Radiographic differential diagnosis of petrous apex lesions. As a consequence of improved diagnostic imaging modalities, otologists have encountered a steadily increasing number of petrous apex lesions in recent years. Contemporary imaging techniques not only provide precise anatomic localization of the lesion, but also are able to suggest specific tissue diagnoses in the majority of cases. Computed tomography (CT), by virtue of its sensitivity and low false-positive rate, is the screening examination of choice in a patient suspected of having a petrous apex lesion. Once a lesion is identified, it is often necessary to obtain a combination of CT and magnetic resonance imaging (MRI). Computed tomography is important in the detection of osseous erosion as well as in the evaluation of the extent of pneumatization and marrow formation. It also provides important details about potential surgical routes to this relatively inaccessible region. Magnetic resonance imaging provides information about the composition of the lesion that cannot be readily discerned on CT scans. In the great majority of cases, it is capable of differentiating between petrous apicitis, cholesterol granuloma, osteomyelitis, cholesteatoma, and neoplasms such as schwannoma, meningioma, chondroma, and chordoma. In the interpretation of MRI scans, a familiarity with the typical appearance of the lesions that affect the petrous apex on T1-weighted, T2-weighted, and gadolinium-enhanced images is essential. A combination of MRI and CT scanning is also necessary to evaluate normal anatomic variations, such as giant air cells and asymmetric bone marrow, which may at times, on MRI alone, simulate pathologic conditions.


Immune-mediated inner ear disease.

Immune-mediated inner ear disease. Recent clinical studies, experimental research, and various testing techniques in otoimmunology have resulted in presentation of the synonymous terms autoimmune sensorineural hearing loss, autoimmune inner ear disease, immune-mediated sensorineural hearing loss, and immune-mediated inner ear disease or disorder. The development of this terminology and the clinical presentation of this disease as well as whether it is really a distinct clinical entity are discussed. Laboratory tests for immune-mediated inner ear disease are presented along with a discussion of progress being made in the growing field of otoimmunology.


Dermoid tumor of the middle ear: case report and literature review. Dermoids and teratomas are frequently described in the head and neck, but are rarely found in the middle ear or temporal bone. We have recently managed a case of an extensive middle ear dermoid occurring in a 14-month-old female. The purpose of this article is to report the presentation and management of this case and to review the literature with respect to this entity.


Blastomycotic cranial osteomyelitis.

Blastomycotic cranial osteomyelitis. This is the second case report of a temporal bone osteomyelitis caused by Blastomyces dermatitidis, which presented as a chronic serous otitis media. The presenting serous otitis media was refractory to conventional medical and surgical management and progressed to a temporal bone osteomyelitis prior to diagnosis. B. dermatitidis is a rare fungal pathogen that causes a systemic pyogranulomatous disease that primarily manifests itself in the skin, bones, pulmonary, and genitourinary systems. If left untreated it is associated with a high rate of mortality. The otologic presentation of this rare disease is emphasized, while the clinical and therapeutic features are reviewed.


Facial and trigeminal neural dysfunction by a primary cutaneous squamous cell carcinoma: MRI and clinicopathologic correlates. Carcinomatous neural infiltration and subsequent neural dysfunction are phenomena associated with the facial nerve and parotid gland tumors, particularly adenoid cystic carcinoma. The association of primary cutaneous squamous cell carcinoma (PCSCC) with these phenomena is not as well recognized, especially with respect to the involvement of the trigeminal nerve. By presenting the case history of a man who successively developed facial and trigeminal neural dysfunction after Mohs chemosurgery of a PCSCC, this paper documents histologically the occurrence of such neural invasion, and illustrates the utility of gadolinium-enhanced magnetic resonance scanning in patient management.


Hearing results following posterior semicircular canal injury during antesigmoid retrolabyrinthine selective vestibular nerve section. The disastrous hearing results in six patients whose posterior semicircular canal was entered during antesigmoid mastoid craniotomy for retrolabyrinthine selective vestibular nerve section were reviewed. The injury occurred during skeletonization of the posterior semicircular canal to maximize intracranial exposure of the eighth nerve. All patients had Meniere's disease. Four patients were deafened, and in two, there was either no serviceable hearing or severe hearing impairment in the operated ear. Caution is urged in posterior semicircular canal labyrinthotomy for vertigo and attempted hearing preservation if a patient has symptoms of endolymphatic hydrops.


Mobilization strategy for guinea worm eradication in Nigeria. The transformation of dracunculiasis from an obscure and neglected rural disease to the highly visible target of a national eradication campaign in Nigeria is described in this report. This process progressed through four overlapping stages: documentation of the extent and nature of the disease as a national problem, demonstration in Nigeria that dracunculiasis could be effectively prevented by targeted provision and use of protected rural water supplies, mobilization for community participation in, and political support of, the eradication effort, and implementation of interventions nationwide. The conduct of the first national village-by-village search for cases and documentation of the adverse socioeconomic impact of the disease (e.g., on rice production) in Nigeria were the key elements used to solicit greater attention to the problem and mobilize support for its eradication. The critical role of the mass media in this effort and other benefits of this mobilization strategy are also highlighted.


The epidemiology of Chagas' disease in a hyperendemic area of Cochabamba, Bolivia: a clinical study including electrocardiography, seroreactivity to Trypanosoma cruzi, xenodiagnosis, and domiciliary triatomine distribution. A clinicoepidemiologic survey of Chagas' disease was conducted in the remote rural village of Tabacal in southcentral Cochabamba, Bolivia. In June and July 1988, we interviewed and examined 153 of 160 villagers > five years old for signs and symptoms of Chagas' disease. All participants had electrocardiograms (EKGs) and serologic analysis performed, and 20 villagers underwent xenodiagnosis. All 40 houses in the village were examined for triatomes, and house construction materials and defects were recorded. Seventy-four percent of all villagers had serologic evidence of Chagas' disease, and were defined as cases. Cases were three and one-half times more likely to have signs and symptoms of heart failure than non-cases (P = 0.2) and were nine times more likely to have EKG conduction abnormalities than non-cases (P = 0.02). Thirty-three percent of all EKG conduction defects occurred in individuals < 35 years of age. All dwellings had evidence of triatome infestation; 72% of the triatomes collected were positive for metacyclic trypanosomes. We conclude that Trypanosoma cruzi infection is highly prevalent in Tabacal and is a common cause of morbidity in that region.


Malaria transmission at a new irrigation project in Sri Lanka: the emergence of Anopheles annularis as a major vector. Malaria transmission was studied in a newly irrigated area of the Mahaweli project in the dry zone of Sri Lanka. Observations were performed for a three-month period following the northeast monsoon. Parasitemia in the population varied from 20.2% in February to 7% in May, and infection was due to both Plasmodium falciparum and P. vivax. Night catches of mosquitoes collected with human bait included a high proportion of Anopheles annularis. Mosquitoes containing sporozoites in the salivary glands were identified by an enzyme-linked immunosorbent assay. Anopheles culicifacies, An. annularis, and An. aconitus were all implicated as vectors in the area. The highest entomologic inoculation rate, 0.12 infected bites/hr, was observed with An. annularis and P. vivax in March. We suggest that a change in the ecosystem from dry zone forest to irrigated cultivated land is the cause of the increased prevalence of An. annularis in this area and its emergence as a major vector of malaria.


Seroepidemiologic studies of humoral immune response to the Plasmodium falciparum antigens in Thailand. We have investigated seroreactivity against Plasmodium falciparum crude parasite antigens, the P. falciparum ring-infected erythrocyte surface antigen (Pf155/RESA), as well as against two synthetic peptides (EENV)6 and (EENVEHDA)3 that represent important epitopes of Pf155/RESA. The study population consisted of 421 children and adult Thais living in an area with moderate malaria transmission. We related these serologic findings to some important epidemiologic baseline data collected in the study area. The parasite rate in study subjects was 18.76%. Sixty-two percent were seropositive to crude P. falciparum antigens, 30.3% to the Pf155/RESA antigen, 23.05% to (EENV)6, and 20.17% to (EENVEHDA)3. Antibody responses to crude P. falciparum antigens and to Pf155/RESA were age dependent and increased with exposure. There was evidence that Pf155/RESA antibodies might play a role in protective immunity in this population. Since Pf155/RESA is a potential vaccine candidate antigen, the information obtained from these field studies will provide some seroepidemiologic baseline data for subsequent vaccine trials.


Simulation of arbovirus overwintering: survival of Toscana virus (Bunyaviridae:Phlebovirus) in its natural sand fly vector Phlebotomus perniciosus. A series of experiments were done to study the effect of simulated summer and winter temperatures on the development of Phlebotomus perniciosus (Diptera:Psychodidae) and on the survival of Toscana virus in transovarially infected insects. Sand flies maintained at 28 degrees C developed relatively fast, with adults emerging from 40 to 55 days after initial oviposition. Similar results were obtained with insects reared at 25 degrees C. In contrast, sand flies maintained at 15 degrees C developed slowly up to the fourth larval instar; at that point, further development ceased and the insects entered diapause. Diapause could be terminated by increasing the ambient temperature to 25 degrees C. The ambient temperatures at which the immature forms were reared (15 degrees C, 25 degrees C, and 28 degrees C) had no effect on the subsequent F1 adult filial infection rates with Toscana virus (49.1%, 47.5%, and 46.5%, respectively). The results of these experiments provide a model of how Toscana virus survives the winter in endemic areas by maintenance in diapausing P. perniciosus larvae. In another experiment, venereal transmission of Toscana virus was shown from transovarially infected males to non-infected virgin females. This is the first demonstration of sexual transmission of a phlebovirus by sand flies. If venereal transmission occurs in nature, it would provide an alternative method of virus amplification in the vector population, in the absence of viremic vertebrates.


