Functional and energetic consequences of chronic myocardial creatine depletion by beta-guanidinopropionate in perfused hearts and in intact rats.

Oral feeding with the creatine analogue beta-guanidinopropionate (beta-GP) reduces myocardial phosphocreatine and creatine concentrations by about 80%in vitro, this is accompanied by reduced contractile performance. We hypothesized, thus, that beta-GP feeding leads to hemodynamic changes in vivo characteristic of heart failure. beta-GP was fed to Wistar rats for up to 8 weeks. In isolated hearts, function was measured isovolumically, myocardial energetics were followed with (31)P-NMR spectroscopy. In vivo hemodynamics were measured with Millar-Tip-catheters and an electromagnetic flow probe. Beta-GP feeding did not alter heart weight. In vitro, diastolic pressure-volume curves indicated structural left ventricular dilatation, and a 36% reduction of left ventricular developed pressure was found; phosphocreatine was reduced by approximately 80%, ATP unchanged and creatine kinase reaction velocity ((31)P-MR saturation transfer) decreased by approximately 90%. The total creatine pool (high-pressure liquid chromatography) was reduced by up to approximately 70%. In contrast to in vitro findings, in vivo cardiac hemodynamics (including left ventricular developed pressure, d P/d t(max), cardiac output and peripheral vascular resistance) at rest and during acute volume loading showed no alterations after beta-GP feeding. The only functional impairment observed in vivo was a 14% reduction of maximum left ventricular developed pressure during brief aortic occlusion. In the intact rat, cardiac and/or humoral compensatory mechanisms are sufficient to maintain normal hemodynamics in spite of a 90% reduction of creatine kinase reaction velocity. However, chronic beta-GP feeding leads to structural left ventricular dilatation.

Aggravation of left ventricular remodeling by a novel specific endothelin ET(A) antagonist EMD94246 in rats with experimental myocardial infarction.

An endothelin (ET(A)) antagonist reduced mortality and an ET(A) + ET(B) antagonist prevented left ventricular dilatation in rats with large myocardial infarction. This study tested the hypothesis that long-term blockade of the ET(A) receptor would have beneficial effects on left ventricular function and remodeling. Three hours after coronary artery ligation or sham operation in rats, EMD94246 (100 mg/kg/day, n=62) or placebo (n=62) was given by gavage. Eight weeks later, left ventricular hemodynamic measurements were performed and left ventricular volume determined with a double-lumen catheter after KCl-induced cardiac arrest. EMD94246 treatment had no effects on mortality or hemodynamic parameters. In rats with large infarcts, EMD94246 significantly increased left ventricular volume (2.5+/-0.1 vs. 2.2+/-0.1 ml/kg; p < 0.05). The nonpeptide ET(A)-selective antagonist EMD94246 promoted chronic left ventricular dilatation in rats with large myocardial infarction.

Splenectomy for hairy cell leukemia in pregnancy.

OBJECTIVE: Hairy cell leukemia is a rare hematologic malignant disease characterized by pancytopenia and splenomegaly. Its occurrence during pregnancy limits treatment with standard chemotherapeutic agents. A woman was found to have hairy cell leukemia and massive splenomegaly late in the second trimester. A review of the literature did not provide a carefully formulated treatment plan. It was believed that splenectomy (the historic therapy for hairy cell leukemia) would likely result in improved hematologic values and allow the pregnancy to progress. STUDY DESIGN: Case report with literature review. RESULTS: Preoperative laboratory studies revealed platelet count 65,000/mm3, hematocrit 28.6%, white blood cell count 4000/mm3, and hairy cell index 0.06 to 0.07. At 24 weeks' gestation, the patient underwent splenectomy with resolution of thrombocytopenia and normal progression of pregnancy without complication. Repeat cesarean section at 38 weeks produced a 2875 gm healthy male infant with Apgar scores of 9 and 9. CONCLUSION: If antepartum management of hairy cell leukemia is warranted, splenectomy is a safe and effective treatment option during the second trimester.

Ultrastructural characterization of substance-P-immunoreactive synaptic terminals in the cat's normal and rhizotomized trigeminal subnucleus caudalis.

