Expression of CA15–3 in renal cell carcinoma

CA15–3 expression was analyzed in renal cell carcinoma (RCC) from the standpoint of the histogenesis of RCC. Tissue sections from surgical specimens of 12 cases of clear cell type RCC and from autopsy specimens of eight fetal kidneys were stained by an indirect immunoperoxi-dase method using DF-3. All the RCC cases stained positively for CA15–3, with 10 of the 12 cases showing strong, diffuse immunoreactivity on the cell membrane. Expression of CA15–3, as well as other markers such as epithelial membrane antigen, neuron-specific enolase, glandular cytokeratin and other lectins, suggest a more complicated histogenesis of RCC, rather than a simple proximal tubular origin.     

Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle

IGF-1 is a potent growth factor for both motor neurones and skeletal muscle. Muscle IGF-1 is known to provide target-derived trophic effects on motor neurones. Therefore, IGF-1 overexpression in muscle is effective in delaying or preventing deleterious effects of ageing in both tissues. Since age-related decline in muscle function stems partly from motor neurone loss, a tetanus toxin fragment-C (TTC) fusion protein was created to target IGF-1 to motor neurones. IGF-1–TTC retains IGF-1 activity as indicated by [³H]thymidine incorporation into L6 myoblasts. Spinal cord motor neurones effectively bound and internalized the IGF-1–TTC in vitro . Similarly, IGF-1–TTC injected into skeletal muscles was taken up and retrogradely transported to the spinal cord in vivo , a process prevented by denervation of injected muscles. Three monthly IGF-1–TTC injections into muscles of ageing mice did not increase muscle weight or muscle fibre size, but significantly increased single fibre specific force over aged controls injected with saline, IGF-1, or TTC. None of the injections changed muscle fibre type composition, but neuromuscular junction post-terminals were larger and more complex in muscle fibres injected with IGF-1–TTC, compared to the other groups, suggesting preservation of muscle fibre innervation. This work demonstrates that induced overexpression of IGF-1 in spinal cord motor neurones of ageing mice prevents muscle fibre specific force decline, a hallmark of ageing skeletal muscle.     

A case of large cell neuroendocrine carcinoma exhibiting rhabdoid features in the esophagogastric junction

We report a case of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction. An 81‐year‐old man presented to Saku Central Hospital Advanced Care Center with a tumor in the esophagogastric junction. During upper gastrointestinal endoscopy, an ulcerative tumor, measuring 4 × 3 cm in diameter, was observed. Computed tomography revealed lymph node metastasis, but no metastasis to other organs was observed. A thoracoscopic subtotal esophagectomy was performed. Histopathologically, anaplastic large cells exhibited a solid growth pattern with focal and geographic necrosis. Approximately half of the tumor cells exhibited large nuclei with conspicuous nucleoli; an eosinophilic “rhabdoid” cytoplasmic inclusion; and a nucleus displaced eccentrically by the cytoplasmic inclusion body. Immunohistochemically, tumor cells, including rhabdoid cells, were focally positive for pan‐cytokeratin and diffusely positive for vimentin and synaptophysin. Additionally, electron microscopy identified dense‐core granules in the tumor cells. Therefore, a diagnosis of large cell neuroendocrine carcinoma with rhabdoid features was made. A few cases of esophageal neuroendocrine tumors with rhabdoid features have been reported in the lung and pancreas; however, this is the first report of large cell neuroendocrine carcinoma with rhabdoid features in the esophagogastric junction.     

Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve

Diabetes mellitus is a growing epidemic with severe cardiovascular complications. Although much is known about mechanical and electrical cardiac dysfunction in diabetes, few studies have investigated propagation of the electrical signal in the diabetic heart and the associated changes in intercellular gap junctions. This study was designed to investigate these issues, using hearts from control and diabetic rats. Diabetic conditions were induced by streptozotocin (STZ), given i.v. 7–14 days before experiments. Optical mapping with the voltage-sensitive dye di-4-ANEPPS, using hearts perfused on a Langendorff apparatus, showed little change in baseline conduction velocity in diabetic hearts, reflecting the large reserve of function. However, both the gap junction uncoupler heptanol (0.5–1 m m ) and elevated potassium (9 m m , to reduce cell excitability) produced a significantly greater slowing of impulse propagation in diabetic hearts than in controls. The maximal action potential upstroke velocity (an index of the sodium current) and resting potential was similar in single ventricular myocytes from control and diabetic rats, suggesting similar electrical excitability. Immunoblotting of connexin 43 (Cx43), a major gap junction component, showed no change in total expression. However, immunofluorescence labelling of Cx43 showed a significant redistribution, apparent as enhanced Cx43 lateralization. This was quantified and found to be significantly larger than in control myocytes. Labelling of two other gap junction proteins, N-cadherin and β-catenin, showed a (partial) loss of co-localization with Cx43, indicating that enhancement of lateralized Cx43 is associated with non-functional gap junctions. In conclusion, conduction reserve is smaller in the diabetic heart, priming it for impaired conduction upon further challenges. This can desynchronize contraction and contribute to arrhythmogenesis.     