Cryptosporidiosis among patients with acquired immunodeficiency syndrome in Zulia State, Venezuela. We studied the prevalence of Cryptosporidium in 29 patients with acquired immunodeficiency syndrome (AIDS) from Zulia State, Venezuela. They ranged in age from five months to 46 years. Two were children and 27 were adults, of which six were women. Of the 21 men, 66.6% reported homosexual behavior. Three stool samples from each patient were examined, and modified Ziehl-Neelsen carbolfuchsin staining of formalinether stool concentrates was used to identify Cryptosporidium oocysts. To detect the presence of other intestinal parasites, direct wet mounts and iron-hematoxylin-stained smears were examined. Cryptosporidium was found in 12 (41.3%) of the patients and was identified as a single parasitic infection in seven of the 12 patients (58.3%). Other pathogenic parasites encountered were Giardia lamblia (3 of 12, 25%), Entamoeba histolytica (1 of 12, 8.3%), Ascaris lumbricoides, Trichuris trichiura, and Strongyloides stercoralis (each 1 of 12, 8.3%). Blastocystis hominis, an organism with an uncertain taxonomic position and pathogenicity, was observed in three of 12 patients (25%). An inflammatory exudate was observed in 10 of 12 patients infected with Cryptosporidium. Most of the patients with this infection presented with chronic watery diarrhea and weight loss. Our results suggest that Cryptosporidium is very common in AIDS patients with diarrhea in Venezuela. However, the role of this parasite as an enteropathogen in these patients is uncertain.


Lymphadenopathy associated with Leishmania braziliensis cutaneous infection. Lymph node involvement by Leishmania during human cutaneous leishmaniasis was reported more than 90 years ago, but the importance of certain Leishmania strains in such dissemination remains largely speculative. We have examined 36 consecutively untreated cutaneous leishmaniasis patients early in their disease; 66.7% had enlarged lymph nodes. Patients with enlarged lymph nodes had higher anti-Leishmania immune responses than patients without such involvement, both at the IgG antibody level (mean +/- SD optical density at 492 nm = 0.163 +/- 0.089 versus 0.098 +/- 0.086; P = 0.009) and in skin test responses (12.4 +/- 10.2 mm versus 5.7 +/- 7.3; P = 0.03). Thirteen (62%) of 21 lymph node cultures and 16 (53%) of 30 cultures from cutaneous sites were positive for Leishmania. Eleven of 13 isolates from lymph nodes were characterized by a panel of monoclonal antibodies, and all were typed as L. braziliensis. Our findings stress the importance of L. braziliensis as an agent involved in the early invasion of the lymphatic system.


Use of enzyme immunoassays to compare the effect and assess the dosage regimens of three Brazilian Bothrops antivenoms. The Butantan Institute Antivenom Study Group (BIASG). The effect of the three main Brazilian polyspecific antivenoms on venom clearance was assessed in 118 moderately envenomed victims of bites by Bothrops species (mainly B. jararaca) in Sao Paulo State, Brazil. Serum samples taken from patients at intervals during their stay in the hospital and at followup approximately four weeks later were tested by enzyme immunoassay for the presence of whole venom and therapeutic antivenom. Results indicated that in patients treated with the standard regimen of either four (40 ml) or eight (80 ml) ampules of each antivenom, venom was cleared from the circulation within four days of antivenom administration. However, high concentrations of antivenom persisted for approximately 10 days and remained detectable until 30-50 days after administration. This suggests that patients may be being treated with excessive amounts of antivenom in Brazil. This practice increases the national cost of antivenom therapy and may contribute to the high frequency of antivenom reactions. Clinically, there was no obvious difference in the efficacy between the three antivenoms.


Lyme borreliosis in genetically resistant and susceptible mice with severe combined immunodeficiency. The evolution of Lyme borreliosis was examined in genetically resistant C.B-17 and susceptible C3H/He(C3H) mice homozygous for the severe combined immune deficiency (scid) gene, or their immunocompetent counterparts. The C.B-17, C.B-17-scid, C3H, and C3H-scid mice were inoculated intradermally with 10(4) Borrelia burgdorferi and examined on days 14, 21, 30, 45, and 60 after inoculation. Spirochetemia was detected through 30 days, but was cleared in all groups by 45 days. Kidney and brain were inconsistently culture positive, but spleen and ear punch samples were positive in most mice. Immunocompetent C.B-17 and C3H mice seroconverted with equivalent IgG titers to B. burgdorferi, while C.B-17-scid and C3H-scid mice did not seroconvert. Arthritis occurred in nearly all joints examined in all genotypes on day 14, was of equal severity among C.B-17, C.B-17-scid, and C3H mice, but was more severe in C3H-scid mice. By days 30 and 45, arthritis began to resolve in immunocompetent mice, with C3H mice having more severe disease than C.B-17 mice. Arthritis persisted in C.B-17-scid and C3H-scid mice. Carditis occurred to an equal degree in all groups on day 14, remained active in scid mice, but regressed in immunocompetent mice at later intervals. Many spirochetes were visualized with silver stain in inflamed synovial tissues of scid mice, and were present in other tissues in smaller numbers. These studies show that specific immunity is not involved in arthritogenesis or genetically determined susceptibility to arthritis, but is involved in arthritis and carditis regression.


Renal pathology in owl monkeys vaccinated with Plasmodium falciparum asexual blood-stage synthetic peptide antigens. Renal specimens from Aotus monkeys were studied by light microscopy and immunohistochemistry to examine pathologic changes following vaccination with synthetic peptides corresponding to the 35-kD, 55-kD, and 83-kD asexual blood stage antigens of Plasmodium falciparum. The monkeys were vaccinated and later challenged with P. falciparum. In the monkeys vaccinated with Centers for Disease Control peptides (group I), specimens from four of six postvaccinated animals had mild to severe mesangial proliferation and two had diffuse interstitial nephritis. Specimens from three monkeys vaccinated with Colombia peptides (group II) had mild to severe mesangial proliferation and one had interstitial nephritis. In the hybrid polymer-vaccinated monkeys (group III), specimens from three animals had mild to moderate mesangial proliferation and one had severe interstitial nephritis. On the other hand, the control group immunized with bovine serum albumin (group IV) showed that specimens from three animals had mild to severe mesangial proliferation and two had severe interstitial nephritis. In the nonimmunized group (group V), specimens from three animals had moderate to severe mesangial proliferation and two had severe and mild interstitial nephritis. Immunohistochemical analysis using the peroxidase-antiperoxidase method revealed mesangial deposits of P. falciparum antigens in 11 of 14 vaccinated monkeys and in five of 10 unvaccinated controls. These results show that treatment of monkeys with prospective malaria vaccines does not increase the frequency of occurrence or of the severity of renal lesions. These data thus provide a baseline for assessing the safety of synthetic malarial vaccines in the future.


Agglutination of Plasmodium falciparum-infected erythrocytes from east and west African isolates by human sera from distant geographic regions. Plasmodium falciparum-infected erythrocytes (PfE) were collected from acutely infected children in The Gambia and Tanzania and cultured for more than 30 hr until the parasites were mature trophozoites. Sera collected from these countries, other African countries, Asia, and South America were used in the PfE microagglutination test to determine whether PfE from East and West Africa share surface antigens. From the patterns of agglutination reactivity, we identified extensive antigenic diversity in surface antigens, but obtained no evidence for greater differences between isolates from East or West Africa and those within one region. The majority of sera from immune adults from The Gambia, Tanzania, Sudan, Nigeria, or Ghana were pan-agglutinating, and agglutinated all PfE isolates from The Gambia and Tanzania. Some sera from immune adults of Irian Jaya also agglutinated each of the seven African isolates, while others agglutinated many but not all of the isolates, similar to sera from immune adults of Flores, Indonesia. In contrast, sera from nonimmune adults from Colombia agglutinated few of the African isolates. It was remarkable, however, that sera from nonimmune Colombians agglutinated any African isolates. Our results are consistent with the following conclusions: some PfE surface antigen(s) are very diverse; this diversity is a feature of the parasite worldwide; the repertoire of isolate-specific surface antigens, although large, includes antigens that are either identical or antigenically cross-reactive in geographically very distant parasite populations; and African adults have pan-agglutinating antibodies that may contribute to protective immunity. Such pan-agglutinating antibodies could reflect the accumulation of a large repertoire of isolate-specific antibodies. The contribution of antibody against any shared PfE surface antigen to the pan-agglutinating reactivities is unknown and awaits development of the appropriate reagents.


The squirrel monkey as an experimental model for Plasmodium falciparum erythrocyte rosette formation. Experimental cerebral malaria was recently found to occur in the squirrel monkey Saimiri sciureus when infected with the human malaria parasite Plasmodium falciparum. This report is concerned with the existence of spontaneous rosette formation ex vivo (infected blood samples) and in vitro (cultured parasites) between red blood cells (RBC) infected with squirrel monkey-adapted P. falciparum isolates and normal squirrel monkey RBC. Transfer of P. falciparum with high rosette formation tendencies (90-100 R+) from one donor monkey to several recipients gave rise to parasites that varied extensively in their ex vivo rosette formation capacity (4-96% R+). However, all individual parasites readily form rosettes after 24 hr of in vitro culture (60-95% R+). Host factors may be involved in the modulation of rosette formation, although it is found to occur both in splenectomized and spleen-intact animals. Cross-rosette formation is seen between parasitized human RBC and normal squirrel monkey RBC and vice versa, and rosettes formed by RBC of the two hosts are similarly affected by pH, temperature, EDTA, trypsin, as well as squirrel monkey and African human hyperimmune IgG. These characteristics of rosette formation are preserved after long-term in vitro culture in human RBC. Rosettes formed by some isolates are highly sensitive to heparin while others are not, suggesting at least two distinct mechanisms of rosette formation. This idea is also supported by the observation that specific squirrel monkey antisera to heparin-sensitive strains does not dissociate rosettes formed by a heparin-resistant strain. The results suggest that rosettes and anti-rosette formation antibodies formed by squirrel monkeys and humans exhibited similar characteristics, and that the squirrel monkey is therefore a good experimental model to study erythrocyte rosette formation and cerebral malaria.


Placental pathology in Plasmodium berghei-infected rats. The pathologic changes in placentae of pregnant rats infected with Plasmodium berghei at different stages of gestation were studied using light and electron microscopy and immunohistochemistry. The major changes observed were thickening and duplication of the trophoblastic basement membrane, and accumulation of parasitized erythrocytes and occasional mononuclear cells in the maternal blood space. Immunohistochemical examination of nine placentae revealed that six stained positively for IgG, two for IgM, and four for P. berghei antigen. No C3 deposition was detected. The findings in this study indicate that the variable parasitologic-clinical course from benign to fatal of P. berghei infection in pregnant rats makes it a potentially valuable model of human gestational malaria infection.


