Pathogenesis of Herpetic Neuritis and Ganglionitis in Mice: Evidence for Intra-Axonal Transport of Infection

The pathogenesis of acute herpetic infection in the nervous system has been studied following rear footpad inoculation of mice. Viral assays performed on appropriate tissues at various time intervals indicated that the infection progressed sequentially from peripheral to the central nervous system, with infectious virus reaching the sacrosciatic spinal ganglia in 20 to 24 hr. The infection also progressed to ganglia in mice given high levels of anti-viral antibody. Immunofluorescent techniques demonstrated that both neurons and supporting cells produced virus-specific antigens. By electron microscopy, neurons were found to produce morphologically complete virions, but supporting cells replicated principally nucleocapsids. These results are discussed in the context of possible mechanisms by which herpes simplex virus might travel in nerve trunks. They are considered to offer strong support for centripetal transport in axons.     

Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer

BACKGROUND AND METHODS: We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS: Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS: The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.     

Peritransplant use of ultraviolet-B irradiation (UV-B) therapy is detrimental to allogeneic stem cell transplantation outcome.

Whole-body UV-B phototherapy has been used for the treatment of graft-versus-host disease (GVHD) of the skin and has systemic immunosuppressive and tolerogenic effects. We hypothesized that whole-body UV-B therapy would improve donor engraftment and decrease the incidence and severity of GVHD that is associated with decreased intensity allogeneic hematopoietic stem cell transplantation. This study tested the feasibility of using UV-B phototherapy that was initiated before grafting and continued until engraftment to determine its effect on transplantation outcome. Eight patients (median age, 55.5 years; range, 32-65 years) with hematologic malignancies were included. Allogeneic peripheral blood stem cells were obtained from matched related (n=5) or matched unrelated (n=3) donors. Conditioning regimen was fludarabine 30 mg/m2 intravenously for 5 days, cyclophosphamide 1 g/m2/d intravenously for 2 days, and equine antithymocyte globulin 30 mg/kg/d for 2 days. GVHD prophylaxis included cyclosporine, methylprednisolone, and escalating doses of narrowband UV-B (311 nm) according to skin tolerance, 3 days a week, from 10 days before to 28 days after transplantation. The conditioning regimen and the UV-B therapy were well tolerated. Two patients received all 14 prescribed UV-B treatments (cumulative doses of 2000 and 3260 mJ/cm2, respectively) and 6 patients received 8 to 13 treatments with a cumulative dose range of 528-3465 mJ/cm2. There was a rapid decrease in epidermal CD1a+ cells by day of transplantation. Myeloid engraftment was rapid. One patient had secondary engraftment failure at 3 months and another had mixed chimerism at day 100. Seven of 8 patients developed severe acute GVHD (grade III, n=5; grade IV, n=2). Six had skin involvement, 5 had gastrointestinal involvement, and 1 had liver involvement. Four patients died (2 from sepsis, 1 from acute GVHD, and 1 from chronic GVHD). Four patients are alive (130-287 days), 3 with extensive chronic GVHD. We conclude that extended peritransplant UV-B therapy at the standard minimally erythemogenic dose is detrimental to the outcome of allogeneic stem cell transplantation. It is unclear how UV-B at this immunsuppressive dose might have altered skin and systemic cytokine and immune cell compositions in the host and increased GVHD- and treatment-related mortalities. Different UV-B dose and schedules should be further explored. However, although other phototherapeutic modalities may be effective against GVHD, extended UV-B therapy should not be used during early phases of decreased conditioning allogeneic transplantation.     

A study of the increased serum level of IgG1 in 'lethargic' mice combined with a depressed thymus-dependent lymphoid system.

In a series of recent studies on 'lethargic' mice, a neurological mutation of the mouse, significant abnormalities were discovered in the thymus and its dependent regions in the lymph nodes and spleen. The present study was made as an approach toward finding the possible causes for these abnormalities. Serum IgG1 levels were stldied in 'lethargic' mutants at the age when severe deficiency of the thymus-dependent lymphoid system is known to occur in the animal. Using the radial immunodiffusion method, it was found that serum IgG1 levels are always significantly higher in 'lethargic' mice than in their normal littermates. Possible causes of the higher IgG1 in the serum of 'lethargic' mice are discussed. The authors note the similarities of other mouse mutations to that of the 'lethargic' mouse and propose the possibility that a common mechanism may account for immunologic deficiencies in several types of mutant mice.     

Evaluation of Questor urine screening system for bacteriuria and pyuria.

