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Biomedical subjects

H Schultz

Publications and source records attributed to H Schultz.

At least 19 recordsLinked to original sources
PubMed1996

The Saudi experience with neutron therapy in locally advanced head and neck cancers.

The neutron therapy program at King Faisal Specialist Hospital and Research Center conducted a phase II study to evaluate the toxicity and efficacy of neutrons against conventional external megavoltage irradiation in patients with locally advanced head and neck malignancy. One hundred and nineteen patients were allocated to receive either photons (46/119) or neutrons (73/119). Radiation effects were scored according to the EORTC/RTOG criteria; data was collected weekly during treatment, once a month for the first year and at 6-month intervals subsequently. While acute effects were scored in all patients, only 59 were evaluable for late effects and locoregional control. A composite of the average reaction results were obtained using this information, to compare them in time, for acute and late effects in both arms of the study. The maximum acute reactions in the two groups were similar. In the majority of the patients (80%) acute skin and mucosal reactions occurred during the last week of treatment. The changes in the subcutaneous tissues and salivary glands became clinically apparent at 3 months or later. Salivary gland toxicity was more severe in the photon arm and the difference was statistically significant at 3 months (P = 0.04) but this was lost at 12 months. Late effects for skin and subcutaneous tissues were significantly more severe in the neutron arm with P values of 0.04 and 0.01 respectively. Three patients in the neutron arm died of grade 4 radiation complications. The local control and survival were similar in both groups.

Carcinoma, Squamous Cell↗
PubMed1996

The superantigen Staphylococcus enterotoxin B induces a strong and accelerated secondary T-cell response rather than anergy.

The primary and secondary immune response of V beta 8+ T cells to the bacterial superantigen Staphylococcus enterotoxin B was compared in BALB/c mice. Secondary responder T cells were found to up-regulate the expression of the adhesion molecule LFA-1 faster, and to enter the cell cycle earlier than primary responder T cells. Both, primary and secondary responder T cells upregulate the expression of CD2 and CD25 and turn into blast cells with superimposable time kinetics. Secondary responder T cells terminate DNA synthesis, blast formation and the upregulation of CD25 and CD2 expression earlier than primary responder T cells and become more rapidly deleted. Two days after superantigen challenge, when primary responder T cells reach peak activity in terms of DNA synthesis and blast formation, secondary responder T cells have returned to the size of microblasts and ceased to replicate their DNA. Whereas our results are consistent with the observations leading to the concept of superantigen-induced T-cell anergy, they demonstrate, by revealing the accelerated vigorous secondary T-cell response to the superantigen, that this concept requires reconsideration.

Animals↗
PubMed1996

Targeting cell-specific gene expression with an adenovirus vector containing the lacZ gene under the control of the CFTR promoter.

In vivo gene therapy requires the development of vectors able to deliver and express therapeutic genes preferentially into specific cell populations. This can be achieved by the manipulation of viral proteins mediating target-cell recognition, as well as by the introduction of tissue-specific promoters into viral vectors. As a first approach towards this goal, we describe here the construction and testing of a recombinant adenovirus expressing the lacZ gene encoding beta-galactosidase under the control of 2 kilobase pairs (kbp) of 5' untranslated DNA sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We show that such a recombinant virus directs beta-galactosidase expression in cell lines expressing CFTR, and in human and murine respiratory tract cells in vitro and in vivo. However, we were unable to demonstrate a cell-type specificity of expression strictly paralleling that of the endogenous CFTR gene. This data indicates that only part of the natural CFTR gene regulation is reconstituted in such a vector.

3T3 Cells↗
PubMed1995

Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif.

