Knowledge and preference for breast conservation therapy among women without breast cancer.

We interviewed 419 adult women in Minnesota, who were selected at random and without a history of breast cancer, to ascertain what percentage could correctly report that cure was the same for breast conservation therapy and mastectomy, what percentage would state a preference for breast conservation therapy rather than mastectomy, and characteristics associated with these outcomes. Nearly all women (n = 360; 86%) had heard of both mastectomy and breast conservation therapy; among these women, 37% correctly reported that the two treatments were equally efficacious. Given a scenario where they were diagnosed with breast cancer amenable to either treatment, 58% of participants stated a preference for breast conservation therapy. Older women were less likely than younger women to know that cure was the same for breast conservation therapy and mastectomy (adjusted OR = 0.5, 95% CI 0.2, 1.0), and women residing in urban areas were more likely to prefer breast conservation therapy over mastectomy compared to rural residents (adjusted OR = 2.2, 95% CI 1. 3, 3.8). Comparing these findings to women diagnosed with breast cancer in Minnesota, breast conservation therapy was found to be performed less frequently than preference for such therapy among women in our study would suggest. Educating women prior to diagnosis about breast cancer treatment options, and exploring reasons for the gap between actual utilization of breast conservation therapy and prediagnosis preference, may be indicated.

Late-onset holocarboxylase synthetase-deficiency: pre- and post-natal diagnosis and evaluation of effectiveness of antenatal biotin therapy.

UNLABELLED: The clinical and biochemical findings in a family with late-onset holocarboxylase synthetase (HCS) deficiency are described. The index patient had two life-threatening episodes of metabolic decompensation at the age of 13 and 18 months with ketotic hypoglycaemia, vomiting and progressive loss of consciousness. The child recovered without biotin therapy. Organic aciduria characteristic of multiple carboxylase deficiency (MCD) was found, however, the key metabolites were only slightly elevated in some samples. Biotinidase deficiency was considered but excluded by the finding of normal plasma biotinidase activity. The correct diagnosis was made only at the age of 19 months when severe MCD was found in lymphocytes in the presence of normal plasma biotin concentration. HCS deficiency was confirmed by fibroblast studies. Biotin therapy (20 or 40 mg/day) prevented further episodes and normalized biochemical parameters with so far normal development. During two subsequent pregnancies, 10 mg biotin/day was administered to the mother from the 20th week of gestation. At delivery plasma biotin in cord blood samples was 3 4 times higher than in maternal plasma. The 2nd child was unaffected. In the 3rd pregnancy prenatal diagnosis was performed at 16 weeks of gestation. The concentration of methylcitrate in amniotic fluid was within the normal range and that of 3-hydroxyisovalerate only slightly elevated. However, enzyme assays in cultured amniotic fluid cells were consistent with an affected fetus. At birth, carboxylase activities in lymphocytes of this newborn were only moderately decreased to 37% of mean normal. HCS deficiency was confirmed postnatally in fibroblasts. Development remains normal on biotin therapy (20 mg/day). CONCLUSION: Prenatal diagnosis in families with milder forms of HCS deficiency has to be performed by enzyme assays in cultured amniotic cells since organic acid analysis of amniotic fluid may be inconclusive in affected fetuses. Biotin administered prenatally is effectively taken up by the fetus and prevents functional deficiency of the carboxylases in an affected newborn.

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: clinical and neuropathological observations in a 33-year-old man.

The syndrome of ichthyosis follicularis, alopecia, and photophobia (IFAP) is an uncommon neuroichthyosis described in only 10 males so far. We report on a man with congenital ichthyosis and alopecia with apparently normal development in early infancy. Photophobia and generalized myoclonicastatic seizures began during or after the first year of age and were associated with progressive impairment of motor skills and mental abilities. He died at 33 years of age. Neuropathological findings showed an unusual deformation of the temporal lobes and olivocerebellar atrophy. Cytogenetic and molecular studies did not uncover deletions in either Xp22.2 to 3 or in Xq27.3 to qter.

Five patients with a biotin-responsive defect in holocarboxylase formation: evaluation of responsiveness to biotin therapy in vivo and comparative biochemical studies in vitro.

