High Degree Of Vascularization Research Articles

Erythropoietin as an angiogenic factor in gastric carcinoma

Previous studies have shown that increased vascularity is associated with haematogenous metastasis and poor prognosis in gastric cancer. The role of erythropoietin (Epo) in angiogenesis has not been completely clarified, although its involvement has been reported. In this study we correlated microvascular density and Epo receptor (Epo-R) expression in endothelial and tumour cells with histopathological type in gastric cancer. Specimens of primary gastric adenocarcinomas obtained from 40 patients who had undergone curative gastrectomy were investigated immunohistochemically by using anti-CD31 and anti-Epo-R antibodies. Stage IV gastric carcinoma had a higher degree of vascularization than other stages, and Epo-R expression in both endothelial and tumour cells increased in parallel with malignancy grade and was highly correlated with the extent of angiogenesis. Epo-R level correlates with angiogenesis and progression of patients with gastric carcinoma and we suggest that Epo might have a trophic effect on the vasculature of the gastrointestinal tract. Understanding mechanisms of gastric cancer angiogenesis provides a basis for a rational approach to the development of an anti-angiogenic therapy in patients with gastric cancer.

Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an uncommon, autosomal dominant hereditary multitumor syndrome caused by germline alterations of the VHL gene, which has been cloned recently and identified as a tumor suppressor gene. The major lesions in VHL disease include hemangioblastomas in the central nervous system and retina, clear cell renal cell carcinomas, pheochromocytomas, pancreatic tumors, epididymal cystadenomas, endolymphatic sac tumors, carcinoid tumors, and multiple cysts of the kidney, pancreas, and epididymis. Compared with sporadic ones, the tumors in VHL disease develop at an earlier age and often multifocally. Histologic features of VHL tumors are characterized by their high degree of vascularization and the presence of a clear cell component. Hypervascularization is induced by overexpression of vascular endothelial growth factor (VEGF), and because the principal function of VHL protein is the negative regulation of hypoxia-inducible mRNAs including VEGF mRNA, inactivation of VHL gene plays critical roles in angiogenesis of the VHL tumors. In addition, since VHL protein is also required for the down-regulation of transcription activity of certain genes for the cell growth and cell cycle, inactivation of VHL gene may contribute to tumorigenesis of the VHL tumors. A significant difference in the frequency of types of VHL gene mutation has been noted among the affected families, known as the genotype-phenotype correlations.

Noninvasive Dynamic Fluorescence Imaging of Human Melanomas Reveals that Targeted Inhibition of bFGF or FGFR-1 in Melanoma Cells Blocks Tumor Growth by Apoptosis

Two prominent biological features of the advanced stages of human melanoma are their high degree of vascularity and high-level expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1). Given these characteristics, human melanoma serves as an ideal model to address an important question regarding the efficacy of angiogenesis-based cancer therapy. To induce tumor growth arrest and regression, does it suffice to block expression of bFGF and/or FGFR-1 in only the melanoma cells, or is it essential to inhibit expression of bFGF and/or FGFR-1 in both the melanoma cells and the melanoma cell-interspersing vasculature? Primary and metastatic human melanomas, grown as subcutaneous tumors in nude mice, were injected twice a week with vector constructs containing the human tyrosinase promoter and antisense- oriented human bFGF or FGFR-1 cDNA. On alternating days, the bFGF and FGFR-1 antisense-targeted tumors received injections of cyanine fluorochrome-conjugated antibodies to a human melanoma and mouse blood vessel marker. Noninvasive, dynamic fluorescence imaging was used to document the cellular events that took place inside the tumors as the result of blocking expression of bFGF or FGFR-1 in the melanoma cells. In vivo, ex vivo, and in vitro fluorescence imaging of the bFGF and FGFR-1 antisense-targeted tumors demonstrated that inhibiting bFGF and FGFR-1 signaling in only the melanoma cells suffices to inhibit tumor growth due to massive induction of melanoma cell apoptosis. The investigations presented in this study document that inhibiting expression of bFGF or FGFR-1 in only the melanoma cells is as effective in blocking tumor growth as simultaneously inhibiting bFGF or FGFR-1 synthesis in the melanoma cells and the melanoma cell-interspersing vasculature. Furthermore, blocking expression of bFGF or FGFR-1 in the melanoma cells did not lead to activation or increased production of another angiogenic molecule, suggesting the absence of a "salvage pathway" that can circumvent or rescue the blockage of bFGF/FGFR-1 in the melanoma cells.