Human African trypanosomiasis: presence of antibodies to galactocerebrosides. Improvements were made in the immunodetection of anti-galactocerebroside (anti-GalC) antibody in sera of patients with human African trypanosomiasis by thin-layer chromatography, enzyme-linked immunosorbent assay, and immunoadsorption. Rabbit anti-GalC antibodies were used to standardize these techniques and demonstrate their specificity. Anti-GalC antibodies were found in the sera of 42.8% of 63 patients with human African trypanosomiasis. Thirty-four control subjects living in the same endemic area were also tested. Anti-GalC levels were higher in human African trypanosomiasis patients with neurologic disturbances compared with patients without such disturbances. These antibodies were distributed mainly between the IgG and IgM classes, but 28% of the patients with human African trypanosomiasis had increased IgA levels without anti-GalC antibody activity.


A polyclonal but not a monoclonal antibody to an M(r) 52-kD protein responsible for a punctate fluorescence pattern in Plasmodium falciparum merozoites inhibits invasion in vitro. A monoclonal antibody, MAb H24, recognized a Plasmodium falciparum antigen with a relative molecular mass (M(r)) of 52 kD that appeared to be a rhoptry component by immunofluorescence microscopy. The antigen is synthesized during both ring and schizont stages, but pulse-chase experiments showed that it is not carried through to the next ring stage after reinvasion. It was not labeled by 3H-glucosamine. The purified MAb failed to inhibit parasite invasion in vitro. The antigen was isolated using affinity chromatography, and used to produce a monospecific polyclonal antibody (PAb H24) in mice. Polyclonal antibody H24 recognized the same antigen as MAb H24 as judged by both immunofluorescence microscopy and immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and was markedly inhibitory in vitro.


Suppression of Plasmodium falciparum infections during concomitant measles or influenza but not during pertussis. In tropical countries, concomitant infections are a continuous problem. In the Rufiji Delta, an area of Tanzania that is holoendemic for malaria, there were outbreaks of influenza A, measles, and pertussis in 1986 and 1987. Significantly lower parasitic prevalences and mean densities of malaria parasites were found in children up to nine years of age who had measles or influenza than in asymptomatic control children. In contrast, children with pertussis had a higher prevalence and mean density than controls. The clinical courses of measles, influenza, or pertussis infections did not appear to be significantly affected by concomitant malaria infections. The reasons for the suppression of Plasmodium falciparum parasitemia during these viral infections are unclear. This effect could not be explained by the presence of fever.


Failure of a synthetic vaccine to protect Aotus lemurinus against asexual blood stages of Plasmodium falciparum. The hybrid synthetic protein SPf(66), which contains small fragments of the 83-kD, 55-kD, 35-kD, and circumsporozoite antigens of Plasmodium falciparum, was studied to determine its protective capacity against malaria infection in Aotus lemurinus monkeys. Two groups of six monkeys each were immunized six times with this polymer, which was mixed with either Freund's adjuvant or aluminum hydroxide. Two groups of five animals each were used as controls and immunized with saline solution mixed with the same adjuvants. Neither antipeptide nor antimalarial antibodies developed after the six immunization doses. Regardless of this fact, the monkeys were challenged intravenously with 10(5) P. falciparum blood stage parasites, and the resultant parasitemia was followed daily on blood smears. Only one monkey from each of the groups immunized using Freund's adjuvant (both experimental and control) was protected. In those immunized using aluminum hydroxide, one animal was protected in the experimental group, but none were protected in the control group. Anti-parasite antibodies developed during the infection, but did not correlate with protection and failed to recognize SPf(66) peptide in an enzyme-linked immunosorbent assay. Immunization with the polymer did not boost natural antibodies present in two of the monkeys before the experiment. Low levels of gamma-interferon were produced in some animals, but were not correlated with protection.


Pathologic changes in the midgut of Culex tarsalis following infection with Western equine encephalomyelitis virus. Midguts of two strains of the mosquito vector Culex tarsalis were examined by light and electron microscopy following infection with western equine encephalomyelitis virus. Infection of the highly susceptible Knight's Landing strain with high-titered blood meals resulted in pathologic changes in the midgut epithelium after 2-4 days of incubation; lesions included sloughing of epithelial cells into the lumen and necrosis of cells in situ. Infection of Knight's Landing strain mosquitoes with low-titered blood meals and infection of the less susceptible Fort Collins strain with high-titered blood meals did not result in a significant increase in detached luminal cells, with respect to uninfected controls. Sloughing of infected cells into the midgut lumen may contribute to modulation of the mosquito infection. Lesions in the midgut of Cx. tarsalis are inconsistent with traditional views that regarded arbovirus infections of mosquito vectors as non-pathologic. These findings demonstrate that mosquito pathology is not an oddity limited to the previously described interaction between Culiseta melanura and eastern equine encephalomyelitis virus, and suggest that alphaviruses in general may adversely affect their mosquito vectors in nature.


Variation in Aedes aegypti mRNA populations related to strain, sex, and development. Translation products were used to monitor changes in gene expression between different strains and developmental stages of Aedes aegypti. Total RNA was isolated from fourth stadium larvae, male and female pupae, and male and female adults collected at fixed time intervals following pupation and ecdysis. Differences in RNA populations were assessed by in vitro translation followed by one- and two-dimensional polyacrylamide gel electrophoresis and fluorography. Variations in gene expression between sexes and during development were examined in Liverpool (LVP) and Rockefeller (RKF) Ae. aegypti strains. Sex-related differences consisted primarily of differing lengths of expression for certain polypeptides, although two-dimensional electrophoresis revealed changes in intensity of a 44-kD polypeptide with a pI of 7.9 between males and females. Fourth stadium larvae, pupae, and adults expressed different translation products, which probably correlated with developmental differences. Strain-related differences were observed between LVP and RKF.


Rates of peptide proteolysis measured using liquid chromatography and continuous-flow fast atom bombardment mass spectrometry. An immobilized digestive enzyme assay, which has been used to determine whether orally administered peptide drugs are hydrolyzed by the digestive system, was applied to the measurement of rates of proteolysis of biologically active peptides. In this study, the rates of hydrolysis by trypsin and chymotrypsin of the pressor agent angiotensin II, the peptide hormone [Arg8]vasopressin, and the peptide drug [deamino-Cys1,D-Arg8]vasopressin were measured. Enzyme immobilization prevented autolytic proteolysis and provided a stable enzyme preparation during the assays. For rate determinations, the disappearance of substrate was measured over time by using either flow injection continuous-flow fast atom bombardment (FAB) mass spectrometry with selected ion monitoring or reversed-phase high-performance liquid chromatography (HPLC) with UV absorbance detection. Compared to the HPLC method, continuous-flow FAB was faster, provided more confident identification of the analyte because molecular weight data was obtained, and could be used for all enzymatic reactions instead of only those in which complete chromatographic resolution of substrate from proteolytic fragments was obtained. The in vitro proteolytic rates measured for the vasopressins were compared to data from rat bioassays and confirmed that the limiting factor in the oral bioavailability of [Arg8]vasopressin was rapid hydrolysis by trypsin in the intestinal lumen. The more bioactive compound, [deamino-Cys1,D-Arg8]vasopressin, was more stable to chymotryptic digestion and completely resistant to trypsinization.


Comparative study of photodissociation and surface-induced dissociation by laser desorption Fourier transform mass spectrometry. Photodissociation (PD) and surface-induced dissociation (SID) are compared for structural analysis of several nonvolatile compounds analyzed by laser desorption Fourier transform mass spectrometry (LD/FTMS). SID and PD of a porphyrin and two metalloporphyrins were investigated using a variety of experimental conditions. Optimum structural information is obtained from PD when parent ions are irradiated for relatively long times (10-30 s) using 575-nm radiation and short times (0.5-1 s) using 308- or 388-nm radiation. Shorter irradiation times in the visible region resulted in less efficient production of structurally significant product ions, while longer times in the ultraviolet region produced more nonspecific fragment ions, apparently at the expense of more structurally significant fragment ions. SID conversion efficiencies for the porphyrins are estimated for collision energies from 25 to 360 eV, with maximum conversion efficiency found using 62- and 115-eV collision energies for the two porphyrins studied. Results from a concurrent study on the combined use of PD and SID for MS/MS/MS are discussed in the context of these results. The MS3 ion spectra generated by the two dissociation techniques differ more significantly than MS2 product ion spectra. These data suggest some general guidelines for MSn studies of nonvolatile compounds analyzed by LD/FTMS, employing PD and SID for ion activation.


Specificity of interneuronal connections. A fundamental problem of neurobiological research is how specific connections between individual neurons are established and maintained. In this report different levels of neuronal specificity are described. Some neuronal populations display region specificity, but within the target region they establish synapses with a variety of neurons. A characteristic feature of the afferent innervation of hippocampal neurons is that many fibers terminate in a laminated fashion. Such a layer specificity is known for the afferents from the entorhinal cortex and for the mossy fibers. The entorhinal afferents terminate in the outer molecular layer of the fascia dentata and in the stratum lacunosum-moleculare of the hippocampus proper. The mossy fibers display both region specificity and layer specificity: they form numerous synapses in hippocampal region CA3 but never invade CA1; in CA3 they are restricted to stratum lucidum. An extremely high degree of neuronal specificity is observed in the case of the axo-axonic or chandelier cells. The axons of these neurons specifically terminate on the axon initial segments of projection neurons in the neocortex, hippocampus and fascia dentata. Thus, these cells not only display a target cell specificity but a selectivity for a distinct portion of the target cell's membrane. Some of the factors that contribute to these different levels of neuronal specificity are briefly discussed. Positional cues as well as diffusible molecules from the target region may guide the outgrowing growth cone to its target. Molecular interactions between pre- and postsynaptic membranes, the functional load of the synaptic contact, and the selective death of a number of neurons and synapses further determine the specificity of interneuronal connections.(ABSTRACT TRUNCATED AT 250 WORDS)


Synaptic reorganization in developing and adult nervous systems. Evidence is accumulating that synapse reorganization already starts during development, soon after first synapses appear. Although remodeling continues throughout ontogenesis, there are apparently (critical) periods which are characterized by enhanced synaptic reorganization. In certain parts of the peripheral and central nervous system, synapses may undergo remodeling which leads to changes in their transmission efficiency or complete elimination of the synaptic junctions, even in adulthood. Synaptic reorganization includes progressive and regressive changes on branches of dendritic and/or axonal processes that accompany the formation and elimination of synapses. Three modes of elimination are presently known: Physiological cell death of synaptically connected neurons is involved, especially during certain developmental periods, during hormonally induced metamorphosis and in the olfactory bulb. Synaptic disconnection ("stripping") and lysosomal degradation predominantly of presynaptic elements occur under different conditions. In order to undergo plastic changes, neurons seem to respond to exogenous or intrinsic factors such as lesions (partial deafferentation and axotomy), long-lasting changes in neuronal activity (e.g. drug application and sensory deprivation), hormonal influences (e.g. sexual hormones) or learning conditions.


