study C3H mice were injected with approximately 4 U of step II TSF; platelet production indices and megakaryocyte ploidy values were measured 1-5 days after treatment. For controls, other mice were injected with saline, human serum albumin (HSA), normal rabbit serum (NRS), or rabbit anti-mouse platelet serum (RAMPS). Platelet counts, platelet sizes, and percent 35S incorporation into platelets were measured using standard techniques. For measurement of megakaryocyte DNA content, bone marrow cells were collected into CATCH medium and incubated with RAMPS, followed by labeling with a saturating concentration of fluorescein-conjugated goat anti-rabbit immunoglobulin F(ab')2 fragment. After washing, the cells were resuspended in propidium iodide, and DNA content was measured by flow cytometry. When compared to suitable control values, the results showed that TSF caused a significant (p less than 0.025) increase in platelet counts of treated mice by 3 days; both TSF and RAMPS caused significant (p less than 0.0005) increases in platelet sizes and percent 35S incorporation into platelets of mice at 2 and 3 days after treatment. The most frequent polyploid DNA class of megakaryocytes from untreated C3H mice was 32N, confirming our previous observation. Both TSF and RAMPS caused significant (p less than 0.0005) increases in the average polyploid megakaryocyte DNA content, with peak values on days 2 and 3. These data show that TSF administered in vivo significantly increases DNA content of mouse bone marrow megakaryocytes.

Increase in circulating megakaryocyte growth-promoting activity (Meg-GPA) following sublethal irradiation is not related to decreased platelets.

In this study, we have used the sublethally irradiated rat as a model to examine the relationship between platelet count and the plasma level of megakaryocyte growth-promoting activity (Meg-GPA) assayed in vitro. Meg-GPA of irradiated rats whose platelet counts were maintained by platelet transfusions was compared to that of irradiated controls allowed to develop thrombocytopenia. The irradiated controls were given either saline, packed red cells, or no other treatment. Blood values were determined and plasma was collected from all groups 11 days after irradiation, predetermined to be the nadir of platelet count and the peak of Meg-GPA. The Meg-GPA of plasma was assayed by culturing in vitro at a final concentration of 30% with rat marrow in methylcellulose and 2-mercaptoethanol for 7 days at 37 degrees C. Plasma from platelet-transfused irradiated rats, when collected at ambient temperature, contained markedly decreased levels of Meg-GPA compared to that present in plasma of irradiated controls. Subsequent in vitro studies indicated that elevated Meg-GPA levels of plasma from irradiated thrombocytopenic rats were drastically reduced by incubation with platelets in vitro at 37 degrees C. Incubation of the same plasma with platelets at 4 degrees C resulted in much less reduction in Meg-GPA. This suggested that the diminished Meg-GPA observed with plasma from the platelet-transfused irradiated rats may have been due to activation and release of Meg-GPA inhibitors from platelets during plasma collection. To investigate this possibility, experiments were repeated in which platelets of irradiated rats were maintained by platelet transfusion, but plasma was collected at 4 degrees C. Under these conditions, the level of Meg-GPA in plasma of the platelet-transfused irradiated rats was not markedly different from that in plasma of irradiated controls. We conclude that in this experimental model, circulating Meg-GPA level is not related to platelet count.

A schedule of recombinant Mpl ligand highly effective at preventing lethal myelosuppression in mice given carboplatin and radiation.

