Neuroendocrine carcinomas (carcinoid tumor) of the testis. A clinicopathologic and immunohistochemical study of ten cases

We studied 10 cases of primary pure testicular neuroendocrine carcinoma. Patients were between 16 and 48 years old and had testicular swelling with pain or a painless testicular mass and no history of neuroendocrine carcinoma or other malignant neoplasm. All underwent orchiectomy. The tumors were low (n = 9) and intermediate (n = 1) grades with a variegated histologic appearance characterized by a nesting pattern, cords of neoplastic cells with rosettes, or sheets of neoplastic cells. Mitotic activity was lacking in 9 cases. In 1 case, mitotic figures ranged from 7 to 8 per 10 high-power fields, and cellular atypia and comedo-like necrosis were present. Immunohistochemical studies using a keratin cocktail, chromogranin, synaptophysin, epidermal growth factor, p53, placental-like alkaline phosphatase, and CD117 (c-kit) were performed in all cases. Keratin, chromogranin, and synaptophysin were positive in all tumors. Clinical follow-up information was obtained for 6 patients (range, 12-60 months): 5 with low-grade tumors were alive 24 to 60 months after diagnosis; 1 with an intermediate-grade tumor died of tumor 12 months after initial diagnosis. The behavior of these tumors, while in the testicular region, correlates well with the histologic grade. We propose replacing the term testicular carcinoid with neuroendocrine carcinoma, which better reflects the nature of these neoplasms.     

Effect of eye rotation on visual-field map onto superior colliculus and visual cortex

We used multiunit recording to assess the effect of rotating one eye approximately 90 degrees at about the time of normal eye opening. Rotation of the eye did not alter the topography of the retinal maps onto visual cortex or superior colliculus. The intorted eye drove cells at most recording points in the contralateral visual cortex and superior colliculus. In its ipsilateral colliculus the intorted eye drove cells at about 10% of the recording points; that is, the temporal retina of this eye was quite ineffective in driving collicular cells. In its ipsilateral cortex the intorted eye drove cells at about 30% of the recording sites. The unoperated eye drove cells at all locations in both colliculus and cortex on both sides of the brain. The effects of extorsion were studied only in the superior colliculus. Extorsion and intorsion produced similar results except that extorsion produced a less severe deficit in the ability of the temporal retina to drive cells in its ipsilateral colliculus. Cutting all the extraocular muscles without eye rotation was studied only in the colliculus and produced results similar to those produced by intorsion and extorsion. However, the temporal retina of the operated eye was more effective after muscle cut alone than after intorsion or extorsion. Forcing the animal to use the rotated right eye alone on alternate days during the first 3 mo of life did not decrease the deficits. Almost all recording sites in the right colliculus were driven only by the unoperated left eye. If the left eye was sutured when the right eye was rotated, only the right eye drove cells in the left colliculus, but the two eyes were about equally effective in the right colliculus; however, rather few sites in the right colliculus were binocularly driven. We conclude that both extraocular muscle section and eye rotation reduce the effectiveness of the uncrossed input from the operated eye to the superior colliculus and visual cortex. The effects on the superior colliculus are, however, greater.     

The immunological significance of histological changes in the spleen and liver in mouse malaria

The spleens and livers of mice were investigated histologically on various days subsequent to infection with Plasmodium berghei yoelii using immunofluorescence and autoradiography. At the height of the parasitaemia, at a time when nonspecific immunosuppression is known to occur, the `thymus-dependent area' round the central arteriole of the spleen was replaced by proliferating lymphoid cells many of which were IgG containing plasmablasts. There was also at this time a considerable decrease in small lymphocytes in this area. The significance of these findings is discussed in relation to the non-specific immunosuppression. In addition evidence for immune complex deposition was obtained in a number of tissues.     

Direct cytotoxic action of Shiga toxin on human vascular endothelial cells.

To help explain a role of the Shiga toxin family in hemorrhagic colitis and hemolytic-uremic syndrome in humans, it has been hypothesized that these toxins cause direct damage to the vascular endothelium. We now report that Shiga toxin purified from Shigella dysenteriae 1 does indeed have a direct cytotoxic effect on vascular endothelial cells in cultures. Human umbilical vein endothelial cells (HUVEC) in confluent monolayers were reduced 50% by 10(-8) M Shiga toxin after a lag period of 48 to 96 h. In comparison, nonconfluent HUVEC were reduced 50% by 10(-10) M Shiga toxin within a 24-h period. These data suggest that dividing endothelial cells are more sensitive to Shiga toxin than are quiescent cells in confluent monolayers. Both confluent and nonconfluent HUVEC specifically bound 125I-Shiga toxin. However, in response to the toxin, rates of incorporation of [3H]leucine into protein were more severely reduced in nonconfluent cells than in confluent cells. Toxin inhibition of protein synthesis preceded detachment of cells from the substratum. The specific binding of 125I-Shiga toxin to human endothelial cells and the cytotoxic response were both toxin dose dependent and neutralized by anti-Shiga toxin antibody. Heat-denatured Shiga toxin was without the cytotoxic effect. In addition, the complete culture system contained less than 0.1 ng of bacterial endotoxin per ml, as measured by the Limulus amoebocyte lysate test.     

