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Biomedical subjects

M Super

Publications and source records attributed to M Super.

At least 37 records · Page 2Linked to original sources
PubMed1998

Antibody-IL-12 fusion proteins are effective in SCID mouse models of prostate and colon carcinoma metastases.

IL-12 is a complex cytokine in both its structure and its range of biologic activities. Fusions of this heterodimeric molecule with an intact antitumor Ab were made to test the feasibility and efficacy of targeting IL-12 to tumors to elicit a local immune response. Fusion proteins composed of the human p35 and p40 subunits had IL-12 bioactivities that were nearly as potent on human immune cells as the rIL-12 standard, but were inactive on mouse cells. Hybrid IL-12 fusion proteins composed of mouse p35 and human p40, fused to Ab, were capable of inducing IFN-gamma, but were much less active on mouse spleen cells than a mouse IL-12 standard. Despite this relatively low activity, the hybrid fusion protein was as effective in a SCID mouse model as a fully active Ab-IL-2 fusion protein in eliminating established pulmonary metastases of CT26 colon carcinoma. Specific targeting of a human IL-12 fusion protein to metastatic prostate carcinoma xenografts was also shown to be effective in SCID mice transplanted with human lymphocyte-activated killer cells. These results demonstrate the importance of directing this potent cytokine to the tumor microenvironment and suggest an important alternative to systemic IL-12 administration or gene therapy for increasing its therapeutic index.

Animals↗
PubMed1998

Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C).

We analysed DNA samples from 26 Pakistani patients with cystic fibrosis (CF) living in the United Kingdom (14 from patients residing in the north west of England, who were referred directly to the North West Regional Molecular Genetics Laboratory, and 12 from other regional molecular genetics laboratories). Of 56 mutations seen in native U.K. CF patients, only DeltaF508, R709X, and 2184insA were detected in the Pakistani patients. Combined SSCP/Heteroduplex analysis, DGGE, and direct DNA cycle sequencing revealed five novel mutations: Y569D, Q98X, 296+12(T>C), 1161delC, and 621+2(T>C), which appear to be specific to Pakistani CF families. In addition, a novel polymorphism, 297-67(A/C), and three previously described rare mutations, 1525-1(G>A), R560S, and 1898+1(G>T), were detected. In the 14 Pakistani CF patients from the north west of England, DeltaF508 accounted for approximately 32% (9/28 chromosomes) and the overall detection rate of CF mutations in this group was approximately 86% (24/28 chromosomes).

Cystic Fibrosis↗
PubMed1998

The use of human glutathione S-transferase A1 in the detection of cystic fibrosis liver disease.

OBJECTIVE: To determine the value of serum human glutathione S-transferase A1 (hGST A1) in the detection of cystic fibrosis liver disease (CFLD). METHODS: Sixty-three children (aged 0.5-16 years) with cystic fibrosis (CF) were screened prospectively for evidence of hepatobiliary abnormalities between February 1993 and February 1996. Comparison was made between clinical examination, abdominal ultrasonic scan, measurement of conventional liver enzymes (LFTs) and serum hGST A1 concentration in the detection of hepatobiliary abnormalities in children with CF. RESULTS: The 5-95% concentration of serum hGST A1 was 1.7-4.27 micrograms L-1 for the control group. The hGST A1 levels in the CF patients were significantly higher than in the non-CF group. Thirty-eight (60%) children had detectable hepatobiliary abnormalities. Ultrasound scanning detected the highest number of abnormalities (41%), followed by hGST A1 (30%). The presence of clinical liver disease was found in 19% of the children. The estimated sensitivities of detecting CFLD by clinical method, ultrasound scan, serum hGST A1, and LFTs would be 32%, 68%, 50% and 16%, respectively. CONCLUSIONS: Serum hGST A1 measurement increases the sensitivity of detecting hepatic abnormalities when included with clinical and ultrasound evaluation although, in some cases with advanced liver disease, serum hGST A1 may be normal. Conventional liver enzyme tests add little information in the detection of CF liver disease.