Neuronal specificity and plasticity in the autonomic nervous system. The autonomic nervous system is divided into the sympathetic, parasympathetic and enteric subdivisions. The present review is focussed upon the highly specialized reflex organization and neurochemistry of sympathetic parasympathetic neurons. The currently available informations allow to conclude that autonomic control of each peripheral target tissue is specifically regulated under normal conditions but nevertheless able to respond to altered conditions by changes in neural activity and mediator expression.


The hypoglossal-facial anastomosis as model of neuronal plasticity in the rat. Hypoglossal-facial cross anastomosis (HFA) causes regeneration with change of function, as the axotomized hypoglossal motoneurons sprout into the facial plexus and reinnervate the mimic musculature. Following HFA, hypoglossal-hypoglossal single anastomosis (HHA) and resection of 8-10 mm peripheral hypoglossal nerve in 190 female adult Wistar rats, we compared the axon reactions in the hypoglossal nucleus during 1) regeneration with change of function, 2) regeneration with restoration of original function and 3) degeneration of the nucleus. Following postoperative survival times of 1-16 weeks we estimated the volume of the hypoglossal nucleus and counted the number of hypoglossal neurons with the physical disector on both sides of the brainstem. Additional sections of the same animals were reacted with anti-synaptophysin, anti-GFAP and the isolectin Griffonia simplicifolia I-B4 (GSA I-B4) as cytochemical markers for presynaptic boutons, activated astroglia and microglia. After HHA and HFA all hypoglossal neurons survive and the volume of the hypoglossal nucleus remains constant. Resection of the hypoglossal nerve leads to the loss of one third of the hypoglossal neurons and of one third of the volume of the hypoglossal nucleus within 16 weeks post operation. Hypoglossal-facial anastomosis and hypoglossal-hypoglossal anastomosis differ in postoperative swelling of the hypoglossal nucleus, microglia and astroglia activation and the duration of synaptic stripping. All differences are limited to the acute growth phase during regeneration. It is concluded that hypoglossal-facial anastomosis provides more stimulation and facilitates faster recovery of the hypoglossal nucleus than does hypoglossal-hypoglossal anastomosis.


Myocardial bridges over coronary arteries in Cercopithecus. The presence of myocardial bridges over the coronary arteries has been studied in 29 monkey (Cercopithecus aethiops) hearts. The great resemblance between the Cercopithecus subepicardial arterial net with the corresponding one in humans has been revealed. There is a high incidence (83%) of myocardial bridges only over the ventricular branches of both coronary arteries. Myocardial bridges are usually (90%) located over the left coronary artery branches, and the left anterior interventricular branch is the most frequently (69%) overbridged vessel. The bridges are always single over the vessel examined and their length varies from 0.5 mm to 31.6 mm. No statistically significant sexual difference in myocardial bridges distribution is reported.


Proteinase, phosphatase and glucuronidase activities in the growing mandible and temporomandibular joint of the guinea pig. This study investigated the effect of muscle function and occlusal form on the activity levels of several enzymes present in the mandible or temporomandibular joint of the guinea pig. Restriction of maxillary width and asymmetric function of the mandible was caused in 12 animals at the age of 10 days, as described in the accompanying paper (Isotupa et al. 1992). Tissue samples from six anatomical sites were obtained from the animals sacrificed 4, 8, or 12 weeks after manipulation (4 animals in each group). Six age-matched animals acted as controls. Five samples were from the following sites of the mandible: the condylar cartilage, the lower and upper parts of processus angularis, and the anterior and posterior halves of the condyle neck. A sample was also obtained from fossa mandibularis of the temporal bone. Buffer extracts of powderized samples were studied for acid and alkaline phosphatase, glucuronidase and two types of proteolytic activity. Although the asymmetric manipulation of occlusion caused observable, localized asymmetric growth, the enzyme findings were not consistently asymmetric. Manipulation generally increased all enzyme activities regardless of whether apposition or resorption was involved. The activities of alkaline phosphatase more consistently showed this pattern, and changes in enzyme activities seemed to be sensitive, reflecting cellular or molecular level of growth. The enzyme activities may also reflect a certain type of after-effect of irritation, or a healing period. The inclusion of several types of enzyme determinations is recommended to complete macroscopic measurements. Subsequent chromatographic and electrophoretic studies are also useful.


Influence of asymmetric occlusal relationships and decreased maxillary width on the growth of the facial skeleton in the guinea pig. The purpose of this study was to evaluate the effect of muscle function and occlusal form on mandibular growth in guinea pigs. We hypothesized that restriction of maxillary width and asymmetric function of the mandible would lead to mandibular asymmetry. The hard palate of 12 animals was exposed at the age of ten days, and cyanocrylate was used to close the midpalatal suture in order to restrict transverse maxillary growth. The right incisors and right molars were ground obliquely at the time of surgery and every two weeks thereafter until the animals were sacrificed 4, 8 and 12 weeks later (four animals in each time group). Six age-matched animals served as controls. Dorsoversal x-rays were taken at sacrifice, followed by the removal of small biopsies from six different sites of the maxillomandibular skeleton for biochemical studies, which will be reported separately. Relative to controls, the treated animals exhibited a narrow maxilla and asymmetry in the height of the ramus and in the length of the mandible from the mental foramen to the angular process. The maximum width between the angular processes of the mandible was extremely narrow, as was the condylar neck especially on the right side. It was concluded that abnormal masticatory muscle function caused by occlusal deviation led to a narrowing and a slight asymmetry of the mandible in the growing guinea pig.


Age-related changes in cholinergic and noradrenergic transmission in the rat cerebellum. A histochemical and immunocytochemical study. The histochemical and immunocytochemical distribution of some cholinergic and noradrenergic markers was compared in the cerebellum of young adult (3-month old) and aged (24-month old) Wistar rats. A decrease in the density and staining of acetyl cholinesterase (AChE) positive fibers, puncta and Golgi cells was found in both the cerebellar cortex and nuclei of aged rats. The age-related changes in choline acetyltransferase immunoreactivity were less pronounced than the changes in AChE activity. A reduction in the density of catecholamine fluorescent fibers and puncta was observed in the cerebellar cortex during aging. In aged rats the increase in monoamine oxidase (MAO)-A activity was more pronounced than the increase in MAO-B activity.


Differentiation of the brain stem structures in the salamander, Hynobius nebulosus. Differentiation of the internal structure of the brain stem was analyzed in the salamander with special reference to neurons distributed in the marginal layer. It was found that the salamander brain stem was at first composed exclusively of the mantle layer. The marginal layer later differentiated peripherally. In these developmental stages, the mantle and marginal layers were clearly differentiated: the former was made up exclusively of the somata, while the latter was composed mainly of nerve fibers. As the development proceeded, these organization patterns were modified: a few cells migrated into the marginal layer. Cells migrating into the marginal layer formed various nuclei and layers such as the raphe nuclei, reticular formation and superficial cellular layers of the optic tectum. In later development stages, fibers in the marginal layer were myelinated, and neurons in the marginal layer were observed to become embedded among numerous myelinated fibers. Cytologically, the majority of neurons in early developmental stages were unipolar, extending a process peripherally into the marginal layer. In later developmental stages, neurons in a deep zone of the mantle layer remained unipolar, whereas those in the marginal layer and in the superficial zone of the mantle layer differentiated into multipolar cells. Thus, (1) the marginal layer differentiated peripherally as a cell free region; (2) cells in the mantle layer later migrated into the marginal layer, changing into multipolar neurons; (3) cells in the marginal layer formed reticular formation as well as various nuclei and layers in the peripheral white matter; and (4) as development proceeded, fibers in the marginal layer became myelinated.


Vascular ontogeny of the septal region in rats. The development of the arterial and venous systems of the septum was studied in rat brains injected daily with India ink, from the 11th embryonic (E) until the first postnatal day. Arterial blood is supplied to the septum by the unpaired hemispheric artery, the stem and septal branches of which are to be recognized on the 14th and 15th embryonic days respectively. At earlier stages, e.g. on E12, a capillary network, the hemispheric plexus, can be seen between the two hemispheres contributing to the blood supply of the septum during the early phase (E14 to E18) of development. From E18 onwards, the arterial supply of the septum is derived only from direct branches of the hemispheric artery; one group of them being dorsal (infracallosal) and the other ventral (subcallosal). The venous drainage of the septum is bidirectional: 1) Veins of the ventral group leading to the interperioptic sinus are seen on E14. At first they collect blood only from a small rostral portion of the septum, but later their territory expands to include the anteroventral two-thirds of the septum. 2) The dorsal septal veins drain into the great cerebral vein (of Galen), or into the superior sagittal sinus directly. Initially, twigs run directly into the great cerebral vein. These later become the tributaries of the internal cerebral vein, which appears on E17 or E18. Until E18 this dorsally-directed drainage predominates, whereas at birth it becomes restricted to one third of the septum as a result of a gradual regression. The development of both arterial and venous circulations of the septum is complete at birth.


A study of human foot length growth in the early fetal period. The length of the human fetal foot was studied in 106 feet from 53 unfixed staged human fetuses (35 males and 18 females) by means of the allometric formula log Y = log b+k log X. The gestational age ranged from 13 to 26 weeks postconception. The measurement taken from the heel to the tip of the longest toe was regarded here as the maximum length of the foot. Growth in length of the foot was analysed in relation to crown-rump length. Our results show that foot length growth is correlated to crown-rump growth and is allometrically positive. No statistically significant difference was found between right and left feet or between male and female fetuses.