Bioreactors for decreasing the growth of brain tumors.

Malignant gliomas are the most common primary brain tumors. They are highly aggressive tumors characterized by a recurrence rate of virtually 100%. Despite significant advances in neuroimaging and neurosurgical techniques, the median survival time of patients with glioblastoma multiforme remains 12 to 18 months. Malignant gliomas are characterized by rapidly dividing cells, which invade into the normal brain, and a high degree of vascularity. Recent experimental evidence indicates that tumor-related angiogenesis contributes significantly to the malignant phenotype.

Diagnosing Sarcoidosis Using Endosonography-Guided Fine-Needle Aspiration

The ability to diagnose sarcoidosis cytologically has been reported previously, but the method is rarely used. Endoscopic ultrasonography (EUS) is a sensitive technique for detecting mediastinal lymph nodes, which in addition provides an opportunity to carry out guided fine-needle aspiration (FNA) cytology. We report herein on the use of EUS-FNA in the diagnosis of sarcoidosis. Nineteen patients with suspected sarcoidosis were investigated using EUS-FNA with a linear echoendoscope and a 22-gauge Hancke-Vilman needle. In all 19 patients, EUS revealed enlarged mediastinal lymph nodes (mean size, 2.4 cm), located subcarinally (n = 15), in the aortopulmonary window (n = 12), or in the lower posterior mediastinum (n = 5). The nodes had an isoechoic or hypoechoic appearance, with atypical vessels in five cases. The amount of aspirate obtained using EUS-FNA was adequate in all patients, and contained blood in excess of normal in some, indicating a high degree of vascularity. Cytology demonstrated epithelioid cell granuloma formation, suggesting sarcoidosis. Mycobacterial cultures were negative in all of the patients except one, in whom the final diagnosis was tuberculosis. The specificity and sensitivity of EUS-FNA in the diagnosis of sarcoidosis were 94% and 100%, respectively. EUS of mediastinal lymph nodes in sarcoidosis reveals certain characteristic features. However, it is not capable of differentiating the lesions from tuberculosis or malignancy. EUS-FNA is a safe and sensitive method of aspirating material for cytology and mycobacterial cultures. We believe it will provide a useful alternative in the diagnosis of sarcoidosis.

Angiogenic balance in human melanoma: expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo.

Tumor angiogenesis, a major requirement for tumor outgrowth and metastasis formation, is regulated by pro- and anti-angiogenic factors. We have studied the expression of a panel of angiogenic factors, and of the angiogenesis inhibitor angiostatin, in a panel of human melanoma cell lines giving rise to xenografts with different vascular densities. Angiogenic-factor expression was analyzed in vitro (cell lines) and in vivo (xenografts), both at mRNA (RT-PCR and Northern blot) and at protein level (ELISA and Western blot). In vitro angiostatin generation was assessed by Western-blot analysis. Expression of bFGF and VEGF was clearly correlated with a high degree of vascularization, confirming the importance of these factors for tumor angiogenesis. In addition, there was exclusive or elevated in vitro expression of angiogenic factors IL-8, PDGF-AB, and, to a lesser extent, midkine in cell lines that formed highly vascularized tumors. A similar angiogenic-factor-expression pattern was found in the corresponding xenografts, with the exception of VEGF. In most cell lines, this factor had low expression in vitro which was strongly enhanced in vivo. Although all 8 melanoma cell lines were able to excise the angiostatin fragment from the plasminogen parent molecule in vitro, cell lines BLM and M14 showed the most potent angiostatin generation. In vitro angiostatin generation by cell lysates prepared from melanoma xenografts was comparable in all xenograft types. Thus, in our model system we found no correlation between angiostatin generation and vascular density. Our study has limited the number of pro-angiogenic factors that may be involved in melanoma angiogenesis, and provides evidence for the notion that regulation of tumor angiogenesis is dependent on multiple factors. Inhibition of angiogenesis for therapeutic purposes, therefore, should preferably not concentrate on a single factor.