Adolescent↗
PubMed1998

Anaesthesia and Prader-Willi syndrome.

A review of a case series of sixteen anaesthetics in eight cases was undertaken to determine whether children with Prader-Willi syndrome present particular problems to the anaesthetist. Children in an early stage of the condition who are below their centile for weight present no specific problems. Children who are heavier than 97th centile weight have problems associated with their obesity: difficult intravenous access and sleep apnoea. Scoliosis was noted in both groups and was not associated with problems after minor surgery.

Adolescent↗
PubMed1997

Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy.

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.

Animals↗
PubMed1997

Familial patent ductus arteriosus: a further case of CHAR syndrome.

We report on a family with patent ductus arteriosus, a distinctive facial appearance with eyebrow flare, a short nose and "duck-bill lips," polydactyly, and fifth finger clinodactyly. The facial traits were consistent with CHAR syndrome. We provide further evidence for evolution of the phenotype with age and describe the previously unreported finding of interstitial polydactyly in this syndrome.

Abnormalities, Multiple↗
PubMed1997

Cystic fibrosis mutations in Romania.

UNLABELLED: We have investigated the genotype in 32 children with cystic fibrosis from Romania. The diagnosis of cystic fibrosis was made on the basis of typical clinical findings and sweat electrolyte levels using the pilocarpine iontophoresis method. CONCLUSION: Genetic analysis of 32 children with cystic fibrosis from Romania showed a 25% incidence of DeltaF508 mutation and a 64.5% incidence of unknown mutations, 5 other known mutations and 1 new mutation 1,717-2(A > G).

Blood Proteins↗
PubMed1997

Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome.

We describe nine children with a similar pattern of features including macrocephaly and cutis marmorata telangiectatica congenita. All were large at birth and had a distinctive capillary haemangioma involving the philtrum and upper lip. The seven who survived all developed hydrocephalus and had developmental delay. Six developed body asymmetry and three had internal arteriovenous malformations. Syndactyly of the second and third toes and/or the third and fourth fingers or toes was commonly seen. All of the cases were sporadic. This condition is easily recognizable and should be considered in the differential diagnosis of patients presenting with overgrowth and macrocephaly.

Abnormalities, Multiple↗
PubMed1997

Confidential inquiry into families with two siblings with cystic fibrosis.

OBJECTIVE: To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed. DESIGN: Retrospective review of case notes. SAMPLE: Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child. MAIN RESULTS: Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%. CONCLUSIONS: (1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.

Abortion, Legal↗
PubMed1997

Velocardiofacial syndrome.

Velocardiofacial syndrome is a syndrome of multiple anomalies that include cleft palate, cardiac defects, learning difficulties, speech disorder and characteristic facial features. It has an estimated incidence of 1 in 5000. The majority of cases have a microdeletion of chromosome 22q11.2. The phenotype of this condition shows considerable variation, not all the principal features are present in each case. Identification of the syndrome can be difficult as many of the anomalies are minor and present in the general population.

Abnormalities, Multiple↗
PubMed1996

Down syndrome with partial duplication and del (21) syndrome: study protocol and call for collaboration. Study I: Clinical assessment.

We report on the clinical and cytogenetic assessment of five cases of Down syndrome phenotype with either a partial duplication of chromosome 21 or a normal karyotype, and we quote a case of del (21q) syndrome. Down syndromes with a partial duplication of chromosome 21 (as well as cases of del (21q), which are partly the phenotypic countertype of trisomy 21) are of paramount importance in the understanding of genes involved in the phenotype of Down syndrome. The goal is to find the relevant genes implicated in the main traits of Down syndrome (i.e. mental retardation, Alzheimer disease, and serious visceral malformations). Such a goal, in our opinion, cannot be reached just by publishing the genotype and the phenotype of a small cohort of patients: 1. a sufficient number of accurate cases is needed, and 2. data have to be computerized for definite conclusions to be reached. The main aims of this report are to present our study protocol and to invite colleagues to participate in a collaborative study in order to collect a maximum of these (rare) cases.