Numerical simulation of aerosol particle transport by oscillating flow in respiratory airways. Particle transport by oscillating flow in a tapered channel or in a tapered tube was computed from the complete equations of motion. These geometries represent a simplified model of the divergent flow field of the mammalian bronchial tree. The computed deformation profile of a line of particles, transported by the oscillatory motion, was compared with prior experimental results and analytical calculations. All three methods agree that there is transport in the divergent direction of the tube by an axial stream of steady drift in the core for moderately high frequency of oscillation (Womersley parameter in the range of 1 to 10). Bidirectional flow is established by an annular stream in the convergent direction, with no net flow on integral cycles of the oscillating fluid. At higher frequency, however, the steady stream transforms to a different shape in the tapered tube, with transport in the divergent direction nearer the walls of the tube, rather than in the core. Transport by the continuing streams with oscillatory ventilation of the respiratory tract should deliver medicinal aerosols of low intrinsic particle mobility to the peripheral regions of the lungs.


Orthopedic prosthesis fixation.

Orthopedic prosthesis fixation. The fixation of orthopedic implants has been one of the most difficult and challenging problems. The fixation can be achieved via: (a) direct mechanical fixation using screws, pins, wires, etc.; (b) passive or interference mechanical fixation where the implants are allowed to move or merely positioned onto the tissue surfaces; (c) bone cement fixation which is actually a grouting material; (d) biological fixation by allowing tissues to grow into the interstices of pores or textured surfaces of implants; (e) direct chemical bonding between implant and tissues; or (f) any combination of the above techniques. This article is concerned with various fixation techniques including the potential use of electrical, pulsed electromagnetic field, chemical stimulation using calcium phosphates for the enhancement of tissue ingrowth, direct bonding with bone by glass-ceramics and resorbable particle impregnated bone cement to take advantages of both the immediate fixation offered by the bone cement and long term fixation due to tissue ingrowth.


Modeling the circulation with three-terminal electrical networks containing special nonlinear capacitors. Development, first of analog and later of digital computers, as well as algorithms for analysis of electrical circuits, stimulated the use of electrical circuits for modeling the circulation. The networks used as building blocks for electrical models can provide accurate representation of the hydrodynamic equations relating the inflow and outflow of individual segments of the circulation. These networks, however, can contain connections in which voltages and currents have no analogues in the circulation. Problems arise because (a) electrical current must flow in closed loops, whereas no such constraints exist for hydraulic models; and (b) electrical capacitors have a number of characteristics that are not analogous to those of hydraulic compliant chambers. Disregarding these differences can lead to erroneous results and misinterpretation of phenomena. To ensure against these errors, we introduce an imaginary electrical element, the nonlinear residual-charge capacitor (NRCC), with characteristics equivalent to those of a compliant chamber. If one uses appropriate circuit connections and incorporates the residual-charge capacitor, then all voltages and currents in the model are proper analogues of pressures and flows in the circulation. It is shown that the capacitive current represents the rate of change of volume of blood inside the vessel, as well as the rate of the corresponding displacement of volume of the surrounding tissue.


The impedance of a spherical monopolar electrode. The impedance of a monopolar electrode immersed in an environmental volume conductor consists of two parts; the impedance of the active electrode-electrolyte interface, and the resistance of the environmental conductor. Two studies were carried out to quantitate these components. First, impedance-frequency data were collected for five spherical stainless-steel electrodes (ranging from 0.473 to 1.11 cm in diameter) immersed in 0.9% saline (p = 70 omega-cm). Impedance measurements were made from 100 Hz to 100 kHz and two sets of data were obtained; one before and one after each electrode was polished with fine emery paper. At low frequency, the measured impedances were high and varied with electrode surface preparation. However, above a transition frequency, the impedances were resistive, independent of the electrode surface preparation, and equal to rho/2 pi d as predicted from the theory. This study indicates that the low frequency impedance of a monopolar electrode is dominated by the impedance of the electrode-electrolyte interface. Above a transition frequency, the resistance of the environmental conductor dominates, the value of this resistance depending on the electrode geometry and the resistivity (rho) of the environmental conductor. A second study was conducted, to examine the effect of the distance to the indifferent electrode. A frequency (100 kHz) above the transition frequency was used and impedance data were collected for various distances between the monopolar and indifferent electrodes. The measured resistance increased asymptotically as the distance between the electrodes was increased. When the indifferent electrode diameter was at least 10 times the diameter of the spherical monopolar electrode, the measured resistance was within 5% of the value predicted for an indifferent electrode at infinity.


Spatial variation of aortic wall oxygen diffusion coefficient from transient polarographic measurements. Polarographic current transients following a voltage step (turn-on transient) were measured with bare cathodes (25 microns diameter) and shallowly recessed oxygen microelectrodes (< 5 microns diameter). Except for the initial part of the current transient, the experimental measurements were in excellent agreement with simple models in the literature, which predict an inverse relationship with square root of t. Turn-on transients were measured in aqueous solutions with known physical properties, and in aortic wall tissue from three different species (n = 6 rabbits, n = 3 dogs, and n = 1 miniature pig). Oxygen diffusion coefficients (D) were determined in vitro by comparing time constants measured by the same microelectrode in saline and in strips of aortic wall tissue at 37 degrees C. On the inner side (endothelium and intima) of the aorta, D averaged (+/- S.E.) 7.0 (+/- 0.8) x 10(-6) cm2/s in 6 rabbits, 6.4 (+/- 1.0) x 10(-6) cm2/s in 3 dogs, and was 4.6 x 10(-6) cm2/s in the pig. On the adventitial side, D was 9.5 x 10(-6) cm2/s in 1 rabbit, 11.4 (+/- 1.2) x 10(-6) cm2/s in 3 dogs, and 8.1 x 10(-6) cm2/s in the pig. For every aortic strip on which D was measured from both sides, D for the inner wall was always lower, overall by a little more than one third (p < 0.001). The lower D on the endothelial side may limit oxygen transport to the vascular wall and play a role in atherogenesis.


Optimization of single electrode tactile codes. The effects of a frequency modulated electrocutaneous signal's (code's) characteristics on the interpretability of the signal were investigated using an electrocutaneous tracking approach. The characteristics investigated include the functional relationship (exponential and hybrid) between an informational signal and the stimulation frequency, the range of stimulation (2-50 Hz and 2-100 Hz), and the impact of pulse width compensation on a code's efficacy. The interpretability of six different single bipolar electrode codes was examined by 30 subjects using a balanced incomplete block experimental design. Codes with exponentially shaped transfer functions resulted in generally lower electrocutaneous tracking errors than codes utilizing hybrid-shaped transfer functions. Hybrid codes had a transfer function that was linear in the lower frequency range and exponential in the higher frequency range. Codes with a 2-100 Hz frequency range were interpreted better than codes with a 2-50 Hz frequency range. The use of pulse width compensation to maintain a more even level of stimulation intensity had a slightly negative effect on the subjects' abilities to cutaneously track the information signal.


Development of a computer model to predict strains in the individual fibers of a ligament across the ligamentous occipito-atlanto-axial (C0-C1-C2) complex. A fresh ligamentous occipito-atlanto-axial (C0-C1-C2) complex was appropriately prepared and serially sectioned into thin slices along the transverse planes. The bony outlines from these slices were digitized and assembled in the proper manner to obtain a three-dimensional model of the complex using the AutoCAD system. Various ligaments were identified on the model and strains in individual fibers of a ligament were predicted based on the principles of rigid body mechanics. The ligament behaviors in axial rotation, flexion, and extension modes were analyzed. The capsular ligament fibers were predicted to undergo strains in all modes. Furthermore, these ligaments experienced the largest strain among the ligaments analyzed. Fibers within a ligament were found to respond differently; some were more active than the others and some did not experience any strain at all. A differential behavior in the right and left side alar ligament fibers was also found in axial rotation. The transverse ligament was predicted to wrap around the dens during axial rotation. The strain within a fiber was found to be a function of the initial length (ligament laxity) and its distance from the center of rotation.


Computationally efficient algorithms for convection-permeation-diffusion models for blood-tissue exchange. Analysis of data on tissue depositions obtained by positron tomographic or NMR imaging, or of multiple tracer outflow dilution curves, requires fitting data with models composed of aggregates of capillary-tissue units. These units account for heterogeneities of flows and multisolute exchanges between longitudinally distributed regions across capillary and cell barriers within an organ. Because the analytic solutions to the partial differential equations require convolution integration, solutions are obtained relatively efficiently by a fast numerical method. Our approach centers on the use of a sliding fluid element algorithm for capillary convection, with the time step set equal to the length step divided by the fluid velocity. Radial fluxes by permeation between plasma, interstitial fluid, and cells and axial diffusion exchanges within each time step are calculated analytically. The method enforces mass conservation unless there is regional consumption. Solution for a 2-barrier, 3-region model, accurate to within 0.5%, are 100 to 1000 times faster than the corresponding, purely analytic solution, and over 10,000 times for a 4-region model. Applications include multiple indicator dilution studies of kinetics of transcapillary exchange and positron emission tomographic studies of the mechanisms of substrate transport into cells of organs in vivo.


Algorithms for a location database.

Algorithms for a location database. The algorithms that drive the ldb location database are described. The program captures data on genetic and physical maps and combines information from different sources into a summary map. To assure portability it was developed in Fortran on a SUN SPARCStation under Unix. The algorithms, which combine rule-based seriation with a minimum deviance bootstrap, allow investigators and chromosome committees to produce a composite location in Mb that integrates partial maps. The program and manual are now available from the authors.


A study on Lu-null families in South Wales. Red cells of 75614 blood donors in South Wales were screened with anti-Lu(b) revealing 54 Lu(b-) donors of which 15 were also Lu(a-) giving a frequency of 0.0002 for the Lu(a-b-) phenotype in South Wales. The families of 11 Lu-null propositi were investigated to determine which of the three known genetic backgrounds, dominant, recessive or X-linked recessive, was responsible for their Lu-null phenotype. In 10 of the 11 families the Lu-null phenotype was caused by the dominant suppressor gene In(Lu). The first reported family demonstrating independence of In(Lu) and LU, through the Au groups, is described together with the third family demonstrating suppression of P1 by In(Lu). The families showed that In(Lu) is not closely linked to HLA. The genetic background for the 11th propositus was not determined; homozygosity of the silent allele LU is a possible but unproved explanation.