Correlation of inflammatory cytokines with arthroscopic findings in patients with temporomandibular joint internal derangements

Purpose: The goal of this study was to evaluate the presence of the inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) within the superior temperomandibular joint (TMJ) space in patients with internal derangements and to compare these values with the pathologic findings seen arthroscopically. Patients and Methods: Thirty patients with symptomatic TMJ dysfunction and clinical and imaging evidence of internal derangements of the TMJ were evaluated. Before entering the superior joint space with the arthroscope, 2 mL sterile saline was injected and, after 30 seconds of equilibration, was aspirated for analysis. The surgeon then performed diagnostic arthroscopy. The degree of synovitis, degeneration, percent condylar roofing, and any pathologic changes, such as perforations, were recorded. The level of total protein in each sample was ascertained, as well as the levels of IL-1β, IL-6, and TNF-α. Results: Of 30 samples tested, three were discarded because of failure to gain access into the superior joint space. Of the 27 remaining samples, IL-6 showed the closest correlation with the level of acute synovitis demonstrated arthroscopically. Two of the higher IL-6 levels (167 and 324 pg/μg protein) were seen with patients with a significant disc perforation. In patients with a high degree of vascularity, IL-6 was found to be between 0 to 581 pg/μg protein with an average of 80 pg/μg protein and a median value of 43 pg/mg. These values significantly correlated with the degree of vascularity ( P ≤ .02). This is in comparison with the 10 remaining patients, who showed significantly fewer vascular changes arthroscopically. In these patients, the range of IL-6 was 0 to 35 pg/μg protein, with an average of 19 pg/μg protein and a median value of 14.5 pg/μg. These values significantly correlated with the smaller degree of vascularity ( P ≤ .02). In seven patients, the role of nonsteroidal antiinflammatory drug (NSAID) use resulted in decreased levels of IL-6, which has been noted in previous studies. In patients with higher rated redundancy of the synovial tissue, the average IL-6 level was 92 pg/μg protein, whereas the median value was 44 pg/μg protein. In patients with little or no redundant synovial tissue, an average IL-6 level of 22 pg/μg protein was present. The median value in these same joints was 15 pg/μg protein. These IL-6 values significantly correlated with the degree of redundancy P ≤ .03). The degree of degenerative change (chondromalacia, fibrilation), disc displacement (roofing), and the presence or absence of adhesions did not significantly affect the levels of IL-6 within the patients studied. The presence of IL-1β and TNF-α was not found to correlate with the arthroscopic findings in the superior joint space. Conclusions: The presence of IL-6 correlated with the degree of acute synovitis. IL-1β and TNF-α were not found in significant levels within the superior joint space. These findings correlated with those reported by other investigators. The production of IL-6 by synovial cells and its role in TMJ disease warrants further investigation.

Processing of tumor tissues for vaccination with autologous tumor cells.

Vaccination with gene-transfected tumor cells has recently been proposed as a new strategy in the immunotherapy of cancer. Since autologous tumor cells provide an optimal antigen profile, the possibility of generating single cell suspensions from renal cell carcinoma (RCC), malignant melanoma (MM), colon carcinoma (CC), and non-small-cell lung cancer (NSCLC) biopsies was investigated. One hundred and seventy-four tumor biopsies were processed by mechanic and enzymatic dissociation, yielding 1-2 x 10(6) cells/g tumor (median), irrespective of tumor type. Primary tumor cell cultures (PTCC) of > or = 10(7) cells were established from 29 of 86 (34%) RCC, 14 of 38 (37%) MM, 11 of 23 (48%) NSCLC and 4 of 27 (15%) CC specimens. The amount of non-tumor cells, as assessed by morphology and immunocytology, was generally low (< 30%) in RCC (35 of 41) and MM (11 of 17), while it exceeded 60% in 8 of 11 PTCC from NSCLC and 3 of 11 CC. A high tumor cell yield was obtained in biopsies with a high degree of vascularization and in the virtual absence of necrosis. Thus, PTCC > or = 10(7) cells were obtained in 73% of MM with a high degree of vascularization and in 22% of MM with a low degree of vascularization (p < 0.007). Long-term tumor cell cultures exceeding 20 passages were established in 24 of 86 (18%) RCC, 7 of 38 (18%) MM and 3 of 27 (11%) CC, while successful implantation in nude mice was achieved in 8 of 20 RCC and 5 of 10 MM. Thus, under the conditions described, > or = 10(7) primary tumor cells of high purity could be generated from about one third of RCC and MM biopsies, while the success rate increased to > 50 and > 70%, respectively, in samples with a high degree of vascularization generated by an optimized biopsy technique excluding necrotic parts.