Biochemical studies in five patients with a defect in biotin-responsive holocarboxylase synthesis are reported. The age of onset (2 d to 6 y) as well as the severity of illness varied considerably. In all patients diagnosis was established by the finding of organic aciduria typical for multiple carboxylase deficiency in a catabolic state. In four patients the response to biotin therapy was evaluated by measurement of mitochondrial carboxylase activities in lymphocytes and by monitoring urinary organic acid excretion. In three patients clinical symptoms disappeared with 10-20 mg biotin/d, whereas normalization of the biochemical parameters required higher doses (20-40 mg/d). The fourth patient required a dose of 100 mg biotin/d before her skin rash disappeared. She remains mentally retarded and shows slightly elevated urinary organic acid excretion. Carboxylase activities were clearly deficient in fibroblasts grown in the commonly used medium which contains 10 nmol/L biotin (contributed by FCS in medium) in two patients. Fibroblasts of the other three patients became deficient only in a low biotin medium (0.1 nmol/L). Reactivation of deficient carboxylase activities in relation to time and biotin concentration correlated well with the severity and age of onset of illness in four patients. In one patient, however, carboxylase reactivation followed a more complex pattern requiring the longest incubation time but only a moderately increased biotin concentration of 19 nmol/L compared with 3-5 nmol/L in normal cells and 34-4000 nmol/L in the other four patients. The results in the five patients are in accordance with a primary defect of holocarboxylase synthetase due to a decreased affinity for biotin, in one patient combined with a decreased Vmax.

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Treatment of infants with indirect hyperbilirubinemia. Readmission to birth hospital vs nonbirth hospital.

BACKGROUND/OBJECTIVE: Indirect hyperbilirubinemia is a common cause for readmission to a hospital during the first week of life. Many newborn nurseries are ill equipped to readmit such newborns. The purpose of this study was to compare the care and treatment of infants with indirect hyperbilirubinemia who were readmitted to their birth hospital with those who were admitted to a hospital that differed from their birth hospital. DESIGN: Retrospective cohort study. SETTING: Children's and community hospitals. PATIENTS: We reviewed the records of 100 newborns who were readmitted during the first week of life (36 were readmitted to their birth hospital) with a primary admission diagnosis of indirect hyperbilirubinemia. RESULTS: Infants who were admitted to their birth hospital were less likely to have blood cultures (none of 36 vs 17 of 64, P = .0005), urine cultures (none of 36 vs eight of 64, P = .02), or more than one complete blood cell count (two of 36 vs 18 of 64, P = .001) performed compared with infants who were admitted to a nonbirth hospital. Antibiotic, intravenous therapy (P = .0005), and emergency department (P = .0001) use was more common among infants who were admitted to a nonbirth hospital. Infants who were admitted through the emergency department at a nonbirth hospital had phototherapy started later (mean +/- SD, 5.3 +/- 1.6 vs 2.2 +/- 1.7 hours; P = .0001) than did infants who were directly readmitted to the same nonbirth hospital. CONCLUSIONS: Readmitting infants with indirect hyperbilirubinemia to birth hospitals or ensuring that accurate, timely, and complete information is obtained from the birth centers by admitting hospital personnel before laboratory studies and treatment are performed will reduce diagnostic workups and should reduce hospital charges for these infants. Phototherapy should be initiated in the emergency department if stabilization is required before admission.

Development of lipolytic activity in gastric aspirates from premature infants.

Neonates, having little or no pancreatic lipase, would have a compromised ability to digest lipids if not for lingual and gastric lipases. To document the postnatal developmental profile of preduodenal lipase activity, 350 premature infants who were at various gestational ages and who had an orogastric tube had their gastric aspirates collected. Two hundred one infants had their gastric aspirates collected within 12 h after delivery. Serial collections were performed in 25 infants at various postnatal ages. Gastric aspirates collected from premature infants had a pH activity profile similar to that of lingual and gastric lipase but different from that of pancreatic lipase, indicating that their origin was from the tongue and/or stomach. Lipolytic activity and pH of these aspirates were quite variable, but no correlation was found between pH and enzyme activity. At birth, lipase activity was lower in the younger infants (< or = 26 weeks, n = 13). It increased to a peak at 30-32 weeks of gestational age and then declined to a lower level at term (> or = 40 weeks, n = 40). Postnatally, a composite plot of the serially collected aspirates also showed a predominant peak at 28-33 weeks of age. Comparison among siblings in twins (n = 12 pairs) and triplets (n = 3) showed great variations in their lipolytic activities, suggesting that the hereditary factor is not a major determinant. Various combinations of antibiotic medications (ampicillin, cefotaxime, gentamicin, and vancomycin) and drugs (dexamethasone, heparin, furosemide, phenobarbital, albumin, and vitamin K) apparently had no effect on the level and development of gastric lipolytic activities.(ABSTRACT TRUNCATED AT 250 WORDS)

[Homozygous C7 defect in a German family]. / Homozygoter C7-Defekt in einer deutschen Familie.