Interphase cytogenetics of the ICF syndrome. Interphase behaviour of centromeric heterochromatin of chromosomes 1 and 16 has been investigated in lymphocytes and fibroblasts of patients with ICF syndrome and of normal subjects with non-isotopic in situ hybridization, using the satellite II-related probe pHuR 195. We found evidence for interphase somatic pairing in ICF lymphocytes with a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal. Somatic pairing was also present in fibroblasts, but with frequencies similar in normal and ICF subjects. The fibroblasts do not have the major chromosomal abnormalities found in lymphocytes. The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes and we postulate that the more decondensed state of chromocentres in the fibroblasts could be the reason for the absence of the major chromosomal abnormalities.


Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Dopa-responsive dystonia (DRD) is one form of childhood-onset idiopathic torsion dystonia. Adult-onset parkinsonism has appeared in several previously unaffected members in families with DRD suggesting that this may be an additional phenotypical expression of the disease. We report a family with DRD in which 2 women and 1 man, unaffected by dystonia, developed tremor-onset parkinsonism after age 50 years. The women continue on a low dosage of levodopa after 9 and 13 years of treatment, with a stable, nearly complete, symptomatic response. This contrasts to the typical long-term treatment complications observed in patients with Parkinson's disease. We assessed nigrostriatal dopaminergic function in the proband, with typical DRD, and the 2 women with parkinsonism using 6-[18F]fluoro-L-dopa positron emission tomography. All 3 had normal striatal 6-[18F]fluoro-L-dopa uptake. These observations provide compelling evidence that "benign" adult-onset parkinsonism may be an expression of the disease in some members of families with DRD and does not support consideration of the DRD gene as a risk factor for development of Parkinson's disease. There may be considerable clinical heterogeneity in DRD depending on the age at onset.


The identification of presymptomatic parkinsonism: clinical and [18F]dopa positron emission tomography studies in an Irish kindred. An Irish kindred is described in which 5 of 10 siblings in the fourth or fifth decade of life developed an akinetic-rigid syndrome clinically indistinguishable from idiopathic Lewy body Parkinson's disease. Four of these patients were scanned by positron emission tomography (PET) with [18F]dopa after clinical diagnosis and in all, a profound impairment of tracer uptake into the striatum was recorded. The fifth patient was initially scanned at a time when he was asymptomatic and normal by clinical examination. His scan showed impaired tracer uptake, indicating a subclinical defect in the presynaptic nigrostriatal system. Within months of his scan, he too developed subtle symptoms and signs of parkinsonism although there was little further clinical progression or change in his PET scan over the following year. A clinically normal sibling was also scanned and found to have subclinical impairment of [18F]dopa uptake in the putamen. The 19-year-old daughter of an affected sibling had a mild postural tremor but no other symptoms or signs. The [18F]dopa uptake in her putamen fell at the borderline between normal and parkinsonian values. This study confirms that PET can identify preclinical parkinsonism in at-risk subjects. The finding of abnormalities in several clinically unaffected family members suggests that family studies based on clinical assessment alone may miss a significant number of subclinically affected individuals, leading to an underestimate of any genetic component to Parkinson's disease.


Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Adenosine is a potent inhibitory neuromodulator and has been proposed as an endogenous anticonvulsant. Depth electrodes modified to include a microdialysis probe were implanted for 10 to 16 days in the hippocampi of 4 patients with intractable complex partial epilepsy to test the hypothesis that during seizures extracellular adenosine reaches levels that may depress epileptiform activity. Samples were collected bilaterally at 3-minute intervals before, during, and after a single, spontaneous-onset seizure in each patient. All seizures commenced in one hippocampus and propagated to the contralateral hippocampus. Extracellular adenosine levels increased by 6- to 31-fold with the increase significantly greater in the epileptogenic hippocampus. During seizures, levels of adenosine in the dialysate reached concentrations as high as 2.5 microM, reflecting extracellular concentrations of approximately 65 microM. Adenosine at concentrations of 40 to 50 microM depresses epileptiform activity in vitro, so the levels we report may suppress seizure activity in vivo. Moreover, adenosine levels remain elevated above basal values for the entire 18-minute postictal period. These data support the role of adenosine in mediating seizure arrest and postictal refractoriness and suggest that treatments which facilitate adenosine may be effective in preventing seizures.


Effectiveness of botulinum toxin administered to abolish acquired nystagmus. We injected botulinum toxin into the horizontal rectus muscles of the right eyes of 2 patients who had acquired pendular nystagmus with horizontal, vertical, and torsional components. This treatment successfully abolished the horizontal component of the nystagmus in the injected eye in both patients for approximately 2 months. Both patients showed a small but measurable improvement of vision in the injected eye that may have been limited by coexistent disease of the visual pathways. The vertical and torsional components of the nystagmus persisted in both patients. In 1 patient, the horizontal component of nystagmus in the noninjected eye increased; we ascribe this finding to plastic-adaptive changes in response to paresis caused by the botulinum toxin. Such plastic-adaptive changes and direct side effects of the injections--such as diplopia and ptosis--may limit the effectiveness of botulinum toxin in the treatment of acquired nystagmus. Neither patient elected to repeat the botulinum treatment.


Serial cranial and spinal cord magnetic resonance imaging in multiple sclerosis. Twenty-nine mildly disabled patients with multiple sclerosis underwent serial clinical and magnetic resonance imaging (MRI) evaluations (pre- and postgadolinium cranial and spinal cord MRI) on at least 3 occasions at 13-week intervals and during periods of suspected relapse. Using clinical judgment of the presence of recent active disease as the gold standard, combined MRI studies confirmed the clinical impression of active disease in 93% of follow-up visits (sensitivity) and the absence of active MS in 63% of follow-up visits (specificity). None of the cranial and spinal MRI-detected abnormalities disappeared. Gadolinium administration particularly increased the yield of spinal MRI. Cranial MRI alone detected 80% of the MRI-active visits. Clinical and MRI concordance was significantly better for the presence of recent disease activity than for the anatomical localization of the presumed site of activity. MRI evidence of apparent ongoing disease activity was seen more frequently in patients believed to have active multiple sclerosis in the preceding year (13 of 21) than in patients who had been in clinical remission for at least the 2 preceding years (2 of 8). Although clinical evidence of new disease activity was much less common in patients with active, chronic-progressive disease (1 of 8) than in patients with active, relapsing disease (9 of 13), the proportion of patients with either infrequent relapses, frequent relapses, or slow chronic-progressive disease in the preceding year in whom MRI activity developed and the pattern of this new MRI activity was similar between these types of active patients.(ABSTRACT TRUNCATED AT 250 WORDS)


HTLV-I-specific cytotoxic T lymphocytes in the cerebrospinal fluid of patients with HTLV-I-associated neurological disease. Recently, it has been shown that in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated neurological disease, high levels of HTLV-I-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood. These CTLs predominantly recognized products of the pX region of HTLV-I, had a CD8+ phenotype, and were human leukocyte class I restricted. Moreover, these responses were not detected in asymptomatic, HTLV-I-seropositive individuals. This implied a role for these CTLs in the pathogenesis of the neurological disorder associated with HTLV-I. We have extended these observations by demonstrating HTLV-I-specific CTLs directly from lymphocytes obtained from the cerebrospinal fluid of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Uncultured cerebrospinal fluid lymphocytes were used directly as effectors on a variety of targets expressing HTLV-I. These cells were lysed in a virus-specific and HLA class I-restricted manner. Moreover, the cerebrospinal fluid lymphocytes were sorted into purified CD8+ populations, cloned by limiting dilution, and assayed for CTL activity. An exceedingly high proportion of these resultant lines were shown to be cytolytic and precursor frequency analysis indicated that as many as 1 in 500 cells were HTLV-I-specific CTLs. The majority of these CTL lines recognized HTLV-I gene products encoded within the pX region of HTLV-I. The significance of these HTLV-I-specific CTLs in the central nervous system of patients with HTLV-I-associated neurological disease is discussed with regard to the potential role of CTLs in the pathogenesis of this disease.


Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Abnormalities in the blood-brain barrier (BBB) may be important in mediating some of the tissue damage that accompanies human immunodeficiency virus (HIV) infection of the brain, as well as in facilitating viral entry into the central nervous system. Accordingly, immunohistochemical detection of fibrinogen (FIB) and immunoglobulin G (IgG) was used as a marker of vascular permeability in formalin-fixed, paraffin-embedded brains of patients with acquired immunodeficiency syndrome (AIDS) who had HIV encephalitis (HIVE) (n = 17) and those who did not have HIVE (n = 16); nonimmunosuppressed patients served as control subjects (n = 22). The sex ratios and postmortem intervals were similar in all groups (p > 0.05), but the age of the two AIDS groups were younger than the control group (43.2 and 40.9 versus 62.5 yr; p < 0.05). The two AIDS groups had higher immunostaining for FIB and IgG than the control group (p < 0.001 and p < 0.0001, respectively) but did not differ from one another. Furthermore, the two AIDS groups had a significantly higher incidence of combined extravasation of both FIB and IgG, whereas the control group had a significantly higher incidence of negative staining for both proteins (p < 0.002). More than 95% of the microglial nodules of HIV were negative for serum proteins; however, all focal lesions with tissue necrosis, including lymphoma, opportunistic infections, and HIV (rarely), contained extravasated serum proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Disease-specific patterns of locus coeruleus cell loss. Computer visualization techniques were used to map and to quantitatively reconstruct the entire locus coeruleus, including the nucleus subcoeruleus, to compare the topographic patterns of cell loss in postmortem brains from patients with Parkinson's disease, Alzheimer's disease, and Down syndrome. There was comparable cell loss in all three diseases (approximately 60%) compared with aged normal subjects, and there was a significant loss of nucleus subcoeruleus cells specifically in patients with Parkinson's disease (63%). There was a significant positive correlation between the magnitude of locus coeruleus cell loss and the duration of Alzheimer's disease, but no such correlation was found for Parkinson's disease. In patients with Parkinson's disease, there was comparable cell loss throughout the rostral-caudal extent of the nucleus; however, in patients with Alzheimer's disease and Down syndrome, the greatest cell loss always occurred within the rostral portion of the nucleus, with a relative sparing of caudal cells. These data are consistent with the hypothesis that cell loss in Parkinson's disease is the result of a pathological process that attacks the catecholaminergic cells of the locus coeruleus and the subcoeruleus in general; in Alzheimer's disease and Down syndrome, however, the pathological process only affects the rostral, cortical-projecting locus coeruleus cells and spares the caudal, noncortical-projecting cells.