Color-coded duplex ultrasonography of extracranial vascular lesions

The diagnostic potential of color-coded duplex sonography in extracranial vascular lesions is evaluated with reference to the literature. Indications for the applications of color-coded duplex sonography comprise congenital vascular anomalies, arteriosclerotic lesions, dissections, aneurysms, arteriovenous fistulas and glomus tumors. New applications consist include monitoring after vascular interventional procedures. Color-coded duplex sonography allows recognition of congenital anatomic variants like agenesis of the internal carotid artery and variations of the origin of the vertebral artery. By superior surface delineation, characterization and quantification of plaques and stenoses are improved because of a new development in ultrasound technique. In cases of vessel dissection color-coded ultrasound is able to depict the dissection membrane, pulse synchronous flow reversal and "reentry" phenomena. Significant carotid bulb ectasia can be demonstrated and differentiated from aneurysm formation by 3D technique and angio-CT. Extracranial arteriovenous fistulas may be localized and detailed with respect to feeding arteries and draining veins. Glomus caroticum and jugular tumors are characterized by a high degree of vascularity and a position in the carotid bifurcation and within the jugular vein, respectively. The position of intravascular devices like detachable balloons and catheters was precisely demonstrated. Color-coded duplex sonography may assume a leading role in the noninvasive evaluation of extracranial vascular lesions. It provides criteria for the necessity and rational application of additional diagnostic procedures (MR, MRA, CT, DSA).

Differential sequestration of parasitized erythrocytes in the cerebrum and cerebellum in human cerebral malaria.

Sequestration of parasitized red blood cells (PRBC) in the microvessels results in impairment of microcirculation with organ dysfunction in complicated human Plasmodium falciparum malaria. In cerebral malaria patients, the percentage of small blood vessels with PRBC sequestration is higher in the brain than in other organs. The clinical severity of cerebral malaria depends on the level of PRBC sequestration in the brain. In our study, postmortem samples from cerebrum and cerebellum of 16 patients who died of P. falciparum malaria were examined and compared using light microscopy. In the cerebellum, the percentage of microvessels with PRBC sequestration was higher than that in the cerebrum. The difference in sequestration rates between cerebrum and cerebellum is statistically significant (P < 0.05). There is a higher degree of vascularity in the cerebellum (7 vessels/mm2) than in the cerebrum (5 vessels/mm2), and the difference is also statistically significant (P < 0.025). Perivascular hemorrhages also occur more frequently in the cerebellum than in the cerebrum. The results of this study, which show that differential sequestration of PRBC occurs in the microvessels of the cerebrum and cerebellum, explain the varied neurologic manifestations that result from cerebral and cerebellar dysfunction in human cerebral malaria. This study also reveals the necessity of postmortem histologic examination of the cerebellum in every suspected case of cerebral malaria.

Proliferation and Interactions of Several Cell Types Encapsulated Within Dense (Non-Porous) Protein-Permeable Polyurethane Membranes

AbstractProtein-permeable dense (non-porous) urethane membranes have been evaluated forin vitrocell culture, and in vivo cell encapsulation. Polyurethane membranes were designed to exhibit permeability to proteins, gases, and nutrients without the existence of pores. The membranes are non-cytotoxic, angiogenic, and permeable to gases, nutrients, secretagogues and cell products via purely concentration-driven transport. Non-anchorage and anchorage dependent cells were grown encapsulated within the membrane and with the membrane as a growth substrate. Several non-anchorage dependent cell types proliferated within the membrane bothin-vitroandin-vivo. Anchorage-dependent cells were grown on the membranes as a substrate. Encapsulated cells have been maintained in culture for up to six months with nutrients supplied only by the external media. Immuno-isolation has been demonstrated with cells implanted into murine hosts. Explants of membrane encapsulated cells exhibited a high degree of vascularization, with little or no fibrous tissue. The ability to support cell growth and function, and the ability to protect xenogenic cells from immunologic rejection suggest that the membranes would be useful in the construction of hybrid artificial organs, devices for cell transplantation, and substrates for cell and tissue culture.