An 11 year old boy with recurrent meningitis/sepsis (once without positive bacterial culture, once with demonstration of Neisseria meningitidis in blood) was evaluated for suspected immunodeficiency. Absent activity of both the classical and alternative pathway of complement suggested a defect of the membrane attack complex. Immunochemical and functional analyses together with family studies revealed a homozygous defect of the seventh component of complement in the boy. This is the first description of C7 deficiency in a German family.

Identification of the gene encoding the major capsid protein of insect iridescent virus type 6 by polymerase chain reaction.

The gene encoding the major capsid protein of Chilo iridescent virus (CIV) has been identified by PCR using oligonucleotide primers corresponding to different regions of the major capsid proteins of Tipula iridescent virus (TIV) and iridescent virus 22 (IV22). A DNA fragment of 0.5 kbp was amplified using two oligonucleotide primers corresponding to the amino acid positions 146 to 153 and 304 to 313 of the major capsid protein of TIV, respectively. The radioactively labelled DNA fragment derived from PCR was hybridized to a CIV gene library. This analysis revealed that only the EcoRI CIV DNA fragment X [2.85 kbp; 0.589 to 0.603 viral map units (m.u.)] hybridized to the amplified DNA fragment. An RNA transcript of about 1.5 kb was identified when the PCR product was used as a hybridization probe. The same RNA transcript was detected when the EcoRI fragments X and Q (5.9 kbp; 0.603 to 0.631 viral m.u.) were used as probes. This indicates that the expected gene is located within map coordinates 0.589 to 0.631 and harbours part of the DNA sequences of fragments Q and X. The analysis of the DNA sequences of this particular region of the CIV genome revealed the presence of one open reding frame of 1401 bp. The DNA sequences of this region encode a protein of 467 amino acid residues with an M(r) of 51.4K. A high degree (64.7%) of amino acid sequence identity was detected between the major capsid protein of TIV and/or IV22 and the amino acid composition of the identified CIV protein.

Determination of the position of the boundaries of the terminal repetitive sequences within the genome of molluscum contagiosum virus type 1 by DNA nucleotide sequence analysis.

The repetitive DNA sequences of the genome of Molluscum contagiosum virus type 1 (MCV-1) have been localized within the terminal regions of the viral genome corresponding to the BamHI MCV-1 DNA fragments B (18 kbp; 0 to 0.095 map units (m.u.)) and E (10.5 kbp; 0.944 to 1 m.u.). The fine mapping of these particular regions of the genome of MCV-1 revealed that the boundaries of the terminal repetitive DNA sequences of the viral genome are located within the DNA sequences of the HindIII MCV-1 DNA fragments K (3.8 kbp; 0.014 to 0.036 m.u.) and J1 (4.1 kbp; 0.962 to 0.985 m.u.). The exact position of the boundary of the repetitive DNA sequences was determined by DNA nucleotide sequencing. The HindIII DNA fragments K and J1 compose 3859 and 4107 bp, respectively. The DNA sequences of HindIII MCV-1 DNA fragment K possess repetitive DNA sequences between the nucleotide positions 1 and 1675 which are homologous to the inverted and complementary DNA sequences of the HindIII MCV-1 DNA fragment J1 between the nucleotide positions 2437 and 4107 (1670 bp). The degree of DNA sequence homology detected between the repetitive DNA sequences in the HindIII DNA fragments K and J1 of the viral genome was found to be 98%. The number of open reading frames (ORFs) detected by the analysis of the DNA sequences of the HindIII MCV-1 DNA fragments K and J1 was found to be 14 (70 to 219 amino acid residues) and 11 (70 to 365 amino acid residues), respectively.

Determination of the coding capacity of the BamHI DNA fragment B of apathogenic Herpes simplex virus type 1 strain HFEM by DNA nucleotide sequence analysis.

Herpes simplex virus type 1 (HSV-1) strain HFEM acquired an apathogenic phenotype due to a deletion within the DNA sequences of the BamHI DNA fragment B of the viral genome. In order to investigate the coding strategy of this particular region of the genome of HSV-1 strain HFEM the DNA nucleotide sequence of the BamHI DNA fragment B was determined. This analysis revealed that the BamHI DNA fragment B of HSV-1 strain HFEM comprises 6593 bp, corresponding to the nucleotide positions (np) 113322 to 117088 and np 120643 to 123465 of the genome of HSV-1 strain 17. According to these data the deletion of the genome of HSV-1 strain HFEM occurred between the np 117089 and 120642. The promoter region of the UL56 gene of HSV-1 strain HFEM is a part of the deleted DNA sequences. Therefore, this gene of HSV-1 strain HFEM is affected and cannot be expressed. The first 35 amino acid (AA) residues of the deduced amino acid sequence of the UL56 open reading frame (ORF) were found to be identical to the amino acid sequence of the UL56 genes of HSV-1 strains 17 and F. However, due to a deletion at np 3494 of the BamHI DNA fragment B of HSV-1 strain HFEM the amino acid composition of the predicted UL56 gene of HSV-1 strain HFEM is different from HSV-1 strain 17 between amino acid positions 36 and 233. In addition the deduced amino acid sequence of the IRL (inverted repeat of the long segment) copy of the IE110 gene of HSV-1 strain HFEM was found to be about 342 amino acids shorter than the amino acid sequence of IE110 gene of HSV-1 strain 17 (775 AA). This was based on a point mutation which was detected within the DNA sequences of Exon 3 of this copy of IE110 gene of HSV-1 strain HFEM.