OBJECTIVE: To determine a thrombopoietin schedule that would effectively enhance hematopoiesis and prevent death in mice after lethal myelosuppression. METHODS: First, we determined whether recombinant Mpl ligand (Mpl-L) has a priming effect on thrombopoiesis in normal mice. Mice were given pegylated recombinant murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF) intravenously as a single injection or as two injections separated by intervals of 1 to 10 days. Second, we examined the scheduling of PEG-rmMGDF that would most effectively reduce thrombocytopenia in mice given a lethal myelosuppressive regimen (80 mg/kg carboplatin + 750 R Cs-137 total-body irradiation). RESULTS: In normal mice, peak platelet count with a 4-day to 8-day interval between PEG-rmMGDF injections was significantly higher than that with single injection. This priming effect was optimal with a 4-day interval between injections. In the lethal myelosuppression model, all mice given intravenous PEG-rmMGDF as a single injection on day 0 or as two injections (on days -4 and 0 or on days 0 and 4) survived; PEG-rmMGDF on day 0 was given immediately after the myelosuppressive regimen. In contrast, all mice given a single intravenous PEG-rmMGDF injection on day -4 or day 4 died. Two PEG-rmMGDF injections given on days -4 and 0 enhanced hematopoietic recovery more than did a single injection on day 0 or two injections on days 0 and 4. CONCLUSION: Mpl-L administration immediately after lethal carboplatin and radiation prevents death and enhances hematopoietic recovery in mice; this protective effect is further enhanced by a priming Mpl-L dose given 4 days before the myelosuppressive regimen.

Comparison of platelet production in two strains of mice with different modal megakaryocyte DNA ploidies after exposure to hypoxia.

Thrombocytopenia develops with prolonged exposure to hypoxia. Although decreases in megakaryocyte numbers due to hypoxia have been well documented, the effects of hypoxia on megakaryocyte DNA content have not been reported. In this study, megakaryocytopoiesis and platelet production were compared in both C3H mice (whose megakaryocyte modal ploidy class is 32N) and C57/BL mice (whose modal ploidy class is 16N), by enclosure in cages covered with silicone-rubber membranes. After equilibration, O2 levels inside the cages were 6%-7%. Hematocrits, platelet counts, platelet sizes, percent 35S incorporation into platelets, megakaryocyte size and number, and megakaryocyte DNA content of mice were measured before and at various days after hypoxia. Although hematocritis increased and platelet counts decreased in both strains of mice with time in hypoxic chambers, megakaryocyte and platelet responses of C3H mice differed from those of C57/BL mice in several respects; hematocrits of C3H mice were higher and platelet counts were lower than those in C57/BL mice. C3H mice produced larger platelets than C57/BL mice in response to hypoxia. Total circulating platelet counts (TCPC) and total circulating platelet masses (TCPM) of both mouse strains showed similar biphasic responses, that is, elevated TCPC and TCPM on days 2-4 and decreased values after 6-14 days of hypoxia. However, hypoxic C3H mice had lower TCPC on days 4-14 and lower TCPM on days 10-14 of hypoxia than C57/BL mice. Both C3H and C57/BL mice had decreased megakaryocyte numbers at 6-10 days of hypoxia, but only C3H mice had decreased numbers of megakaryocytes at day 14. Elevated megakaryocyte size was observed in both mouse strains at day 14 of hypoxia. However, after hypoxia, C3H mice showed a greater depression in megakaryocyte number and a larger increase in megakaryocyte sizes than did C57/BL mice. C3H mice maintained 32N as the modal megakaryocyte DNA content through day 10 of hypoxia, but 64N was the modal megakaryocyte DNA content at day 14; 16N remained the modal megakaryocyte DNA content in hypoxic C57/BL mice. Hypoxic C3H mice had an increase in 16N megakaryocytes after 6 days of hypoxia, followed by an increase in the proportion of 64N cells at 14 days compared to values of untreated C3H control mice. Hypoxic C57/BL mice had an increased proportion of 16N cells at 6 days but a decreased proportion of 32N cells at 14 days. These studies demonstrate that the decreased platelet production resulting from prolonged exposure to hypoxia is primarily the result of decreased differentiation of hematopoietic precursors into the megakaryocyte lineage rather than decreased megakaryocyte DNA content, because higher ploidy classes actually increase as thrombocytopenia becomes more severe. Stem cell competition could explain the findings of reduced platelet production and increased red blood cell production in both strains of mice after exposure to hypoxia.

Possible dihydroepiandrosterone-induced mania.