Suppression of postischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep. To determine the effect of suppression of epileptiform activity that develops after hypoxic-ischemic injury in the immature brain, chronically instrumented near-term fetal sheep (119-133 days) were subjected to 30 minutes of complete cerebral ischemia: 6 were given a 0.3-mg/kg bolus of MK-801 at 6 hours after the insult followed by continuous infusion of 1 mg/kg over the next 36 hours, and were compared to 6 control sheep. Electrocorticographic activity and edema within the parasagittal region of the cortex were quantified with real-time spectral analysis and impedance measurements, respectively. Histological outcome was assessed 72 hours later. The intense epileptiform activity seen from 9 +/- 2 to 30 +/- 3 hours in the control group was completely suppressed in the MK-801-treated group. The onset of secondary cortical edema was delayed from 9.4 +/- 1.1 hours to 14.8 +/- 0.7 hours (p < 0.01). Neuronal damage was reduced, particularly in the lateral cortex and hippocampus (p < 0.05). Infarction of the parasagittal cortex was not prevented. These results suggest that N-methyl-D-aspartate-mediated epileptiform activity that develops after a global hypoxic-ischemic insult worsens neuronal outcome in the immature brain.


Electron transfer complex I defect in idiopathic dystonia. It has been suggested that dystonia is caused by an autosomal gene with reduced penetrance and a consequent biochemical abnormality affecting cell activity within the basal ganglia. No consistent biochemical disturbance has been identified. In the present study, activities of the mitochondrial electron transfer complexes were measured in platelets of 31 patients with idiopathic dystonia. Enzyme assays of these patients were compared to measurements in 28 control subjects. A significant decrease of complex I activity was observed in the majority of the patients, whereas the activities of other electron transfer complexes were normal. The severity of the complex I defect was more pronounced in patients with the segmental or generalized form than in those with focal dystonia. Complex I activity was not age dependent in the patients or control subjects. Although the electron pathway in complex I is disturbed in patients with idiopathic dystonia, complex I protein content seems to be normal. Whether abnormalities of complex I activity play a role in the pathogenesis of idiopathic dystonia remains to be determined.


Neuropsychological features of familial Alzheimer's disease. It has been proposed that early-onset familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease (AD) have different causes, with FAD due to a single dominant gene with disease onset before the sixth decade, whereas sporadic AD has a later onset and is not associated with a dominant pattern of inheritance. Given these differences, we questioned whether these etiologically distinct forms of AD also differ neuropsychologically. In this study we performed neuropsychological evaluations on patients from two well-documented families with FAD and a group of patients with sporadic AD. The groups were matched on global disease severity at entry. Two groups of education- and age-matched normal controls were recruited for comparison. The groups were analyzed for psychometric findings and pattern of deficits. Both patients with FAD and patients with sporadic AD showed a similar pattern of neuropsychological impairment relative to age-matched controls, i.e., mildly to moderately impaired verbal performance and concentration, severely slowed psychomotor speed, and severely impaired delayed recall of verbal material. There were no differences in pattern suggestive of disproportionately severe anomia, amnesia, agnosia, or apraxia in the early onset FAD group, as has been reported previously.


Neurological rehabilitation.

Neurological rehabilitation. Increasingly, neurologists are participating in the rehabilitation of disorders of the nervous system. Compelling reasons why neurologists, especially those with academic interests, should become involved in rehabilitation include the opportunity to observe patients in the recovery phases of their illnesses and to study issues relating to functional recovery, exposure to patients (such as those with spinal cord injury) who are often not seen by neurologists in the acute phase, and the opportunity to help establish a scientific base for rehabilitation medicine. Many areas of investigation can contribute to the scientific basis of neurological rehabilitation. Among the most promising are regeneration in the central (CNS) and peripheral nervous systems, adaptive mechanisms following CNS injury, computational neuroscience, neuromuscular physiology of chronic denervating conditions (e.g., the post-polio syndrome), and outcome studies of both physical and pharmacological therapeutic modalities. While there may be financial advantages to involvement in neurological rehabilitation, these are probably overestimated and interest in this field would continue to grow without them. There is a need for enhanced training in this subspecialty, including the development of dual certification programs in neurology and rehabilitation medicine.


Dopamine D1 and D2 receptors in progressive supranuclear palsy: an autoradiographic study. Dopamine D1 and D2 receptors were studied in brain tissue sections from a typical patient with progressive supranuclear palsy and in 7 age-matched brains. The density of D1 receptors in the caudate-putamen and frontal cortex of the patient was within control limits. By contrast, the density of nigral D1 receptors and striatal D2 receptors was dramatically reduced in the patient as compared to the control brains. This work shows again that the loss of striatal D2 receptors is the most plausible explanation for the poor response to dopaminergic drugs in patients with progressive supranuclear palsy. While the loss of nigral D1 receptors can be explained by the loss of nigral neurons, it seems that neurons bearing striatal D1 receptors are spared in progressive supranuclear palsy. The clinical effects of selective D1 agonists are worth testing in this devastating disorder.


Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. The genetic mutation of X-linked recessive bulbospinal neuronopathy is amplification of a polymorphic tandem CAG repeat in the androgen receptor gene. We studied this CAG repeat in 26 Japanese patients from 21 families with X-linked recessive bulbospinal neuronopathy. The number of CAG repeats was significantly correlated with the age at onset of limb muscular weakness (r = -0.596, p < 0.001) and age-adjusted scored disability (r = 0.446, p < 0.03). The length of the CAG repeat therefore seems to be a determinant factor of clinical severity.


[Non-Hodgkin's lymphoma and AIDS: histopathologic features]. HIV-related non-hodgkin lymphomas currently occur in 5 to 8% of AIDS patients. AIDS-related lymphomas are high-grade tumors with the morphologic characteristics of either small noncleaved cell lymphomas of the Burkitt type or large cell centroblastic and immunoblastic lymphomas. Mixed features may be found, making classification difficult. Useful methods for characterizing AIDS-related non-hodgkin's lymphomas include immunophenotypic studies using B-cell differentiation and activation antigens (HLA-DR, CD10, CD19, CD20, CD21, CD22, CD23, CD38), evaluation of expression of surface immunoglobulins (IgS), activation and proliferation (CD25, CD30, CD71, Ki67), and identification of T-cell markers (CD1, CD2, CD3, CD4, CD5, CD7, CD8). Cases studied were of the B-cell type. Comparison with morphologic features revealed that Burkitt's lymphomas were monoclonal and expressed B-cell markers (CD10, CD19, CD20, CD22, CD38) and surface immunoglobulins, especially IgM kappa. This immunophenotype is similar to that of large cell or centroblastic non-hodgkin's lymphomas, suggesting that Burkitt lymphomas originate from centrofollicular cells. Immunoblastic non-hodgkin's lymphomas were monotypic or polytypic and expressed CD10 and CD38 antigens but not the other B-cell antigens Furthermore, a very large number of cells stained positively with the Ki67 antibody demonstrating that most lymphoma cells were undergoing cycling.


[Large cell lymphomas: effect of histologic groups on the prognosis. Study of 210 cases treated with the same therapeutic protocols]. As part of a study of two therapeutic protocols initiated in 1982 and 1985, respectively, for localized (n = 134) and disseminated (n = 76) large cell lymphomas, histologic type was determined for each patient by several pathologists using the Kiel classification for morphologic features and the international working formulation for protocol assignment and multifactorial statistical analysis. Therapeutic results in the two hundred and ten cases were correlated with a number of prognostic factors including age, stage, tumor size, extranodal disease, and clinical or biological markers for disease activity such as the LDH level. The previously reported influence of histologic subgroup on prognosis was not found with these highly effective protocols, whether histologic type was considered alone or in combination with other prognostic factors. The only consistent finding was that anaplastic large cell lymphomas, despite their aggressive features, were most likely to have a favorable outcome.


[AIDS-related progressive multifocal leukoencephalopathy limited to U fibers, responsible for subacute encephalopathy with normal CT scan findings]. A 41-year-old male homosexual with AIDS was hospitalized for temperature elevation to 40 degrees C with confusion. Neurologic evaluation found psychomotor slowing and temporospatial disorientation with no focal signs. The CD4 count was 100/mm3. CSF analysis and the CT scan were normal. Despite antiviral treatment the patient died fifteen days after admission. Gross appearance of the brain was normal. Histologic examination disclosed multiple, small foci of demyelination characteristic of progressive multifocal leukoencephalopathy. These foci were disseminated among the U fibers. In situ hybridization and immunocytochemical studies demonstrated papovavirus particles in oligodendrocytes and a few astrocytes. This case shows that papovavirus infection in AIDS patients may be responsible for a diffuse febrile encephalopathy with normal CT scan findings and a rapidly progressive course.


[Keratosis of the oral cavity].

[Keratosis of the oral cavity]. Among white lesions of the oral cavity, keratoses can be suspected clinically but should be confirmed by histologic studies. Only examination under the microscope can demonstrate superficial keratinization of the epithelium. Irritative keratosis, dysplastic and malignant keratoses, and specific clinico-pathologic keratoses are reviewed successively. The differential diagnosis of white lesions of the oral cavity is discussed.


[Necrotizing sialometaplasia].

[Necrotizing sialometaplasia]. Necrotizing sialometaplasia is an infrequent, nonmalignant, self-limited condition involving the accessory salivary glands. Clinical and histologic features of necrotizing sialometaplasia may mistakenly suggest malignant disease. This fact emphasizes the importance of carefully correlating clinical and pathologic findings and of looking for histologic criteria indicative of nonmalignant disease. Three cases are discussed and the relevant literature is reviewed.


