Effects of nisoldipine on coronary collateral perfusion and hemodynamics in chronically instrumented dogs

The effect of a new dihydropyridine slow-channel calcium blocking agent, nisoldipine, on hemodynamics and myocardial blood flow in normal and collateral-dependent areas distal to a chronic coronary artery occlusion were studied in chronically instrumented, conscious dogs. Nisoldipine produced significant and dose-related decreases in arterial blood pressure, an elevation of heart rate and large increases in coronary blood flow velocity. In dogs with an Ameroid constrictor previously implanted to enhance coronary collateral development, this agent produced large increases in perfusion distal to a chronic coronary artery occlusion. In addition, despite a reduction in arterial pressure, nisoldipine preserved renal cortical, intestinal and skeletal muscle blood flow while increasing tissue flow within liver and cerebral cortex. Thus, nisoldipine increases oxygen supply to collateral-dependent myocardium in the presence of reduced driving pressure for collateral perfusion.     

Surgical therapy for thyroid carcinoma: a review of 1249 solitary thyroid nodules

A total of 1249 "cold" solitary thyroid nodules were excised at the Brigham and Women's Hospital from 1948 through 1987. Of these nodules, 241 showed malignant conditions: 123 were papillary, 42 were mixed papillary-follicular, and 43 were pure follicular carcinomas. There were also 23 anaplastic, 8 medullary, and 3 Hürthle cell carcinomas. These patients were followed up from 3 to 31 years, with a mean range of 10 years. Fifty-three patients with well-differentiated tumors underwent total thyroidectomies, and 179 underwent subtotal thyroidectomies (excluding anaplastic, medullary, and Hürthle cell tumors). Regional lymph node involvement was commonly found but appeared not to affect survival; tumor size and local spread and extent of thyroid gland involvement did affect survival. A small percentage of well-differentiated thyroid tumors do, in time, undergo anaplastic change that leads to metastasis and death. There was no 30-day mortality rate. The late mortality rate was 2% for papillary and 14% for follicular carcinomas. Papillary tumors are becoming more common. Older aged patients and male patients appear to carry poorer prognoses for survival. The total thyroidectomy procedure has not improved survival over subtotal thyroidectomy and carries a higher complication rate.     

Cerebellar diaschisis revisited: pontine hypometabolism and dentate sparing.

A unilateral supratentorial lesion may cause hypometabolism in the contralateral cerebellar hemisphere (crossed cerebellar diaschisis). We analyzed glucose metabolism, measured by PET-FDG, in the posterior fossa in 67 patients (78 PET studies) with primary unilateral supratentorial brain tumors selected for visually obvious metabolic asymmetry in the cerebellar hemispheres. We found that glucose utilization was 17% lower in the contralateral cerebellar cortex (compared with the ipsilateral one), consistent with the selection criterion, and 19% lower in the ipsilateral pons, wherein lie the first order synapses of the corticopontocerebellar pathway. This finding helps to validate the prevalent view that cerebellar diaschisis is due to interruption of afferent input from the corticopontocerebellar pathway. However, glucose metabolism in the contralateral dentate nucleus was relatively preserved--only 2% less than the ipsilateral dentate. This "dentate sparing" suggests preservation of afferent input to the largest of the deep cerebellar nuclei from the Purkinje cells in the cortex, despite interruption of the major excitatory input to the Purkinje cells.     

Relationship between numbers of beta adrenergic receptors in lymphocytes and disease severity in asthma

In order to assess the status of beta adrenergic receptors in bronchial asthma, binding studies using (−) [³H] dihydroalprenolol (DHA) were performed on lymphocytes of 10 control subjects and 11 stable asthmatic patients. Specific DHA binding was generally lower at all DHA concentrations in asthmatics. At 12 nM DHA concentration, specific DHA binding was 391 ± 40 fM/mg protein in controls and 263 ± 35 fM/mg protein for asthmatic subjects (p < 0.05). A highly statistically significant positive correlation between specific DHA binding (at 12 nM DHA) and FEV₁/FVC% was observed (r = 0.93, p < 0.01), with those asthmatic subjects with the more severe airway obstruction and disease severity showing lower DHA binding. The results of the study suggest that a lymphocyte beta adrenergic receptor defect may be present among some patients with asthma. The magnitude of the receptor abnormality appears to be related to disease severity and degree of airway obstruction as measured by FEV₁/FVC%. Documentation of drug consumption was made, and restriction of beta adrenergic agonists was attempted; theophylline and corticosteroids were the predominant drugs used in the study. Even with these precautions, it is possible that the differences in DHA binding observed among subjects are the results of greater drug (e.g., theophylline and corticosteroids) consumption by the clinically more severe patients. On the other hand, the lymphocyte receptor alteration noted may reflect a more general beta adrenergic receptor abnormality in bronchial asthma.     

Spike patterning by Ca2+-dependent regulation of a muscarinic cation current in entorhinal cortex layer II neurons

In entorhinal cortex layer II neurons, muscarinic receptor activation promotes depolarization via activation of a nonspecific cation current (I(NCM)). Under muscarinic influence, these neurons also develop changes in excitability that result in activity-dependent induction of delayed firing and bursting activity. To identify the membrane processes underlying these phenomena, we examined whether I(NCM) may undergo activity-dependent regulation. Our voltage-clamp experiments revealed that appropriate depolarizing protocols increased the basal level of inward current activated during muscarinic stimulation and suggested that this effect was due to I(NCM) upregulation. In the presence of low buffering for intracellular Ca(2+), this upregulation was transient, and its decay could be followed by a phase of I(NCM) downregulation. Both up- and downregulation were elicited by depolarizing stimuli able to activate voltage-gated Ca(2+) channels (VGCC); both were sensitive to increasing concentrations of intracellular Ca(2+)-chelating agents with downregulation being abolished at lower Ca(2+)-buffering capacities; both were reduced or suppressed by VGCC block or in the absence of extracellular Ca(2+). These data indicate that relatively small increases in [Ca(2+)](i) driven by firing activity can induce upregulation of a basal muscarinic depolarizing-current level, whereas more pronounced [Ca(2+)](i) elevations can result in I(NCM) downregulation. We propose that the interaction of activity-dependent positive and negative feedback mechanisms on I(NCM) allows entorhinal cortex layer II neurons to exhibit emergent properties, such as delayed firing and enhanced or suppressed responses to repeated stimuli, that may be of importance in the memory functions of the temporal lobe and in the pathophysiology of epilepsy.     

NK cells developing in vitro from fetal mouse progenitors express at least one member of the Ly49 family that is acquired in a time-dependent and stochastic manner independently of CD94 and NKG2

NK cells developing in vitro from fetal progenitors in the presence of IL-2 are phenotypically and functionally indistinguishable from mature adult NK cells, with the exception that they generally lack surface expression of any of the Ly49 molecules that have previously been examined. Using two recently developed anti-Ly49 mAb, we show here that most of these NK cells in fact express high levels of at least one previously uncharacterized member of the Ly49 family, most likely Ly49E. Detailed kinetic and clonal analysis revealed that these Ly49 molecules were acquired in a progressive and stochastic manner independently of CD94 and NKG2. CD94 and NKG2 were both expressed early in NK cell development, sometimes in the absence of NK1.1, with CD94 invariably being expressed at two different levels. IL-4 differentially inhibited the expression of CD94 and Ly49 receptors, but had little or no effect on the expression of NKRP1 molecules.