MYOEPITHELIOMA OF THE PAROTID GLAND

Two cases of myoepithelioma occurring in the parotid gland were reported. These tumors consisted of spindle cells that exhibited an arrangement similar to leiomyoma or fibroma. The diagnosis was made on the basis of characteristic ultrastructural as well as immunohistochemical findings : The tumor cells of the two cases likewise contained myofilaments and gave a positive result for the S-100 protein immunohistochemical technique. ACTA PATHOL. JPN. 35 : 409–417, 1985.     

FROZEN SECTION DIAGNOSIS OF HYPERTENSIVE PULMONARY VASCULAR CHANGES AT SURGERY FOR CONGENITAL HEART ANOMALIES

Frozen sections of lung biopsy were prepared in 30 cases of congenital heart anomalies with pulmonary hypertension, and evaluation of severity of the pulmonary vascular changes was made during the surgery. Statistically, significant difference was not found between the diagnosis made by frozen sections and those made by paraffin sections. It is concluded that rapid and accurate diagnosis of pulmonary vascular changes can be made by means of frozen section diagnosis. This method will prove to be clinically important by assisting during operation in rapid assessment of indication for total correction of congenital heart anomalies. ACTA PATHOL. JPN. 35 : 803–807, 1985.     

Epstein-Barr virus-infected lymphocytes in non-neoplastic lymph nodes of patients infected with human immunodeficiency virus

Non-Hodgkin's lymphomas occurring In AIDS patients (AIDS NHL) are known to be highly associated with Epstein-Barr virus (EBV). However, there have been no previous detailed studies of the distribution of EBV-Infected non-neoplastic lymphoblasts, which may act as precursors of AIDS-NHL In the present study, an attempt was made to detect such EBV-Infected cells in patients' lymphoid organs. Fifteen non-neoplastic lymph nodes obtained from HIV-positive individuals were processed for in situ demonstration of EBV-encoded small RNA (EBER-1) and EBVencoded latent membrane proteln 1 (LMP-1). An Increased number of EBER-1–expressing cells were observed (9/15). EBER-1–positive cells were present much more frequently in advanced cases, as evaluated using the histopathologic criteria of Grund-mann (1/6 cases showing irregular follicular hyperplasia; 3/4 showing the beginning follicular destruction; 2/2 showing progressive follicular destruction; 3/3 showing follicular involution). LMP-1 was detected in 3/9 EBER-1–positive cases, and all three of these cases were at the most advanced stage. Furthermore, cells expressing LMP-1 were larger (62.83±6 μm²) than EBER-1 + LMP-1^-- cells (29.05±7 μm²). These results indicate that cells with latent expression of the EBV gene increase in number in lymphoid organs of HIV-infected individuals at an advanced stage and that some of the cells are in a transformed state. It is possible to speculate that these cells are precursors of AIDS-NHL     

Clathrin-mediated endocytosis in snake motor terminals is directly facilitated by intracellular Ca2+

At the snake neuromuscular junction, low temperature (LT, 5–7°C) blocks clathrin-mediated endocytosis (CME) while exocytosis is largely unaffected. Thus compensatory endocytosis that normally follows transmitter release is inhibited, or 'delayed' until the preparation is warmed to room temperature (RT). This delay was exploited to observe how changes in bulk [Ca²⁺]_i directly affect CME. Motor terminals were loaded with fura-2 to monitor [Ca²⁺]_i. With brief stimulation at LT, [Ca²⁺]_i transiently increased but returned to baseline (∼63 n m ) in < 8 min. After 15 min at LT, [Ca²⁺]_i was altered by incubating preparations in the Ca²⁺ ionophore ionomyocin. Preparations were then warmed to RT to initiate delayed endocytosis, which was quantified as uptake of the fluorescent optical probe sulforhodamine 101. Endocytosis was more rapid when [Ca²⁺]_i increased; the rate at 300 n m Ca²⁺ was ∼double that under basal conditions. Thus the rate of CME – isolated from stimulation, transmitter release, and other forms of endocytosis – is directly influenced by intraterminal Ca²⁺.     