A recently described downstream target of mitogen-activated protein kinases (MAPKs) is the MAPK-activated protein (MAPKAP) kinase 2 which has been shown to be responsible for small heat shock protein phosphorylation. We have analyzed the mechanism of MAPKAP kinase 2 activation by MAPK phosphorylation using a recombinant MAPKAP kinase 2-fusion protein, p44MAPK and p38/40MAPK in vitro and using an epitope-tagged MAPKAP kinase 2 in heat-shocked NIH 3T3 cells. It is demonstrated that, in addition to the known phosphorylation of the threonine residue carboxyl-terminal to the catalytic domain, Thr-317, activation of MAPKAP kinase 2 in vitro and in vivo is dependent on phosphorylation of a second threonine residue, Thr-205, which is located within the catalytic domain and which is highly conserved in several protein kinases. Constitutive activation of MAPKAP kinase 2 is obtained by replacement of both of these threonine residues by glutamic acid. A constitutively active form of MAPKAP kinase 2 is also obtained by deletion of a carboxyl-terminal region containing Thr-317 and the A-helix motif or by replacing the conserved residues of the A-helix. These data suggest a dual mechanism of MAPKAP kinase 2 activation by phosphorylation of Thr-205 inside the catalytic domain and by phosphorylation of Thr-317 outside the catalytic domain involving an autoinhibitory A-helix motif.

3T3 Cells↗
PubMed1995

Aerosol-mediated delivery of recombinant adenovirus to the airways of nonhuman primates.

At present, it is conceivable that gene therapy of the cystic fibrosis airway epithelium is possible using the direct transfer of a functional human cystic fibrosis transmembrane conductance regulator (CFTR) gene to a wide variety of patients' tracheo-bronchial cells. Here we describe a novel approach (aerosolization) to deliver a replication-deficient adenovirus carrying the CFTR gene (Ad.CFTR) to the airways. Results obtained in vitro and in Rhesus monkeys suggest that the delivery of recombinant adenovirus as an aerosol is feasible and is not associated with severe toxicity after single or double administration depending on the Ad.CFTR dose. This study supports the concept of aerosolization as a delivery method for adenovirus-mediated lung gene therapy.

Adenoviridae↗
PubMed1995

Trans-complementation of E1-deleted adenovirus: a new vector to reduce the possibility of codissemination of wild-type and recombinant adenoviruses.

Treatment of cystic fibrosis by gene therapy will require the development of vectors capable of efficient and safe transfer of a functional cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to airway epithelia. To achieve this goal, replication-deficient (E1-) adenoviruses (Ad) are promising vectors. We have previously demonstrated efficient CFTR gene delivery to the airways of cotton rats and rhesus monkeys using a replication-deficient adenovirus, Ad-CFTR. Here, we have investigated an important safety issue, the interaction between the vector and wild-type virus which can provide the missing E1 function in trans. We show that Ad5 can mobilize the defective Ad-CFTR genome in vitro and in cotton rats. However, the extent of the complementation in vivo by wild-type virus is limited because no additional spreading or shedding of Ad-CFTR to trachea, lungs, and stools is elicited. To attenuate Ad-CFTR further, a mutation was introduced in the cis-acting regulatory sequences that control the encapsidation of the viral genome. We demonstrate that when cells are coinfected with wild-type virus and the new attenuated vector, the viral DNA containing the natural encapsidation sequences is preferentially packaged, leading to a rapid dilution of the recombinant virus.

Adenoviridae↗
PubMed1994

Activation of human T cells by the superantigen Staphylococcus enterotoxin B: analysis on a cellular level.

Superantigens interact with and activate a sizeable fraction of T cells characterized by expression of specific V beta gene segments of their antigen receptor. The massive activation of T cells in an organism is considered responsible for clinical symptoms associated with superantigen-producing bacteria. Here we studied the in vitro activation of human T cells by the superantigen Staphylococcus Enterotoxin B on a cell by cell basis. Superantigen-reactive T cells were stained with a V beta 12-specific monoclonal antibody and analyzed in a cytofluorograph. Blast formation of SEB-reactive T cells occurs within 12 h and reaches a plateau after 24 h. Double-staining of V beta 12+ T cells with antibodies against different T cell activation or adhesion surface molecules revealed a time-dependent differential upregulation for CD2, CD11 = LFA-1, CD25, CD28, CD69, and HLA-DR. The expression of CD3, CD4 and CD5 was not influenced by the superantigen. The rapid phenotypic changes of superantigen reactive T cells in terms of marker expression and cell size could provide early tools in diagnosing diseases caused by superantigens.