Color Doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization.

Color Doppler sonographic findings on 38 lesions in 31 patients who had primary hepatocellular carcinoma were evaluated before and after transcatheter arterial embolization and compared with dynamic CT and hepatic arteriographic findings. All lesions that were observed with dynamic CT or arteriography were correctly identified on color Doppler sonography. Peritumoral pulsatile flow was the predominant color Doppler flow seen in all lesions. Mixed pulsatile and continuous flow were noted in larger tumors and in tumors with a higher degree of vascularity, as determined by arteriography. Two weeks after treatment, color Doppler flow was still identified in 18 lesions (47%), corresponding to dynamic CT or arteriographic findings documenting residual tumor. Histopathologic examination, performed in 10 other lesions, showed that the tumor was completely necrotic in five. These five necrotic tumors were not visible on color Doppler flow images after treatment. Viable tumor was observed in the five remaining lesions, all of which were shown on color Doppler flow images after treatment. During the 6- to 16-month follow-up period, color Doppler flow images showed recurrence of 13 (50%) of 26 lesions, corresponding to tumor recurrence as shown by CT and arteriography. We conclude that color Doppler sonography is useful for imaging hepatocellular carcinoma, for evaluating residual tumor after treatment, and for imaging tumor recurrence during follow-up.

Suppression of basic fibroblast growth factor expression by antisense oligodeoxynucleotides inhibits the growth of transformed human astrocytes.

Basic fibroblast growth factor (bFGF) is a heparin-binding protein expressing potent mitogenic and angiogenic properties. Elevated levels of bFGF have recently been described in human glioma cell lines. The high degree of vascularity and invasiveness which characterize human gliomas suggest that activated expression of bFGF or similar proteins may be related to the aberrant growth patterns of these tumors. The influence of endogenous bFGF on glioma cell growth in vitro was evaluated in the present study by down-regulating bFGF expression using antisense oligonucleotide primers. The addition of 50 microM bFGF-specific antisense primer to the human glioma cell line SNB-19 resulted in an 80% inhibition in glioma growth. This effect was saturable and specific. Antisense primers directed to two different sites of bFGF mRNA were effective in suppressing SNB-19 growth, whereas sense strand primer was ineffective. Furthermore, only the antisense primer significantly reduced the specific activity of bFGF protein in SNB-19 cell extracts. Neither antisense or sense primers inhibited the growth of non-transformed human glia. bFGF mRNA was detected in both transformed and non-transformed human glia by polymerase chain reaction analysis suggesting that alterations in bFGF isoform content or activity may be specifically related to abnormal growth control in human gliomas.

Treatment of Oral Mucous Cysts With an Argon Laser

To the Editor.— Mucous cysts (MC) of the minor salivary glands are oral soft-tissue lesions that arise as domeshaped swellings. The most common sites of predilection are the mucous surface of the lower lip and the buccal mucosa. The wall of these lesions is mostly composed of granulation tissue with a high degree of vascularization. 1 Mucouscysts seem to develop as a result of the escape of mucus through a ruptured duct into the adjacent connective tissue. 2 The blue-green light of the argon laser is selectively absorbed in the hemoglobin molecule of the intravasal erythrocytes and transformed to heat resulting in destruction of vascular tissues. 3,4 The heat generated also causes nonspecific epidermal and upper dermal coagulation necrosis with subsequent fibrosis. The rationale for treating MC with the argon laser was the high vascular component of the lesions' wall, as well as the nonspecific shrinkage effect due to heat. This is the first report on the successful treatment of MC of the oral cavity with an argon laser.

Unique patterns of brain metastasis produced by different human carcinomas in athymic nude mice.

The purpose of this study was to develop an in vivo model to study the growth pattern and biological behavior of brain metastases produced by different human carcinomas. To do so, human tumor cells from 8 different carcinomas of the colon, breast, kidney and lung were injected into athymic nude mice either by a direct intracerebral route or into the internal carotid artery. All carcinoma cells invaded through the blood-brain barrier and produced progressively growing lesions in the brain parenchyma. Unique patterns of growth were discernible among the carcinomas. Human colon carcinomas produced multiple lesions that spread by extension. Lung carcinoma cells produced widespread lesions throughout the brain. A very high degree of vascularization was associated with lesions produced by renal-cell carcinoma. The influence of estrogen on the growth of estrogen-receptor-positive human breast carcinoma cells was well demonstrated in this model. We conclude that the athymic nude mouse can be a useful model for studies of the biology and perhaps therapy of brain metastases produced by human carcinoma cells.