Network-based activity induced by 4-aminopyridine in rat dorsal horn in vitro is mediated by both chemical and electrical synapses

This study investigated the role of electrical and chemical synapses in sustaining 4-aminopyridine (4-AP)-evoked network activity recorded extracellularly from substantia gelatinosa (SG) of young rat spinal cord in vitro . Superfusion of 4-AP (50 μ m ) induced two types of activity, the first was observed as large amplitude field population spiking activity and the second manifested within the inter-spike interval as low amplitude rhythmic oscillations in the 4–12 Hz frequency range (mean peak of 8.0 ± 0.1 Hz). The AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μ m ) abolished field population spiking and disrupted 4–12 Hz rhythmic oscillatory activity whereas the NMDA receptor antagonist d -AP5 (50 μ m ) had no significant effect on either activity component. The glycine receptor antagonist strychnine (4 μ m ) and the GABA_A receptor antagonist bicuculline (10 μ m ) diminished and abolished, respectively, field population spiking and both antagonists reduced the power of 4–12 Hz oscillations. The non-specific gap junction blockers carbenoxolone (100 μ m ) and octanol (1 m m ) attenuated both types of 4-AP-induced activity. By comparison, the neuronal-specific gap junction uncouplers quinine (250 μ m ) and mefloquine (500 n m ) both disrupted 4–12 Hz oscillations but only quinine reduced the frequency of field population spiking. These data demonstrate the existence of 4-AP-sensitive neuronal networks within SG that can generate rhythmic activity, are differentially modulated by excitatory and inhibitory ionotropic neurotransmission and are at least partly reliant on neuronal and/or glial-mediated electrical connectivity. The physiological significance of these putative intrinsic SG networks and the implications in the context of processing of nociceptive inputs are discussed.     

Oxyphilic cell variant of endometrioid adenocarcinoma

A case of oxyphllk cell variant of endometrlold adenocarclnorna is presented. To the best of our knowledge, there have been only three such cases reported in the English literature. The patient was a 35-yearold Japanese female (gravida 0, para 0). She was sllghtly obese with profuse vaginal bleeding. Histologlcal examlnation of the resected uterus revealed endometrlold adenocarcinoma with an exclusive oxyphllic cell component. There was no evidence of myornetrial Invasion nor lymph node metastases. Reported cases of oxyphilic cell varlant of endometrioid admocamlnoma, lncludlng the present case, were stages 0–1 and grades 1–2. Although further study is necessary to evaluate this variant, oxyphllk cell variant seems to be an early stage of ademcarcinoma and should be differentiated from eosinophllk mgtaplasia and other types of adenocarcinoma of the endometrium.     

MORPHOMETRIC ANALYSIS OF HUMAN NEUROMUSCULAR JUNCTION IN DIFFERENT AGES

Application of morphometric analysis to the study of neuromuscular junction is helpful to the quantitative approach of ultrastructural changes. In this study, twelve autopsied subjects of different ages were examined on the ultra-structure of neuromuscular junctions using morphometric analysis. The postsynaptic area and postsynaptic membrane length were significantly greater in adults than in infants. The results indicate that the number and/or depth of the secondary synaptic clefts of adults are greater than those of infants. In the aged subjects, presynaptic membrane length and postsynaptic membrane density showed a significant decrease. The latter observations were thought to be the results of regressive changes of pre- and postsynaptic structure with aging. The variations of each structural element were also studied. The large variations were found in the postsynaptic area, postsynaptic membrane length, and membrane length ratio of adults and aged group. On the other hand, variations in postsynaptic membrane density were small in all age groups. The importance of the knowledge of these age related changes and variations in the studies of neuromuscular junction was discussed. ACTA PATHOL. JPN. 34: 1243–1249. 1984.     

A MORPHOLOGICAL ANALYSIS OF VALVULAR THICKENING IN THE CONGENITALLY MALFORMED HEARTS

A total of 787 cases with various congenital heart anomalies was histopathologically studied for valvular thickening, especially from the view point of response to mechanical stimulation (hemodynaqic changes). Macroscopically, both atrioventricular and semilunar valve leaflets showed difhse and rugous thickening of the body with thickened chordae tendineae or widened noduli Morgagni and/or Arantil and separation of the commissure in cases with increased blood flow or, enlarged volume. They showed localized thickening at the distal ends including the line of closure and prominent noduli in cases with increased pressure. Histological examination revealed that the increased flow made the proximalis thickened, the increased volume made the Abrosa thickened and the increased pressure made the spongiosa hypertrophied. The combined hemodynamic stresses made any of the combination of the 3 types of morphological change. Some of the connective tissue disease such as gargoylism and Marfan syndrome showed the same rule superimposed to their basic disorder. Crasy valvular changes associated with chromosome anomalies such as mongolism, 15 and 18–trisomy were exceptionally out of the rule of hemodynamic changes.     

Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions. We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases. Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent. Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.     

Regional distribution of asthma-related hospital treatment periods in Finland in 1972–86

We examined the use of asthma-related hospital services in geographically different areas of Finland in 1972–86, using data obtained from hospital discharge registers. A total of 254402 cases diagnosed as asthma was identified (diagnosis 493, International Classification of Diseases, 8th Revision ), information on the patient's place of residence enabling comparison of the southern, western, eastern, and northern parts of the country. Annual hospitalizations and the occurrence of new cases were calculated relative to the population, the former being found to increase throughout the country during the period studied, the most marked rise being 8.8% in Northern Finland (95% confidence interval 6.4–11.3%), and the smallest, 1.1%, in Western Finland (−0.2 to +2.5). A corresponding trend was also noted in the annual occurrence of new cases, which increased most in Northern Finland, i.e. by 4.8% (3.0–6.6), and decreased in Western Finland by 2.9% (– 3.6 to –2.1). The change in asthma and the organization of treatment and factors related to the cold environment may, in combination, contribute to difficulties in the treatment of asthma in Northern Finland.     

Secular changes in incidence and mortality associated with Staphylococcus aureus bacteraemia in Quebec, Canada, 1991–2005

In order to examine secular changes in the incidence and mortality associated with Staphylococcus aureus bacteraemia before and after the emergence of methicillin-resistant S. aureus (MRSA), a retrospective cohort study of 815 patients with S. aureus bacteraemia was performed in the Estrie region of Quebec, Canada, between 1991 and 2005. The primary outcome was all-cause 30-day mortality. Between 1991–1993 and 2003–2005, the proportion of cases attributed to endocarditis and pneumonia increased from 4% to 11% and from 2% to 11%, respectively, while that attributed to catheter infections decreased from 49% to 17%. MRSA was almost absent in 1991–1999, but accounted for 10% and 20% of cases in 2000–2002 and 2003–2005, respectively. The population incidence of bacteraemia caused by methicillin-susceptible S. aureus (MSSA) remained stable between 1997 and 2005, while that of MRSA increased from 0 to 7.4/100 000. Risk-factors for mortality included age, co-morbidities, female gender, residence outside the city of Sherbrooke, pneumonia (OR 3.35, 95% CI 1.96–5.73) or endocarditis (OR 2.89, 95% CI 1.67–5.01) as the source, and an absence of treatment. After adjusting for confounders, patients with MRSA bacteraemia had a higher mortality rate than those with MSSA bacteraemia (OR 2.21, 95% CI 0.99–4.96, p 0.053). Mortality in patients with MSSA bacteraemia was 19% (16/83) in 1991–1993, 23% (26/113) in 1994–1996, 29% (50/173) in 1997–1999, and 28% (52/185) in 2000–2002, decreasing to 15% (28/192) in 2003–2005, which impacted on the relative mortality rates of MRSA and MSSA. MRSA did not replace, but added to, an existing stable incidence of MSSA bacteraemia.     

Angiomyofibroblastoma of the vulva: A clinicopathologic study of seven cases

A clinicopathologic and immunohistochemical review was made of seven cases of angiomyofibroblastoma. The patients were middle-aged women who had a slowly growing mass, measuring 1.5–6 cm in maximum dimension, located sub-cutaneously in the vulva. The tumors were well-demarcated and characterized by well-vascularized, alternating hyper-cellular and hypocellular edematous areas composed of bland, plump spindle- or oval-shaped stromal cells frequently aggregated around small blood vessels. An epithelioid appearance of the stromal cells was seen in two cases. Immunohistochemically, the stromal cells were consistently positive for vimentin and desmin, but negative for muscle specific actin, a-smooth muscle actin, myosin, cytokeratins, S-100 protein or von Willebrand factor. Ultrastructurally, the plump stromal cells had a small amount of peripherally located rough endoplasmic reticulum, numerous pinocytotic vesicles and abundant intermediate filaments, on which immunogold probes for desmin were localized, whereas fine filaments were few and there were no electron dense plaques. Thus, while the proliferating stromal cells expressed an immunohistochemical profile of peculiar myoid differentiation, ultrastructural findings differed from those of smooth muscle cells or those seen in typical myofibroblasts. At 1–4 years after surgery, there was no evidence of recurrence.     

Prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction

The prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction are uncertain. We studied 61 consecutive esophagogastrectomy specimens with adenocarcinoma, which were subjected to extensive histopathologic examination. Barrett esophagus was found in 64% of the cases (39 of 61), but had been recognized in only 38% of the patients with Barrett-associated carcinoma who had undergone preoperative endoscopy with biopsy (13 of 34). The median extent of Barrett esophagus with adenocarcinoma was 5 cm (range, 1 cm to 12 cm), and distinctive-type ("specialized") Barrett mucosa predominated (35 of 39; 90%). The Barrett adenocarcinomas were centered in the distal esophagus 2 cm +/- 0.3 cm above the esophagogastric junction. The patients with Barrett adenocarcinoma showed a striking predominance of white men (34 of 39; 87%) in contrast to gastric adenocarcinoma cases (21 of 69; 30%) and to Barrett patients without carcinoma or dysplasia (75 of 149; 50%), but similar to patients having adenocarcinoma of the esophagus or esophagogastric junction without demonstrable Barrett esophagus (16 of 22; 73%). Our findings suggest that most adenocarcinomas of the esophagus or esophagogastric junction are Barrett carcinomas, rather than gastric cardiac cancers or other types of esophageal adenocarcinoma; most Barrett adenocarcinomas occur in short segments of Barrett esophagus, which may be difficult to detect at endoscopy; and white men with Barrett esophagus may constitute a clinically identifiable at-risk group suitable for surveillance.     

The impact of legal termination of pregnancy and of prenatal diagnosis on the birth prevalence of Down syndrome in Denmark

A considerable reduction in number of livebirths for mothers over 35 was observed in Denmark from 1960 to 1980. Birthrates for those aged 35–39 fell by 58.8%, for those aged 40–44 by 78%. In 1979–1980 100 infants with Down syndrome were born among 116757 newborns, a birth prevalence of 0.86 per 1000, which was significantly lower than the incidence of 1.17 per 1000 when the prenatally diagnosed cases were included. The reduction was noticeable for the age group over 35 where it fell to 1.89 per 1000 for mothers 35–39 and 6.48 per 1000 for mothers over 40.
The utilization of prenatal diagnosis was 72 per 100 livebirths for women 35 and older in the Copenhagen area and 56 per 100 livebirths for the rest of the country, with differences in different areas.
The number of induced abortions for women 35 years and older was 9265 against 6597 livebirths. The estimated number of Down syndrome cases averted by unrestricted abortion was 61, twice the number prevented by amniocentesis (31), with the greatest impact for mothers over 40.
An increased risk of Down syndrome for the age group 35–39 was observed when liveborn and prenatal cases were considered together showing an incidence of 6.89 per 1000, with the highest incidence in the Copenhagen area, 8.70 per 1000, more than double the incidence of 3.04 observed in Copenhagen from 1960 to 1971, for the same age group.     

The anatomical relationship of the iliocava junction to the lumbosacral spine and the aortic bifurcation

This study dissected 42 cadavers to investigate the level of the iliocava junction and the relationship with the lumbosacral spine and the aortic bifurcation. The iliocava junction was between L4 and S1, most often at the level of L5 (64%) and on the median third of the spine (55%). The average height of the iliocava junction was 15.5 mm. The mean interiliac angle was 69°. It was not related to the width of the iliocava junction. The iliocava junction covered the whole of the L5-S1 disc in 12% of cases. The iliocava junction was located above the aortic bifurcation only in 1 case. The mean distance between iliocava junction and aortic bifurcation was 19 mm. The variability of the iliocava confluence is high and complicates the anterior approach to the lumbosacral spine.     

SARCOIDOSIS OF THE SPINAL CORD

The authors report a female elderly patient with quadriplegia, hypesthesia below the neck, and rectourinary dysfunction, which were found at autopsy to have been caused by involvement of the lower cervical and upper thoracic segments of the spinal cord in systemic sarcoidosis. Sixty cases of spinal cord sarcoidosis reported in the literature are also reviewed. Most patients had clinical signs which mimicked those of a spinal cord tumor or meningomyelitis. Only in less than one-third of the cases had sarcoidosis been diagnosed before neurological symptoms occurred. Macroscopically, most intramedullary lesions formed a mass, whereas extramedullary lesions usually manifested as meningitis. Histologically, perivascular distribution of sarcoid granulomas was noted in our patient as well as in many cases reported in the literature. The clinical course of the patients with spinal sarcoidosis was usually poor when early diagnosis was not made. ACTA PATHOL. JPN. 35: 1007–1022, 1985.