Antigens, CD↗
PubMed1994

In vivo adenovirus-mediated transfer of human CFTR cDNA to rhesus monkey airway epithelium: efficacy, toxicity and safety.

We have administered replication defective recombinant adenovirus harboring the human CFTR cDNA (Ad.CFTR) to lungs of Rhesus monkeys and assessed toxicity, efficiency of gene transfer and containment of recombinant adenovirus in the lungs. Gene transfer efficiencies, as measured by PCR analysis, were dose-dependent. Administration of low dose Ad.CFTR [1.5 x 10(7) plaque forming units (p.f.u.)] was not accompanied by any clinical chemical or histopathological changes. Mild to moderate multifocal perivascular and peribronchial lymphocytic infiltrates were found upon histopathological analysis only after administration of a high dose of recombinant adenovirus, although not accompanied by changes in clinical chemical parameters. Long-term expression (up to 128 days) was found after administration of recombinant adenovirus. Re-challenging of the monkeys treated with high-dose recombinant adenovirus resulted again in gene transfer at all levels of lungs and airways, without being accompanied by additional histopathological changes. Circulating anti-adenovirus antibodies were elicited. Animals treated with high-dose adenovirus secreted virus in pharynx and faeces for maximally 2 and 4 days after administration, respectively. These results show that recombinant adenovirus can be used for efficient delivery of genes into primate airway epithelium without signs of severe toxicity.

Adenoviridae↗
PubMed1993

Surveillance following orchidectomy for stage I seminoma of the testis.

From 1985 to 1988, 261 unselected patients entered a nationwide Danish study of surveillance only for testicular seminoma stage I. The median follow-up time after orchidectomy was 48 months, range 6-67 months. 49 patients relapsed (19%). Sites of relapse were paraaortic lymph nodes in 41 patients, pelvic lymph nodes in 5, inguinal lymph nodes in 2 and lung metastases in 1 patient. The median time to relapse was 14 months, range 2-37 months. The 4-year relapse-free survival was 80%. 37 of the relapsing patients (76%) had radiotherapy as relapse treatment. Of these patients, 4 (11%) had a second relapse and received chemotherapy. 1 died of disseminated seminoma. Of the relapsing patients, 12 (24%) had chemotherapy as relapse treatment because of bulky (11 patients) or disseminated disease (1 patient). None of these patients have had a second relapse. However, 2 patients died of infection due to chemotherapy-induced neutropenia. Thus, there have been three seminoma-related deaths (1.1%). The testicular tumour size had an independent prognostic significance. The 4-year relapse-free survivals were 94, 82 and 64% for tumours < 3, 3 to < 6 and > or = 6 cm, respectively. Patients with tumours > or = 6 cm will now be given prophylactic radiation treatment, whereas we will continue to use surveillance only after orchidectomy for patients with tumours < 6 cm.

Adult↗
PubMed1993

Characterization of anergy to the superantigen Staphylococcus enterotoxin B.

In vivo administration of superantigens leads to activation and subsequent depletion or anergy of T cells expressing defined V beta-T cell receptors (TCR). Superantigens have therefore become intensively studied tools for examining parameters of immunoregulation and they may represent model antigens for pathogenic agents. An HIV-encoded superantigen has for example been implicated in the dramatic loss of helper T cells in AIDS. We investigated the response of V beta 8+ T cells in mice after primary and secondary exposure to the superantigen Staphylococcus Enterotoxin B (SEB).