AIMS--To evaluate the Questor automated bacteriuria and pyuria screening system; to compare its performance with that of a reference method; and to assess its usefulness in a routine clinical laboratory. METHODS--The Questor urine screening system was compared with a comprehensive regimen to detect urinary tract infection, using pour-plate viable counts to determine the numbers of bacteria present in urine samples, a wide range of other cultural methods, microscopic findings and clinical information. RESULTS--The optimal performance in detecting significant growths was a sensitivity of 93%, a specificity of 74%, a positive predictive value of 43% and a negative predictive value of 98%. The list price per test is 0.17 pounds and the capital cost of the system is 39,950 pounds. Questor can test 50 samples an hour and can be operated by one member of the laboratory staff, who is not required to make interpretative judgments--for example, a medical laboratory assistant. CONCLUSIONS--The sensitivity and specificity of the Questor was better than that obtained from other screening systems using the same protocol. The system was easy to use and is a useful addition to the methods available for screening for bacteriuria.     

Irregular geometries in normal unmyelinated axons: A 3D serial EM analysis

Summary Axons have generally been represented as straight cylinders. It is not at all uncommon for anatomists to take single cross-sections of an axonal bundle, and from the axonal diameter compute expected conduction velocities. This assumes that each cross-section represents a slice through a perfect cylinder. We have examined the three-dimensional geometry of 98 central and peripheral unmyelinated axons, using computer-assisted serial electron microscopy. These reconstructions reveal that virtually all unmyelinated axons have highly irregular axial shapes consisting of periodic varicosities. The varicosities were, without exception, filled with membranous organelles frequently including mitochondria, and have obligatory volumes similar to that described in other neurites. The mitochondria make contact with microtubules, while the other membraneous organelles were frequently found free floating in the cytoplasm. We conclude that unmyelinated axons are fundamentally varicose structures created by the presence of organelles, and that an axon's calibre is dynamic in both space and time.These irregular axonal geometries raise serious doubts about standard two dimensional morphometric analysis and suggest that electrical properties may be more heterogeneous than expected from single section data. These results also suggest that the total number of microtubules contained in an axon, rather than its single section diameter, may prove to be a more accurate predictor of properties such as conduction velocity. Finally, these results offer an explanation for a number of pathological changes that have been described in unmyelinated axons.     

Underdiagnosis of genital herpes by current clinical and viral-isolation procedures.

BACKGROUND. The current clinical strategy for diagnosing genital herpes simplex virus (HSV) infection in women relies on clinical findings plus the selective use of viral culture. The effectiveness of this approach for identifying women with genital herpes is unknown. METHODS. We performed physical examinations, colposcopy, Pap smears, viral cultures, and HSV type-specific serologic assays of 779 randomly selected women attending a sexually transmitted disease clinic. RESULTS. Evidence of HSV type 2 infection was detected in 363 women (47 percent), and 9 others (1 percent) had positive cultures indicative of urogenital or anal infection with HSV type 1. Of these 372 women, only 82 (22 percent) had symptoms. Fourteen women (4 percent) had viral shedding without symptoms, 60 (16 percent) had formerly had symptomatic episodes, and 216 (58 percent) had antibodies to HSV-2 with neither viral shedding nor a history of clinical episodes. Characteristic ulcerations of the external genitalia were present in only two thirds of the 66 women with positive HSV cultures; the others had atypical genital lesions or asymptomatic viral shedding. Isolation of HSV from a genitourinary tract specimen was the most sensitive (77 percent) test for confirming a first episode of infection. The detection of HSV-2-specific antibodies was the most sensitive (97 percent) way to confirm symptomatic reactivations of HSV-2 infection. HSV-2 serologic testing also identified the 290 women with asymptomatic HSV-2 infections (37 percent), including 14 (5 percent) who were shedding virus asymptomatically on the day of the examination. CONCLUSIONS. The current strategy for diagnosing genital HSV infection in women misses many cases. Newly developed type-specific serologic methods can identify women with recurrent genital HSV-2 infection, as well as those with unrecognized or subclinical infection.     

Cigarette smoking and the intention to quit among pregnant smokers

Research has demonstrated that smoking during pregnancy has deleterious effects on the health of the unborn child as well as the mother. The present study examined whether pregnant smokers would have a greater intention to quit smoking, whether the stage of pregnancy would influence the intention to quit, and whether variables which have predicted cessation among pregnant smokers would also predict intention to quit. The results indicated that pregnant women did not have a significantly greater intention to quit smoking compared to nonpregnant smokers, despite the health risks to their child. Women who were further along in their pregnancy and women who smoked more cigarettes on a daily basis demonstrated the least intention to quit. Notably, women in the first trimester showed the greatest intention to quit, suggesting that pregnant women may be most receptive to quitting during their first trimester.