Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats.

Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3beta (GSK3beta), thereby inhibiting cell death. However, the role of Akt/GSK3beta signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5 mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3beta (Ser9) in the hippocampal CA1 subregion after tGCI. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3beta (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3beta (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of Akt and GSK3beta was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCI. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCI, had enhanced and persistent phosphorylation of both Akt and GSK3beta after tGCI. These findings suggest that activation of the Akt/GSK3beta signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCI.     

Angiotensin I-converting enzyme inhibitor improves reactive hyperemia in elderly hypertensives with arteriosclerosis obliterans.

Endothelial function in elderly hypertensive patients with arteriosclerosis obliterans has not been evaluated. We examined whether antihypertensive drugs improve vasodilatory response to reactive hyperemia of the limbs in elderly hypertensive patients (83 +/- 8 [SD] years) without (n=46, 0.9 < or = ankle-brachial pressure index < or = 1.4) and with (n=24) arteriosclerosis obliterans (ankle-brachial pressure index < 0.2). Patients were randomized for treatment with monotherapy of either temocapril (14 with and 26 without arteriosclerosis obliterans) or amlodipine (10 with and 20 without arteriosclerosis obliterans) for 6 months. Blood flows of the forearms and legs were measured by strain-gauge plethysmography. The vasodilatory response to the release of compression of the forearms and thighs at 200 mmHg or 20 mmHg more than systolic blood pressure for 5 min and to sublingual administration of nitroglycerin (0.3 mg) was assessed. The maximum reactive hyperemic flow in 35 legs with arteriosclerosis obliterans was significantly (p < 0.001) decreased compared to the value in legs in the control hypertensive subjects. Moreover, maximum reactive hyperemic flow in the forearms of patients with arteriosclerosis obliterans was significantly (p = 0.002) decreased compared to that in the control subjects. Blood pressure was similarly decreased by treatment with temocapril or amlodipine. Response to nitroglycerin (0.3 mg) was not changed by either drug. Treatment with temocapril significantly improved maximum reactive hyperemic flow of not only the legs and forearms in control hypertensives but also the legs and forearms in patients with arteriosclerosis obliterans, and attenuated the worsening of activity of daily living in these patients, although treatment with amlodipine did not. These results suggest that the angiotensin-converting enzyme inhibitor temocapril has a beneficial effect on endothelial function in elderly patients with arteriosclerosis obliterans.     

Synergistic suppression of the clonogenicity of U937 leukemic cells by combinations of recombinant human interleukin 4 and granulocyte colony-stimulating factor.

The actions and interactions of purified recombinant human (rh) interleukin 4 (IL-4) and granulocyte colony-stimulating factor (G-CSF) on the clonogenicity of human leukemic cell line U937 were studied in vitro. Parameters analyzed were the suppression of stem cell generation using sequential clonal cultures, alterations of surface antigen expression, and morphological changes. IL-4 alone (10 U/ml) and G-CSF alone (1000 U/ml) only slightly reduced colony numbers (80% +/- 7% and 87% +/- 7% of control colonies, respectively). However, IL-4 interacted synergistically with G-CSF to further reduce the colony number (46% +/- 8% of control colonies) and suppress the self-renewal ability (clonogenicity) of U937 cells. This synergistic effect was not eliminated by cultures containing neutralizing concentrations of anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF), anti-interleukin 6 (anti-IL-6), anti-interferon-alpha (anti-IFN-alpha), anti-IFN-gamma, anti-transforming growth factor-beta (anti-TGF-beta) serum, and anti-tumor necrosis factor-alpha (anti-TNF-alpha) serum. The coexistence of IL-4 and G-CSF was required for at least 48 h to reveal the synergistic action as assessed by preincubation and delayed addition experiments. Combinations of IL-4 and G-CSF showed a significant increase in CD11b expression on U937 cells. This action was not observed with HL60, K562, ML-1, or KG-1 leukemic cell lines, and IL-4 did not show any synergistic suppression of clonogenicity of U937 leukemic cells in combination with other cytokines tested in this study. These results suggest that IL-4 in combination with G-CSF may have some capacity to synergistically suppress human leukemic cells of specific types with loss of clonogenicity.     