Deafferenting injuries often cause transient or permanent physiological alterations within the central projection field of affected primary afferent fibers. Aberrant sensory perceptions, dysesthesias, and hyperalgesias represent the clinical sequelae of such injuries; however, the results of experimental deafferentations have been subject to a variety of interpretations (Rodin and Kruger, 1984b). Neurochemical studies show an increased sensitivity of partially deafferented neurons to substance P (SP). Our previous studies (Hoffmann et al., 1991) documented, primarily at the light-microscopic level, a moderate transient loss of SP-immunoreactive (SPIR) boutons in the trigeminal subnucleus caudalis (Vc)--a loss that seemed to preferentially affect the slightly larger, possibly complex boutons with multiple contacts. However, despite the elimination of the trigeminal input, the larger boutons reappeared. In the present study, therefore, we examined Vc using electron-microscopic immunocytochemistry, in order to document these changes over time and to clarify the structure and relationships of this population of boutons. SPIR boutons occurred in lamina I and II degrees of the substantia gelatinosa of Vc, ranged in size from 1 to 5 microns in diameter, and displayed mixed populations of clear and dense-core vesicles. Most formed single or multiple axodendritic junctions, but a significant number engaged in axoaxonic contacts with both SPIR-labeled and unlabeled terminals. A small number appeared to be the central element of a typical glomerulus, particularly in lamina II degrees. Three to seven days following an ipsilateral retrogasserian rhizotomy, synaptic degeneration was evident in the substantia gelatinosa and often involved glomerular terminals. However, most of these were SPIR-negative and occurred primarily in lamina II degrees. Those SPIR boutons that displayed degenerative features often made single or multiple axodendritic contacts, and in some instances were scalloped. By 30 days, most remaining SPIR boutons were small, with a lower incidence of contacts; however, some of these were axoaxonic. In addition, many SPIR terminals were only very lightly stained--a feature not encountered to such an extent in the contralateral Vc. At 45 days, complex SPIR boutons were again evident in the field, and some showed densely packed vesicles. An increased incidence of clusters of two to four SPIR axoaxonic contacts was also observed. Finally, almost all SPIR boutons encountered at this stage were intensely stained. It is suggested that these alterations represent a compensatory neuroplastic response on the part of overlapping cervical and cranial primary afferents to the partial deafferentation resulting from the interruption of the trigeminal root.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of sympathetic neurons in orofacial and upper extremity nerves: implications for causalgia.

This study compared nerves of the orofacial region with nerves frequently associated with causalgia to determine if there is a significant difference in the proportion of sympathetic neurons within these nerves, which may account for the lower incidence of orofacial causalgia. Three orofacial and two upper extremity nerves were examined. Each nerve was transected and labeled with horseradish peroxidase to identify the cell bodies of neurons contributing axons to the nerve. The study included two trials per nerve, for a total of 10 trials in eight cats. The trigeminal and dorsal root ganglia, containing sensory neurons (SN), and the stellate, middle, and superior cervical ganglia, containing postganglionic sympathetic neurons (PGSN), were sectioned and reacted with tetramethyl benzidine to visualize the labeled neurons. The total number of labeled PGSN and SN were counted and the ratio (PGSN:SN) determined for each of the five nerves. The average PGSN:SN ratio from upper extremity nerves (0.40) is 2 1/2 times greater than the ratio determined for branches of the trigeminal nerve (0.16). The lower proportion of sympathetic neurons within the trigeminal nerves provides an anatomic explanation for the lower incidence of orofacial causalgia consistent with the currently accepted etiology.

Ulex europaeus agglutinin-I binding to dental primary afferent projections in the spinal trigeminal complex combined with double immunolabeling of substance P and GABA elements using peroxidase and colloidal gold.

Ulex europaeus agglutinin I (UEA-I) is a plant lectin with an affinity for L-fucosyl residues in the chains of lactoseries oligosaccharides associated with medium- and smaller-diameter dorsal root ganglion neurons and their axonal processes. These enter Lissauer's tract and terminate within the superficial laminae of the spinal cord overlapping projections known to have a nociceptive function. This implies that the surface coatings of neuronal membranes may have a relationship with functional modalities. The present investigation further examined this concept by studying a neuronal projection with a nociceptive function to determine whether fucosyl-lactoseries residues were incorporated in its primary afferent terminals. Transganglionic transport of horseradish peroxidase (HRP) following injection into tooth pulp chambers was employed to demonstrate dental pulp terminals in the trigeminal spinal complex, while peroxidase and fluorescent tags were used concomitantly to stain for UEA-I. Double immunolabeling for substance P (SP) and gamma-aminobutyric acid (GABA) using peroxidase and colloidal gold allowed a comparison of the distribution of a known excitatory nociceptive transmitter with that of UEA-I binding in specific subnuclei. Synaptic interrelationships between UEA-I positive dental pulp primary afferent inputs and specific inhibitory terminals were also examined. SP immunoreactivity occurred in laminae I and outer lamina II (IIo) of subnucleus caudalis (Vc) and in the ventrolateral and lateral marginal region of the caudal half of subnucleus interpolaris (Vi), including the periobex area in which Vi is slightly overlapped on its lateral aspect by cellular elements of Vc. The adjacent interstitial nucleus (IN) also showed an intense immunoreactivity for this peptide antibody. UEA-I binding displayed a similar distribution pattern in both Vc and Vi, but extended into lamina IIi and the superficial part of Lamina III in Vc. Dental pulp terminals were found to have a comparable distribution; however, many extended into the dorsal portion of the caudal half of Vi and the ventromedial quadrant of rostral Vi. Electron-microscopic analysis showed that transganglionically labeled dental pulp terminals contained ovoid, complex membrane-bound vacuoles laden with transported HRP. The preterminal axon and synaptic membranes of those dental pulp terminals located in zones of Vc and Vi displaying an affinity for UEA-I were usually characterized by a patchy, electron-dense coating of the peroxidase tag. SP was demonstrated ultrastructurally with Protein-A colloidal gold (3-nm particles), whereas GABA immunoreactivity was revealed by the avidin-biotin-peroxidase method.(ABSTRACT TRUNCATED AT 400 WORDS)

Synaptic substrates for enkephalinergic and serotoninergic interactions with dental primary afferent terminals in trigeminal subnucleus interpolaris: an immunocytochemical study using peroxidase and colloidal gold.