BACKGROUND: Dehydroepiandrosterone (DHEA) is among the most abundant steroids in the human body and appears to have diverse biochemical activities. This multifunctional hormone has long been a compound of interest to research psychiatrists. Its recent promotion and availability as an over-the-counter supplement to the general public has led to widespread use. Little is known about potential adverse effects of DHEA when consumed on an acute or chronic basis. We report a case of mania in an older man acutely admitted to our psychiatric facility with no previous personal or family history of bipolar disorder that appeared to be related to recent DHEA use. The patient had initiated DHEA use 6 months prior to admission and was taking 200-300 mg/day at the time of presentation. METHODS: He was treated with valproic acid 500 mg twice daily. RESULTS: The patient showed sufficient improvement to be discharged following a 7-day inpatient hospitalization. CONCLUSIONS: A wide range of medications have been associated with the induction of hypomania and mania, and we have provided a brief discussion of the potential for DHEA to trigger manic symptoms.

AlphaIIbbeta3-mediated outside-in signaling induced by the agonist peptide LSARLAF utilizes ADP and thromboxane A2 receptors to cause alpha-granule secretion by platelets.

The peptide LSARLAF (LSA) causes alphaIIbbeta3-dependent platelet activation that results in alpha-granule secretion and aggregation. LSARLAF-induced, alphaIIbbeta3-mediated outside-in signaling causing alpha-granule secretion and platelet aggregation was studied using washed mouse platelets. ADP receptor antagonists, enzyme inhibitors, normal platelets and platelets from mice that lack either Galphaq or thromboxane (Tx) A2 receptors were used for this investigation. The results demonstrate that LSA-induced alphaIIbbeta3-mediated signaling producing aggregation of washed platelets is mediated through the release of ADP and thromboxane, which cause alpha-granule release by mediating their effects though Galphaq and/or Gi depending on the level of LSA used to activate the platelets. Specifically, alphaIIbbeta3 elicited aggregation of washed platelets in response to a low level of LSA requires signaling through the ADP receptor P2Y1 and Galphaq, and the ADP receptor P2Y12 and Gi as well as TxA2 receptors. However, this aggregation is independent of Galphaq and TxA2 signaling in response to high LSA concentrations, but is dependent on ADP signaling through its receptor P2Y12, and therefore presumably Gi, regardless of the level of LSA used to activate the platelets. PKC function is required for ADP secretion and the subsequent signaling through P2Y12 regardless of the level of LSA used to activate the platelets. The end point of the LSA-induced alphaIIbbeta3-mediated signaling characterized in this study is alpha-granule secretion, which provides the fibrinogen required for aggregation of washed platelets.

The roles of ADP and TXA in botrocetin/VWF-induced aggregation of washed platelets.

BACKGROUND: Binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex initiates a cascade of events leading to alphaIIbbeta3 activation and platelet aggregation. The roles of ADP and thromboxane A2 (TXA2) in agglutination-induced GPIbalpha-mediated platelet activation have not been fully described. METHODS: Botrocetin and human VWF were used to stimulate washed mouse platelets. Platelets deficient in TXA2 receptors, Galphaq, or alphaIIbbeta3, and inhibitors and chelating agents were used to investigate the roles of TXA2, ADP, alphaIIbbeta3 and Ca2+ in botrocetin/VWF-induced signaling. RESULTS: Our data demonstrate that botrocetin/VWF/GPIbalpha-mediated agglutination results in calcium-independent protein kinase C (PKC) and phospholipase A2 (PLA2) activities required for GPIbalpha-elicited TXA2 production that in turn causes dense granule secretion. Aggregation of washed platelets requires TXA2-induced alphaIIbbeta3 activation and ADP signaling. TXA2 or ADP can activate alphaIIbbeta3, but both are required for alpha-granule secretion and aggregation. Botrocetin/VWF-induced dense granule secretion is Galphaq-dependent. alpha-Granule secretion requires initial ADP signaling through P2Y1 and subsequent signaling through P2Y12. Signaling initiated by agglutination is propagated and amplified in an alphaIIbbeta3-dependent manner. CONCLUSIONS: In contrast to adhesion or shear stress-induced GPIb-elicited signaling, agglutination-elicited GPIb signaling that activates alphaIIbbeta3 requires TXA2. Agglutination-elicited TXA2 production is independent of Ca2+ influx and mobilization of internal Ca2+ stores. Therefore, our results demonstrate that agglutination-elicited GPIb signaling causes alphaIIbbeta3 activation by a mechanism that is distinct from those used by adhesion, or shear stress-induced GPIb signaling.