Vascularization of a lobster muscle.

The vascularization of the distal accessory flexor muscle (DAFM) in the walking legs of the lobster, Homarus americanus, was examined with dye injection and electron microscopy. Vascularization of this flat, thin DAFM is via two vessels, one supplying the tendinal region of the muscle and the other the exoskeletal region. The vessels that originate from the single major limb vessel, subdivide extensively over the DAFM and form a profuse network that has hitherto gone unnoticed. The degree of vascularization of individual fibers was determined by periodic sampling along its length with thin-section electron microscopy. At each and every sampling station, individual fibers had several (seven to eight), small-diameter (4 μm) blood vessels in their cross-sectional profile. In contrast, nerve terminals of the excitor and inhibitor axon were rarely encountered. This high degree of vascularization was found amongst fibers that are from different regions of the DAFM and differ in the performance of their excitatory synapse but are similar in their structural and contractile properties.

The radioscapholunate ligament: a gross and histologic description.

The anatomic relationships of the carpal radioscapholunate ligament to its contiguous structures were analyzed by studying 1) 12 grossly dissected fresh adult wrists, and 2) multiple histologic sections from six adult wrists. Observations indicate that the radioscapholunate ligament originates from the prominence between the scaphoid and lunate articular facets on the distal articular surface of the radius, and from the palmar margin of the distal radius, deep and medial to the origin of the radiotriquetral and radiocapitate ligaments. The primary insertion of the radioscapholunate ligament is the medial margin of the proximal pole of the scaphoid. The ligament secondarily inserts into the lateral margin of the lunate and significantly contributes to the proximal portion of the scapholunate interosseous ligament. The radioscapholunate ligament is distinguished morphologically from the other palmar radiocarpal ligaments by its loosely organized collagen fibers and relatively high degree of vascularity. The radiotriquetral and radiocapitate ligaments are composed of densely fasciculated collagen fibers surrounded by perpendicularly oriented perifascicular and epiligamentous fibers. A fibrous capsular layer covers the most superficial aspect of each carpal ligament. On the deep surfaces of these ligaments, a condensation of epiligamentous fibers forms a synovial capsular layer. The palmar radiocarpal ligaments are truly intracapsular structures, as they are interposed between the fibrous and synovial capsular layers. No histologic evidence of elastin is present within the substance of these ligaments.

The magnocellular and parvocellular paraventricular nucleus of rat: Intrinsic organization

The magnocellular and paravocellular regions of the rat hypothalamic paraventricular nucleus (PVN) were examined in several hundred brains. Converging qualitative and quantitative anatomical methods, including Golgi impregnations, Nissl stains, silver stains, and immunocytochemistry were used to study the intrinsic organization of the PVN with light, scanning, and transmission electron microscopy. A computer-assisted quantitative analysis of dendritic branching patterns was used to examine total dendritic length, center of mass, orientation of dendritic tree, and several other parameters of dendritic organization and revealed statistically significant differences between cells in the lateral and posterolateral magnocellular and medial parvocellular areas of PVN. Electron microscopy, Golgi impregnation, and neurophysin immunohistochemistry showed that dendrites of posterolateral cells were generally oriented perpendicular to the third ventricle; dendrites of cells in the lateral PVN usually projected medially from the perikaryon. Cells in the medial zone of PVN had dendritic trees which often paralleled the third ventricle. Large numbers of axons entered and left PVN ventrally near the midline and laterally in the area of the posterolateral PVN; axons generally were oriented parallel to the mean major axis of dendritic trees in these areas. Ultrastructural examination of serial thin sections showed a peculiar astroglia multiple lamellar isolation of axodendritic synaptic contacts. Intrinsic axons commonly arose from parvocellular but not from magnocellular neurons and contacted dendrites of both medial parvocellular and more lateral magnocellular neurons. Synapses were found on shafts and spines of dendrites, on perikarya and somatic appendages, and invaginated into the soma. Both dendrites axons with large neurosecretory vesicles and immunostained with neurophysin antiserum were found postsynaptic to other axons. Presynaptic neurosecretory axons were not found within the PVN. A semiquantitative analysis of catecholamine axons identified with the glyoxylic acid method and fibers immunoreactive with ACTH and Substance P antisera indicated that the parvocellular region of PVN received ggreater innervation than the lateral magnocellular area; similarly, a reater density of stained fibers was found in the medial parvocellular PVN region with Golgi impregnations and silver stains. With a stereological analysis of 1-micrometer plastic sections, the parvocellular area had a significantly greater neuropil to cell volume ration, with cells accounting for 48 +/- 9% in the lateral magnocellular zone, but only for 26 +/- 7% in the parvocellular area. A quantitative analysis of vasculature from thin sections showed that the PVN had 3.3 times more blood vessels, and 3.6 times more lumen perimeter than a control area ventrolateral to PVN; an interesting finding here was that the medial parvocellular PVN had a high degree of vascularity, not significantly different from the lateral magnocellular zone...