Animals↗
PubMed1993

[Effect of cholelithiasis and cholecystectomy on duodenogastric biliary reflux].

The aim of this work was to study the influence of cholelithiasis and cholecystectomy on duodenogastric biliary reflux. Total bile acid concentration (TBAC) in fasting gastric juice was measured in 23 consecutive patients with cholelithiasis and functioning gallbladder before and at least 3 months after cholecystectomy (group 1) and in 14 healthy volunteers (group II). In group two, TBAC was 8.5 +/- 2.8 uMol/l (mean +/- sem), the preoperative value in group I was 32.8 +/- 8.9 uMol/l and the postoperative value 69.9 +/- 14 uMol/l (p < 0.002 compared with group II and < 0.035 compared with preoperative values). These results suggest that cholelithiasis, even with a functioning gallbladder is associated with a significant increase in bile reflux to the stomach, with raises further after cholecystectomy.

Adult↗
PubMed1993

Thermal artifacts and inter-gynecologist variation of laser cone biopsies of the cervix.

OBJECTIVE: To evaluate the extent of thermal artifacts and the inter-gynecologist variation in CO2 laser cone biopsies for cervical intraepithelial neoplasia (CIN) using high power density. METHODS: All 1180 histologic sections from 93 CO2 laser cone biopsies performed by nine gynecologists were evaluated by morphometry. Power density of 19,700 W/cm2 and spot size of 0.43 mm were used. The lengths of different epithelia, the distance from CIN to the excision margins, the thermal artifacts, and the extension of denudation were analyzed. Mean values and standard deviations were analyzed for all indices. The inter-gynecologist variation was analyzed using one-way analysis of variance, Tukey-Kramer Honestly Significant Difference test, and chi 2 contingency table analysis regarding cones classified as "good" or "not good". RESULTS: The mean length of analyzed surface per cone was 134 mm. In 3% of the sections, the sum of artifacts at the external excision margin exceeded the average "minimum free distance" from CIN to the margin (2.88 mm). At the endocervical excision margin, the free distance was exceeded in 17% of the sections. Eighteen percent of the cones had CIN at the excision margins, with no significant differences between gynecologists (P = .83). Differences existed between gynecologists regarding free minimum distance and minor thermal artifacts at the external margin, but when clinically relevant groups were applied, no significant differences were found (P > .05). CONCLUSION: We found that a high power density at CO2 laser cone biopsy resulted in specimens with minimal thermal artifacts compared to other authors who used low power density. No clinically relevant differences were found between the gynecologists regarding free margins or artifacts.

Adult↗
PubMed1993

[Perinatal herpes infection. Clinical aspects--therapy--follow-up].

Herpes simplex virus may cause serious infections in neonates. In case of foetal infection in the first trimenon, abortions, stillbirth, prematurity, intrauterine growth retardation (not obligatory) and various malformations may result. Neonatal HSV infection is mostly the consequence of intrapartum virus acquisition during passage through the birth canal. The infection is mostly localised on the skin, at the eyes or the mouth or disseminated with or without HSV meningoencephalitis. It is difficult to establish the diagnosis, because neonatal herpes disease in the early stage is not easy to distinguish from other diseases in the newborn such as RDS, NEC or ICH. Antiviral therapy with aciclovir is the treatment of choice and seems to improve the outcome of neonatal herpes. Prognosis depends on early therapy. Treatment should be initiated in relation to clinical findings, because available diagnostic techniques do not always permit an early detection of the disease.

Acyclovir↗
PubMed1993

[Intrauterine stab injury with a knife in the head of a fetus in the 29th week of pregnancy].

Penetrating head trauma in children causes uncommon and potentially life-threatening injuries. We report on a case of penetrating cranial stab wound to the right parietal region of the head to a 29-week fetus. The child was delivered by emergency Caesarian section. Neurosurgical intervention after birth was necessary. The injury caused a posthaemorrhagic hydrocephalus. Real-time ultrasound examination visualises the brain damage and the development of a hydrocephalus e vacuo.