Adolescent↗
PubMed1996

Noonan syndrome: coagulation and clinical aspects.

The study aims were to review the clinical features of a group of patients with Noonan syndrome and to further elucidate their bleeding tendency. Eighteen patients (12M, 6F) aged 2.6-13.3 years underwent a clinical assessment, a questionnaire of their bleeding tendency and laboratory coagulation studies. Nine had cyanotic spells or breathing difficulties after birth; 11 had poor feeding or weight gain. Increased bruising or bleeding was reported in 12 (67%), four of whom had bleeding from the oral cavity. Excessive bleeding was not reported from operative procedures in other sites. Partial thromboplastin time was prolonged in 10 (56%) associated with low levels of clotting factors, particularly XI and XII. Bleeding times were normal; one had marginal thrombocytopenia. Coagulation results did not correlate with bruising history and may not predict bleeding risk. Care is required when Noonan syndrome patients undergo surgery, particularly of the oropharynx, with immediate availability of suitable blood products.

Adolescent↗
PubMed1996

Familial bilateral periventricular nodular heterotopia mimics tuberous sclerosis.

A mother and daughter with an initial diagnosis of tuberous sclerosis are described. The daughter presented with partial seizures at the age of 8 months. Computed tomography showed uncalcified periventricular nodules which on magnetic resonance imaging were ovoid, almost contiguous, of grey matter density, and did not enhance with gadolinium. Brain imaging of her asymptomatic mother was similar. Absence of severe mental retardation, extracranial hamartomas, and depigmented patches distinguishes familial bilateral periventricular nodular heterotopia (FNH) from tuberous sclerosis. FNH is probably inherited as an X linked dominant with lethality in males.

Adult↗
PubMed1996

A genetic register for von Hippel-Lindau disease.

A genetic register for von Hippel-Lindau disease was set up in the north west of England in 1990. Population statistics, clinical features, age at onset, and survival of 83 people affected with von Hippel-Lindau (VHL) disease were studied. In addition, the effectiveness of the screening programme used and the occurrence of central nervous system haemangioblastomas in the general population were examined. The diagnostic point prevalence of heterozygotes in the North Western Region was 1 center dot 18/100 000 (1/85 000) people, with an estimated birth incidence of 2 center dot 20/100 000 (1/45 500) live births. The mutation rate was estimated directly to be 1 center dot 4 x 10(-6)/gene/generation (1/714 200). The mean age at onset of first symptoms was 26 center dot 25 years, with cerebellar haemangioblastoma being the most common presenting manifestation (34 center dot 9% of cases). The mean age at diagnosis of VHL disease was 30 center dot 87 years. Overall, 50 patients (60 center dot 2%) developed a cerebellar haemangioblastoma, 34 (41 center dot 0%) a retinal angioma, 21 (25 center dot 3%) a renal cell carcinoma, 12 (14 center dot 5%) a spinal haemangioblastoma, and 12 (14 center dot 5%) a phaeochromocytoma. Mean age at diagnosis of renal cell carcinoma (38 center dot 9 years) was significantly higher than that for cerebellar haemangioblastoma (30 center dot 0 years) and retinal angioma (21.1 years). Mean age at death was 40 center dot 9 years with cerebellar haemangioblastoma being the most common cause (47 center dot 7% of deaths). A total of 65 VHL manifestations were diagnosed asymptomatically following appropriate clinical and radiological screening tests, and failure to detect manifestations of VHL disease in spite of appropriate screening occurred on only two occasions. The use of DNA linkage analysis and direct mutation testing reduced the personal risk of carrying the VHL gene to below 1% in 14 people. In addition to the 83 clinically affected subjects, three obligate carriers who were considered to be lesion free in spite of extensive screening tests were identified. Fourteen percent of all CNS haemangioblastomas on the regionally based Cancer Registry were found to occur as part of VHL disease, but investigations for VHL in apparently sporadic disease appeared to be limited.

Adolescent↗