Pemphigus Vulgaris Associated with Autoimmune Hemolytic Anemia and Elevated TNFα

A 76-year-old female was admitted with many bullae and erythema on her trunk and extremities. A biopsy specimen showed significant intercellular edema in the lower epidermis and eosinophilic infiltration into the dermis and the epidermis. Immunofluorescent staining revealed the deposition of IgG in the intercellular area of her prickle cells. From these histologic findings and the typical clinical features, we diagnosed her as having pemphigus vulgaris. Examination of her blood revealed that she also suffered from autoimmune hemolytic anemia. Despite intensive treatment with prednisolone, she finally died. This case is of interest because of its rarity and the TNFα detected significantly in the blister fluid of this patient.     

A case report of paraplegia following an operation for thoracic aortic aneurysm--with special reference to pathological findings of the spinal cord

A 60-year-old man suffered from paraplegia after the operation for thoracic aortic aneurysm and died 10 months after the operation. Detailed examination on the distribution of spinal cord lesions and of the locations of anterior radicular arteries revealed that the spinal cord ischemia occurred at the mid-thoracic segments between T-6 and T-10; the artery of Adamkiewicz entered at T-12; another radicular artery entered at T-4. We concluded that the spinal cord ischemia was caused by the interruption of the radicular artery at T-4 and that the segments nourished by the blood flow of the artery of Adamkiewicz were intact. We suggest that in some patients important radicular arteries other than the artery of Adamkiewicz are essential to preserve blood flow to the upper or middle thoracic spinal segments.     

Tissue renin content in superficial, midcortical, and juxtamedullary afferent arterioles in rabbits]

Tissue renin content within the kidney decreases from outer to inner cortex. However, it is not known whether this gradient is due to a decrease in the number of afferent arterioles from the outer to inner cortex or the decrease in renin content per afferent arteriole. Furthermore, it is still controversial whether sodium depletion increases or decreases this gradient. According to Taugner et al., sodium depletion induces the extension of renin positive part of afferent arterioles from vascular pole toward interlobular artery. Since the length of extension may differ among superficial, midcortical, and juxtamedullary afferent arterioles, the observed gradient may vary depending on whether the entire afferent arteriole or only the vascular pole is examined. In the present study, we microdissected the entire afferent arterioles from superficial, middle, and juxtamedullary cortex of rabbit kidney, and examined tissue renin content. We studied: 1. whether tissue renin content per afferent arteriole decreases from the outer to inner cortex. 2. whether sodium depletion affects the gradient of tissue renin content within the cortex. In result, we reached the conclusions, as follows: 1. Tissue renin content per afferent arteriole decreases steeply from superficial to midcortical to juxtamedullary afferent arterioles. 2. The absolute difference in renin content among the three types of afferent arterioles becomes greater during sodium depletion. The internephron heterogeneity of tissue renin content may contribute to functional heterogeneity.     

Estimating neuron dendritic length in 3D from total vertical projections and from vertical slices

The recently developed method of total vertical projections is illustrated to estimate the total dendritic length of a human Substantia Nigra neuron. Next, the length of the different orders of dendritic branches, and the mean segment length for each order - commonly regarded as important parameters in neuron physiology - are also estimated. Finally, it is shown how to estimate the mean dendritic length in a population of neurons from vertical slices of arbitrary and unknown thickness. Being unbiased and highly efficient, the proposed methods offer interesting alternatives to current procedures used for the metric analysis of neuron arborizations.     

Study of the transformation of weddellite to whewellite in calcium oxalate stones by x-ray diffraction

A clay film was made of the stone powder and water drops on a slide glass and dried at 100 to 110 degrees C or at room temperature in the horizontal position for 20 calcium oxalate stones which had been received between April, 1978 and August 1980. Each clay film was scanned with an X-ray diffractometer using CuK alpha radiation, stored at room temperature in a wooden sample case and analysed again by X-ray five to seven years after the first X-ray analysis. Then the recent diffractograms of 20 powder samples were compared with the previous ones regarding the peak heights at 14.2 degrees, 14.8 degrees and 25.8 degrees (2 theta), which were considered representative of weddellite, whewellite and apatite contents and designated as Iwe, Iwh and Iap, respectively. Since there was a good correlation between Iwe/Iwe + Iwh + Iap and weddellite/weddellite + whewellite + apatite that was determined by thermogravimetry (Fig. 1), the transformation rate of weddellite to whewellite can be expressed as the change of Iwe/Iwe + Iwh + Iap. One sample Iwe/Iwe + Iwh + Iap of which decreased by 48% in seven years (Fig. 3) and another sample Iwe/Iwe + Iwh + Iap of which increased by 10% in five years (Table) were excluded from this study because the clay films of these samples might have been overheated or incompletely dried before the first X-ray analysis.(ABSTRACT TRUNCATED AT 250 WORDS)