[Heart-lung transplantation. A necropsy study of thirty-seven patients]. Between 1987 and 1992, thirty-seven heart-lung transplant recipients had a postmortem examination at the Pitié-Salpêtrière Teaching Hospital in Paris, France. Except for three patients who survived 2 months, 4 months and 16 months after transplantation, respectively, most patients died in the early postoperative period (mean survival time = 34.6 days). Autopsy disclosed minor acute heart rejection in four patients and minor acute lung rejection in three patients. Five patients had obliterating bronchiolitis that was the cause of death in two cases. Main causes of death included perioperative pleural bleeding, respiratory infection with or without septicemia, diffuse alveolar lesions (adult respiratory distress syndrome and/or pulmonary edema undergoing organization) and multiple organ failure. Hemodynamic and respiratory complications responsible for multiple organ failure in the perioperative period, as well as pre-existing morbid conditions such as cirrhosis of the liver induced by heart failure, may have a major bearing on the outcome of heart-lung transplantations.


[Polymorphous low-grade adenocarcinoma of the minor salivary glands. Seven cases]. Seven cases of polymorphous low-grade adenocarcinoma of the minor salivary glands are reported. This fairly recently described tumor, which is not exceptional, is characterized by a polymorphous architecture, fairly uniform cytologic features, and a marked tendency to infiltrate neighboring structures with perineural spread in virtually every case. Immunohistochemical and ultrastructural studies reported in the literature have demonstrated that the tumor cells exhibit epithelial and myoepithelial differentiation. These tumors probably arise from reserve cells in terminal ducts. The histologic study should eliminate two other tumors that carry a very different prognosis, i.e., pleiomorphic adenoma and the tubular, cribriform variety of cystic adenoid carcinoma. Low-grade polymorphic adenocarcinomas grow slowly. Recurrences are infrequent. Metastases are rare and involve only regional lymph nodes. The morphologic features and course of these tumors explain the term "low-grade polymorphous adenocarcinoma" used to designate them.


Cancer morbidity and mortality in USA Mormons and Seventh-day Adventists. Comparison of cancer morbidity and mortality rates between Mormons and Seventh-day-Adventists and the corresponding rates in the Federal Republic of Germany and the United States, reveals that mortality from malignant neoplasms in general is much lower in Mormons and Seventh-day Adventists than in the Federal Republic of Germany. The difference concerns in particular the tobacco-dependent tumors: compared to the rate of affected males in the Federal Republic of Germany, only some 25% of Mormon males are getting lung cancer. Similar patterns are found in laryngeal carcinoma. Tumors that are related to both alcohol and tobacco, such as carcinomas of tongue, pharynx and esophagus, are also significantly less frequent in Mormons. Malignant neoplasms of the female genital tract show distinct analogies: cervical carcinoma has a morbidity rate of only 26.7% of affected women in Germany. Accordingly, mortality rates of Mormons and Seventh-day Adventists show a significant lower level when compared with cancer data of lung, colon and rectum, and prostate from the best German cancer registry (Saarland). Some tumor rates are higher in Mormons, e.g. malignant melanoma, also all types of malignant lymphoma and myeloma. The life expectancy is generally elevated by 2-4 years in Mormons and Seventh-day Adventists. The association with the particular life style of both religious groups, especially the strict reduction of tobacco consumption, and factors of dietary and other habits is discussed.


Immunoreactivity of calmodulin, S-100 protein alpha and beta subunits in rat submandibular glands. The calcium-binding proteins calmodulin and S-100 protein alpha and beta subunits were studied in Rat submandibular salivary gland using monoclonal antibodies and immunoperoxidase staining. Histologically, Rat submandibular gland consists of acinar and ductal components. The latter include intercalated, granular convoluted tubule, striated and excretory ducts. Ultrastructural studies of adult Rat granular convoluted tubule show granular cells, pillar cells and transition cells. Immunostaining for S-100 alpha and calmodulin was observed in granular convoluted tubule pillar cells and transition cells, whereas cells of striated ducts and intercalated ducts stained positive for calmodulin. S-100 beta staining in acinar cells was visible as a fine granular pattern. Although immunohistochemical localization in rat submandibular gland differed for S-100 alpha and beta subunits, expression was similar for S-100 alpha and calmodulin in the granular convoluted tubule segment. No immunodeposition of calmodulin, S-100 alpha or S-100 beta was found in granular cells, which contain growth factors such as EGF and NGF.


[Oncogenes and tumor-suppressor genes].

[Oncogenes and tumor-suppressor genes]. Tumors arise as a result of a chain of genetic alterations that impair normal cell functions and lead to invasion and development of metastases. These genetic alterations may result either in qualitative or quantitative changes in genes that play a key role in normal cell function, called proto-oncogenes, or in inactivation of genes that normally inhibit cell growth, called tumor suppressor genes. Whatever the mechanism involved, responses of the cell to changes in the environment become inappropriate. This paper successively reviews the various categories of proto-oncogenes, the mechanisms by which proto-oncogenes can be activated, and several examples of tumor suppressor genes. The various genetic factors involved in cell transformation probably act together to create a network of molecular interactions that results in tumor progression.


A new model for testing gametocytocidal effects of some antimalarial drugs on Plasmodium falciparum in vitro. A technique is described for obtaining pure gametocyte cultures of Plasmodium falciparum, using pyrimethamine at the minimum concentration for inhibition of asexual parasites. Routine cultures producing sexual stages were exposed to pyrimethamine on days 5 and 6. These cultures grew synchronously and contained gametocytes of stages II, III and V on day 7, 9 and 15 of the cultures respectively. The pyrimethamine-treated gametocytes were more infective to mosquitoes than were untreated controls. This model for the culture of pure gametocytes was used to observe the activity of chloroquine, halofantrine, pyrimethamine and quinine on the gametocyte stage III of Plasmodium falciparum strain NF54 in vitro. NF54 was shown to be sensitive to chloroquine, quinine and pyrimethamine, but the results showed that halofantrine was the most effective drug in reducing the number of gametocytes. A concentration of 3 x 10(-9) M halofantrine was lethal to both asexual parasites and gametocytes. The gametocytocidal EC90 of chloroquine (1 x 10(-6) M) and that of quinine (9 x 10(-7) M) were equal to the minimum inhibitory concentration of asexual stages of isolates of P. falciparum considered as highly resistant to these drugs. A high concentration of pyrimethamine (1 x 10(-4) M) had, in contrast, little effect on gametocytes.


Malaria parasitological indices in the Cordillera Province (Santa Cruz Department, Bolivia). In 1988-1989, as part of a co-operative programme with the local Unidad Sanitaria, two cross-sectional surveys were carried out to study the prevalence of malaria in eight villages in the rural areas near Camiri, Boyuibe and Gutierrez (Cordillera Province, Santa Cruz Department, Bolivia). Thick and thin blood films were collected from all available two- to nine-year-old children at the end of the dry season, in the first survey (252 samples), and after the rainy season, in the second survey (346 samples). The parasite and gametocyte indices increased between surveys from 1.59-25.72 and from 0.40-1.73, respectively. All infections were due to Plasmodium vivax. Both prevalence and parasite load were lower in children aged two to four years than in older children. Prevalences, parasite loads, and parasite densities were highest in rural areas near Camiri and Gutierrez.


Oxido-reductive functions of Entamoeba histolytica in relation to virulence. Entamoeba histolytica can reduce nitro-blue tetrazolium (NBT) in Hank's balanced salt solution to almost the same extent as in Eagle's minimal medium. Further, this reduction was stimulated only to a minor degree by glucose, pyruvate and DL-serine, substrates known to support respiratory activity (O2 uptake) in E. histolytica. However, both NADH and NADPH increased NBT reduction several-fold, the effect being greater with NADPH. A sizeable proportion of this endogenous dye-reducing capability (in Hank's solution) was associated with low-speed sediments obtainable from amoebic homogenates, which also shared the bulk of 125I labelling (when the homogenates were prepared after surface labelling with Na 125I). Conversion of the dye to formazan was strongly inhibited by -SH blocking agents, but was not influenced by rotenone and antimycin A. The activity was also inhibited by H2O2, but stimulated by catalase. Superoxide dismutase only slightly curtailed NBT reduction in intact cells, but inhibited it in homogenates in a concentration-dependent manner to a maximal extent of 33%. Almost the same degree of curtailment of this activity was induced by anaerobic conditions. Both concanavalin A (Con A) and phorbol myristate acetate stimulated the activity in intact cells, though the effect of Con A was nullified by alpha-methyl mannoside. Both NBT-reducing capability and alcohol dehydrogenase activities were higher in the more virulent IP:106 strain, and they increased with time in cultures of NIH:200 in a cholesterol-enriched environment.


The efficacy of chemotherapy with mebendazole in human cystic echinococcosis: long-term follow-up of 52 patients. Sixty patients with Echinococcus granulosus infection of the liver, lungs, bone and/or soft tissues were treated for several months with oral mebendazole (50-60 mg kg-1 day-1), in divided doses after fat-rich meals, either without surgery (WS), post-surgery (PS) or pre- and post-surgery (PPS). Long-term follow-up, possible for 52 of the patients, showed that WS, PS and PPS patients have so far remained disease-free following treatment for (means +/- standard deviations) 65.5 +/- 37.7, 82.5 +/- 37.0 and 84.1 +/- 28.3 months, respectively. Ultrasound and computed tomography scans were similar in WS and PPS patients post-treatment. Blood eosinophil levels, which were sometimes elevated initially, returned to normal in all patients and this decrease indicated cyst degeneration before this was evident on the scans. Treatment of patients with cystic echinococcosis may no longer require surgery.


Antibodies of different immunoglobulin isotypes in serum and bile of patients with clonorchiasis. Specimens of serum and bile from patients were assayed by an enzyme-linked immunosorbent assay to reveal antibodies specific to antigens from adult Clonorchis sinensis. Antibodies of the IgG isotype showed the greatest elevation during infection (Student's t-test, P < 0.001), whereas serum IgA and IgE and secretory IgA in bile were moderately elevated (P < 0.05). Major differences in the distribution of antibodies among the IgG subclasses were observed between patients who were and those who were not infected. IgG4 antibody levels were elevated in the serum and bile of infected patients, and there were significant correlations between the levels of IgG and IgG4 antibodies and the intensity of infection.