Pain processing in the trigeminal complex has been thought to reside primarily in the spinal subnucleus caudalis (Vc). However, trigeminal tractotomies eliminating primary afferent input to Vc and severance of secondary trigemino-thalamic fibers from Vc do not disturb pain perception from the central face and oral cavity. Furthermore, large numbers of neurons that are highly responsive to noxious stimuli and suppressed by inputs from the periaqueductal gray and raphe complex have been identified in subnuclei interpolaris (Vi) and oralis (Vo). Therefore, the purpose of this study was to assess the distribution and spatial arrangements of nociceptive modulatory transmitters with nociceptive afferents and trigemino-thalamic relay cells in the rostral portion of the spinal trigeminal nuclear complex. The dental pulp contains predominantly nociceptors that project to all three subdivisions of the trigeminal spinal complex. These projections were visualized by anterograde transganglionic transport of horseradish peroxidase or by degeneration following administration of toxic ricin to the pulp chambers. The spatial arrangements of dental primary afferents with enkephalinergic (ENK) and serotoninergic (5HT) inputs was then assessed by employing avidin-biotin peroxidase and protein-A colloidal gold double-labeling immunocytochemistry. Trigemino-thalamic relay cells were also labeled by retrograde transport of HRP after stereotaxic injections into the ventrobasal thalamus. ENK and 5HT immunoreactivity was found in the ventrolateral quadrant and lateral margin of Vi, together with the adjacent interstitial nucleus (IN). This activity extended from the caudal pole of Vi and the periobex region, where it was most dense, rostrally to a position approximately 2.9 mm from the Obex. Neither ENK nor 5HT immunoreactivity was observed in Vo. Primary dental afferents projected into the ventromedial quadrant of rostral Vi and were found in the ventrolateral quadrant and dorsal aspect of the subnucleus farther caudally. They appeared as simple boutons with single contacts or as larger, sometimes scalloped terminals that formed multiple contacts. Postsynaptic elements were usually small dendritic profiles, although relay cell somata rarely received primary afferent inputs. Many primary afferents entered areas of synaptic clustering and contacted enkephalinergic dendrites, some of which were also postsynaptic to serotoninergic synapses. Alternatively, primary afferents contacted unlabeled processes that were also postsynaptic to the enkephalinergic element to form a triad arrangement. The least common occurrence was axo-axonic contacts in which enkephalinergic synapses were presynaptic to primary afferents. Both enkephalinergic and serotoninergic synaptic categories displayed round vesicles and generally formed asymmetric junctions.(ABSTRACT TRUNCATED AT 400 WORDS)

Malignant Brenner tumor of the ovary.

Three cases of stage III malignant Brenner tumor of the ovary in which chemotherapy or radiotherapy favorably altered the clinical courses are reported, and the literature is reviewed.

Leiomyosarcoma of the breast: a case of long survival and late hepatic metastasis.

A case of leiomyosarcoma of the breast that metastasized to the liver 15 years after mastectomy is reported. Leiomyosarcoma appears to have less aggressive biologic behavior than other types of breast sarcomas. Analysis of the reported cases of smooth muscle tumors of the breast revealed some guidelines for the histologic diagnosis of these tumors. Tumors with three or more mitoses per 10 HPF are leiomyosarcomas, and those with no mitotic activity, necrosis, and significant cellular atypia are leiomyomas. The borderline cases are best considered smooth muscle tumors with uncertain malignant potential.

Fibrinogen heterogeneity in cancer, in occlusive vascular disease, and after surgical procedures.

Electrophoresis in 3.5% polyacrylamide gel was used to determine the patterns of fibrinogen heterogeneity in healthy subjects, in postoperative patients and in patients with cancer or occlusive vascular disease. Two major and one minor fibrinogen fractions, differing in molecular weight, were identified, and their concentrations in blood determined. The high-molecular-weight (HWM) fraction was found in greatest concentration after operation, during the period of hyperfibrinogenemia, whereas no simultaneous increase of lower-molecular-weight (LMW and LMW') fractions occurred, suggesting that these were derivatives of HMW ("native") fibrinogen. No correlation between the concentrations of the LMW and LMW' fractions and fibrinolytic activity was found, suggesting that direct degradation of HMW fibrinogen by plasmin was unlikely. The high fibrinogen level in cancer patients was related to increased concentrations of HMW and LMW fractions, whereas in the vascular-disease patients it was due exclusively to increased concentrations of LMW and LMW' fibrinogen. Serial observations indicated little fluctuation in the concentration of these fractions, indicating a persistently accelerated rate of conversion of HMW to LMW and LMW' fibrinogen in occlusive vascular disease. Possible pathogenic implications are discussed.