In vivo phase variation and serologic response to lipooligosaccharide of Campylobacter jejuni in experimental human infection

Some Campylobacter jejuni strains which exhibit mimicry of gangliosides in their lipooligosaccharides (LOSs) are associated with development of Guillain-Barré syndrome, which complicates the selection of a suitable C. jejuni strain in a live-attenuated vaccine. C. jejuni 81-176 is the most well characterized strain available, but structurally, LOS of C. jejuni 81-176 exhibits mimicry of predominantly GM2 and GM3 gangliosides. We compared the antiganglioside human serologic responses of 22 volunteers post-oral vaccination (two-dose series, 14 days apart) with a killed whole-cell C. jejuni vaccine, those of volunteers (22 following initial challenge and 5 upon rechallenge) experimentally infected with the homologous C. jejuni vaccine strain 81-176, and those of 12 volunteers used as controls (placebo recipients). All volunteers were evaluated using thin-layer chromatography immuno-overlay and a panel of nine gangliosides at days 0, 21, and 28 either postvaccination or postinoculation. Antiganglioside antibodies were identified at baseline in 6 of the 61 volunteers (9.8%). There were no antiganglioside antibodies observed following vaccination or experimental infection rechallenge. Evidence of seroconversion was observed in 2 of 22 (9.1%) in the initial infection challenge group, comparable to 1 of 12 (8.3%) in the placebo recipients. Additional testing of seven selected volunteers in the initial challenge group at days 0, 3, 7, 10, 21, 28, and 60 showed that when antiganglioside antibodies occurred (mostly anti-GM1 and -GM2), responses were weak and transient. Furthermore, evidence from serologic probing of LOSs of isolates recovered from stools of six volunteers indicated that the isolates had undergone antigenic phase variation in ganglioside mimicry during passage in vivo. Collectively, with the exception of one volunteer with anti-GM2 antibodies at day 60, the results show an absence of persistent antiganglioside antibodies after experimental infection with C. jejuni or following administration of a killed C. jejuni whole-cell oral vaccine, although LOS phase variation occurred.     

Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed

Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.     

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.     

Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization

Dentine dysplasia type II is an autosomal dominant disorder in which mineralization of the dentine of the primary teeth is abnormal. On the basis of the phenotypic overlap between, and shared chromosomal location with, dentinogenesis imperfecta type II, a second disorder of dentine mineralization, it has been proposed that the two conditions are allelic. As recent studies have shown that dentinogenesis imperfecta type II results from mutation of the bicistronic dentine sialophosphoprotein gene (DSPP ), we have tested this hypothesis by sequencing DSPP in a family with a history of dentine dysplasia type II. Our results have shown that a missense change, which causes the substitution of a tyrosine for an aspartic acid in the hydrophobic signal peptide domain of the protein, underlies the phenotype in this family. Biochemical analysis has further demonstrated that this mutation causes a failure of translocation of the encoded proteins into the endoplasmic reticulum, and is therefore likely to lead to a loss of function of both dentine sialoprotein and dentine phosphoprotein.     

Smoking and Drinking Behavior in Patients with Head and Neck Cancer: Effects of Behavioral Self-Blame and Perceived Control

Patients who continue to use tobacco or alcohol following treatment for head and neck cancers are at greater risk for cancer recurrence and mortality. The present study examined the effects of behavioral self-blame and perceived control over health on smoking and alcohol use in a sample of 55 patients with cancers of the head and neck. Measures of self-blame, perceived control, and depression were administered and an assessment of past and current smoking and drinking behavior was obtained. As anticipated, continued smoking after completion of oncologic treatment was predicted by the interaction of behavior specific self-blame and perceived control. Patients who attributed the cause of their cancer to their past substance use exhibited a lower likelihood of smoking only if they also held the expectancy that their future cancer-related health was contingent on their own behavior. Among patients not holding the belief that cancer recurrence was contingent on their own actions, self-blame was associated with a higher probability of continued smoking. Self-blame and perceived control had no effect on continued alcohol use.     

Developments in cardiovascular ultrasound. Part 2: Arterial applications

Many of the changes resulting from arterial disease can be measured, using Doppler ultrasound for measurement of blood velocity and B-scan imaging for measurement of tissue structure and composition. Wall thickness, the degree of arterial narrowing and plaque volume can be measured using B-scan imaging, and 3D ultrasound can be used to improve the accuracy of measurements of plaque volume and for improved visualisation of complex arterial geometries. Measurement of the dynamic properties of the arterial wall permits estimation of wall elasticity and plaque motion. From the Doppler signal, measurements of blood velocity are used to estimate the degree of arterial narrowing and volumetric flow, although measurement errors can be large. Wall shear stress can be estimated by measuring the velocity gradient at the vessel wall. The problems of inadequate spatial resolution and interference from overlying tissue are largely removed when intravascular systems are used, and these have superior capability in the assessment of arterial structure and tissue composition. However, measurement of quantities relating to blood flow is more difficult using the intravascular approach, as the indwelling cather disturbs the blood flow pattern, and currently, assessment of flow and vessel cross-section are not performed at the same site.