Abdominal Injuries↗
PubMed1993

[Necrotizing enterocolitis in the newborn infant. Pathogenetic risk factors in a 3 year analysis].

In a clinical study possible risk factors causing necrotizing enterocolitis (NEC) were studied in 17 preterm infants with NEC and compared with a control group of 17 healthy preterm infants. We found a more frequent rate of blood exchange transfusions and a lower rate of breast milk feeding in patients who later developed NEC than in the control group. But there were no differences between both groups concerning factors promoting hypoxia of the gut, the number of infections, antibiotic treatment, or hyperosmolar enteral feeding. The preterm infants with NEC did not show any characteristics in history, physical examination and clinical course. These children could not be distinguished as a risk group for this illness from the newborn infant control group. Therefore, with the exception of breast milk feeding, no special prevention of the necrotizing enterocolitis can be recommended.

Birth Weight↗
PubMed1992

[Screening for uterine cervix cancer in Storstrøm, Vestsjaelland and Bornholm counties during 1979-1989].

We studied the use of Pap smears in three counties in Denmark, where the screening activity has been organized in different ways. The county of Storstrøm had an organized screening programme in 1979-82. Women aged 30-50 years were invited personally, and 91% participated. The same response rate is seen in the county of Bornholm today, where women aged 25-54 years are invited. No invitations are sent in the counties of Storstøm and Vestsjaelland today, and only 66%-69% of the 30-50 year old women are screened. The Danish National Board of Health recommends commencement of screening at the age of 23 years. However, 53%-57% of the women aged 15-22 years are screened in Storstrøm and Vestsjaelland counties today. The percentages of women screened in the older age groups are, on the other hand, low. Only 10%-17% of women aged 60-75 years were screened in 1985-89. The Danish National Board of Health recommends that women aged 23-75 years should be screened once every third year and that positive, atypical and unqualified smears should be followed-up. The county of Bornholm has an organized screening programme, but 21% of the Pap smears are nevertheless used outside the national recommendations. The county of Vestsjaelland has no organized screening programme and 42% of the Pap smear are used outside the national recommendations. It would be possible to screen a considerably higher percentage of the women aged 23-75 years if the screening activity was well organized.

Adult↗
PubMed1992

A multicenter phase II study of carboplatin in advanced ovarian carcinoma: final report.

A phase II trial of single-agent carboplatin in advanced ovarian cancer was performed by 19 institutions from 10 European countries. A total of 260 patients were treated, with a median age of 55 (range: 20-79) years. Karnofsky performance status was 80-100 in about two-thirds of the patients. Prior therapy consisted of surgery only in 31 patients, irradiation in 9, chemotherapy without cisplatin in 45, and with cisplatin in 175. Carboplatin was administered as second-line therapy in about one-half and as third-line or more in one additional third of the study population. Initial dose was 400 mg/m2 in 90, 360 mg/m2 in 152, and 320 mg/m2 or less in 18 patients. A total of 971 courses (mean 3.7, median 2, range: 1-13) of therapy were administered. A total of 16 complete and 46 partial responses were observed in 226 evaluable patients, for an objective response rate of 27%. Efficacy was greater in chemotherapy-untreated patients (51% vs. 23%, p = 0.002). In cisplatin-pretreated patients activity was significantly higher in non-refractory patients (26% vs. 4%, p = 0.015). Myelosuppression was the most significant side effect. However, low hematologic counts seldom translated into clinically significant complications. Patients with impaired baseline creatinine clearance and poor performance status were at higher risk of developing severe myelosuppression during the initial course of treatment. Non hematologic side effects were rare and mild, except for emesis. Carboplatin has a definite role in the treatment of ovarian cancer, but almost complete cross-resistance with the parent compound was observed clinically.

Adult↗