Prophylaxis of carbamazepine-induced hyponatremia by demeclocycline in six patients.

BACKGROUND: Hyponatremia has been reported to occur in approximately 5% of carbamazepine-treated patients who otherwise do well on that agent. Demeclocycline has been used in the treatment of hyponatremia of various etiologies including one case of carbamazepine-induced hyponatremia. METHOD: We extended these observations by studying the effects of demeclocycline on carbamazepine-induced hyponatremia in six psychiatric inpatients. RESULTS: Once serum sodium concentrations had normalized after carbamazepine discontinuation, demeclocycline prevented further decreases in sodium levels upon rechallenge with carbamazepine in five of six patients. Gender, smoking, and neurologic compromise may have played a role in the development of carbamazepine-induced hyponatremia as well as response to this strategy, although our sample size is too small to make firm conclusions. CONCLUSION: Demeclocycline was successfully used in the prophylaxis of carbamazepine-induced hyponatremia and may be useful in cases that respond best to carbamazepine treatment.

Efficacy and adverse effects of clozapine in four elderly psychotic patients.

BACKGROUND: Clozapine is an atypical antipsychotic agent that is effective in refractory schizophrenic patients. Older patients may have various psychotic manifestations that may not be responsive to typical neuroleptic therapy. There may also be patient-specific factors--declines in reserve capacity and homeostasis, and age-related changes in the pharmacokinetics and pharmacodynamics of drugs--in older patients that increase their susceptibility to the side effects of psychotropic medications. While clozapine has few extrapyramidal side effects, it has other side effects that may be problematic in the older population. METHOD: In our geropsychiatric unit, clozapine was prescribed for four patients over the age of 65 years. All patients were either experiencing psychotic symptoms refractory to other antipsychotic medications or had relative contraindications to a typical neuroleptic. Two of the four were chronic schizophrenics, and three of the four also presented with dementia. RESULTS: Two of the four patients did eventually receive relief of psychotic symptoms from clozapine. All four experienced events after initiation of clozapine therapy, which included falls (2 patients), symptomatic bradycardia (2 patients), and delirium (1 patient). All these adverse effects occurred on doses ranging from 6.25 to 37.50 mg/day, and the three patients with moderate-to-severe dementia experienced these severe adverse effects after administration of the first dose. CONCLUSION: Clozapine may be a useful drug for older patients with psychotic symptoms; however, at current dosage recommendations, adverse events may occur, especially on first dose. Well-designed studies need to be performed to assess the effectiveness and dosage ranges for this population.

Obsessive-compulsive disorder in elderly patients.

Obsessive-compulsive disorder (OCD) is a common illness which starts in young adulthood and persists into late life. OCD is associated with dysregulation of the serotonin system and may also be related to the dysregulation of dopamine. When OCD starts in an elderly patient, either an organic or a neurological diagnosis should be considered. Clomipramine and serotonin reuptake inhibitors are the mainstay of treatment for OCD. Choice of a particular agent should be based on the patient's previous response and the adverse effect profile of the drug. Pharmacokinetics should also be a consideration due to age-related changes in hepatic and renal function leading to increased plasma concentrations as well as prolonged elimination half-lives of these agents. Behavioural therapy, in addition to pharmacological management, is essential to treat compulsions and to improve response.