CIRCULATION OF THE HUMAN THYROID

The gross blood supply of the thyroid gland is a matter of common knowledge, but the finer details of the circulation are not well described. There are certain facts about the vascularity of this organ that make for difficulty in demonstration and description. The thyroid is said to have the richest blood supply of any organ in the human body. This high degree of vascularity is well illustrated in the figures given by Burton-Opitz. 1 In his chart for the volume of blood per minute per hundred grams of organ, the thyroid heads the list. It receives 560 cc. of blood per minute per hundred grams. This is from two to ten times the quantity given for other organs. Such a great volume per minute can be possible only in the presence of a rich capillary bed. This highly vascular character provides such a complex network of vessels as seen

“The Micrococcus of Tubercle”

AN article on “Disease Germs,” by Dr. W. B. Carpenter, in the current number of the Nineteenth Century, contains the following:—“Another line of inquiry which has obviously the most important bearing upon human welfare is the propagability of the micrococcus of tubercle by the milk of cows affected with tuberculosis, a question in regard to which some very striking facts have been brought before the Medical Congress by a promising young pathologist”—naming myself; and I hope that I am sufficiently grateful to a veteran in science for his complimentary if not altogether accurate reference to my work. What I did say at the recent Medical Congress, and at much greater length in a small volume entitled “Bovine Tuberculosis in Man” (London, 1881)—Dr. Carpenter will find it, I think, among his books—was not anything about “the micrococcus of tubercle,” but about a variety of somewhat technical morphological details in respect to which certain cases of tuberculosis in man resembled the tuberculosis or “pearl disease” of the bovine species, I did indeed introduce half a page at the end of my essay to show how clear was the issue between my view of tuberculosis communicated from the cow and the view which Dr. Carpenter has been expounding, and I hope you will have room for the passage:—“The doctrine of a tuberculous virus was stated by Klebs in 1868, and has been advocated by him, as well as by Cohnheim, in recent writings. In its latest form this doctrine asserts the existence of a specific minute organism to whose agency the infection is due. The minute organism is called by Klebs Monas tuberculosum. The method of proof which I have followed in this work makes it impossible that the infective agency of a minute organism should in any way come into my view of the communication of bovine tuberculosis to man. I have rested the whole case upon certain minute identities of form and structure in the infected body, due to the mimicry of infection. Among other points there were the leaf-like and cord-like outgrowths of the pleura and peritoneum, these being the early stages of the lentil-like or pearl-like nodules and their connecting threads; the lymphatic glands, with distinct nodular formations in their substance; the lungs, with smooth-walled closed vomicæ or with encapsuled nodules. In the new formations generally there was a particular pattern of microscopic structure, in which giant-cells and epithelial-like cells figure largely, and there was a relatively high degree of vascularity. In all these points the disease in man is a mimicry of the parent disease in the bovine animal. That mimicry is not only in single features, but it is of the whole disease. It is possible to conceive of the juices and particles of the primarily diseased body acquiring a kind of spermatic virtue which gave them the power to communicate the specific disease as a whole and in all its several manifestations to another body in which they should happen to lodge. But it is hardly possible to think of a neutral living organism being charged with the power of conveying so complex details of form and structure from one body to another” (“Bovine Tuberculosis in Man,” pp. 103, 4).