Identification and mapping of origins of DNA replication within the DNA sequences of the genome of insect iridescent virus type 6.

The origins of DNA replication of the genome (209 kbp) of Chilo iridescent virus (CIV), which is circularly permuted and terminally redundant, were identified. The defined genomic library of CIV, which represents 100% of DNA sequences of the viral genome (e.g., all 32 EcoRI CIV DNA fragments), was used for transfection of Choristoneura fumiferana insect cell cultures (CF-124) that were previously infected with CIV. The plasmid rescue experiments were carried out to select those recombinant plasmids that were amplified during viral replication in CIV-infected cell cultures. It was found that six recombinant plasmids harboring the EcoRI DNA fragments C [13.5 kbp, 0.909-0.974 map units (m.u.)], H (9.8 kbp, 0.535-0.582 m.u.), M (7.25 kbp, 0.310-0.345 m.u.), O (6.5 kbp, 0.196-0.228 m.u.), Q (5.9 kbp, 0.603-0.631 m.u.), and Y (2.0 kbp, 0.381-0.391 m.u.) were able to be amplified under the conditions used. This indicates that the CIV genome possesses six DNA replication origins. Subclones of the EcoRI CIV DNA fragments C and H were screened under the same conditions. It was found that DNA sequences within the EcoRI DNA fragments C and H at the genome coordinates 0.924-0.930 and 0.535-0.548, respectively, contain origins of viral DNA replication. The DNA nucleotide sequences of the EcoRI CIV DNA fragment Y (1986 bp) were determined for identifying the DNA sequence of the corresponding origin of DNA replication. The computer-aided analysis revealed the presence of a 15-mer inverted repeat at nucleotide positions 661-675 and 677-691 (661-TAAATTTAATGAGAA-G-TTCTCATTAAATTTA-692). The analysis of the DNA sequence of the EcoRI DNA fragment H corresponding to the particular region at the genome coordinates 0.535-0.548 (1) showed that this region contains a 16-mer inverted repeat at the nucleotide positions 1315 and 1332 (1315-TAAATTTTAATGGTTA-A-TAACCATTAAAATTTA-1347), which is very similar to the inverted repetition found within the EcoRI DNA fragment Y. The successful recognition and amplification of the single-stranded synthetic DNA sequences of both strands of CIV-ori-Y (nucleotide position 661-691) using phage M13 system in CIV-infected cells is strong evidence that the CIV-ori-Y is bidirectionally active, and this DNA sequence is considered to be the origin of DNA replication within the EcoRI CIV DNA fragment Y.

Primary structure of the large (L) RNA segment of nephropathia epidemica virus strain Hällnäs B1 coding for the viral RNA polymerase.

The L RNA segment of the nephropathia epidemica virus (NEV) strain Hällnäs B1 was characterized by molecular cloning of the corresponding cDNA and subsequent determination of the DNA nucleotide sequence. The L RNA segment is 6550 nucleotides long with complementarity of 20 bases at the 3' and 5' termini. The viral messenger sense RNA contains one major open reading frame (ORF) with a coding capacity of 2156 amino acid residues encoding a protein with a calculated molecular weight of 246 kDa and an IEP of pH 7.4. Comparison of the deduced amino acid sequences from NEV hantavirus and Bunyamwera virus (BWV) L segment messenger sense RNAs, revealed a high degree of diversity (overall amino acid identity, 17%). However, three clusters of 30-40% amino acid identity were detected. One of these domains, containing an Asp-Asp motif found in many RNA polymerases, also shares amino acid sequence homology with the PB1 polymerase component of influenza type A. These results indicate that the L RNA segment of the NEV codes for the viral RNA-dependent RNA polymerase. The data presented here complete our previous studies on the characterization of the NEV genome by cDNA sequencing of the viral M and S RNA segments.

Identification and characterization of a Hantavirus strain of unknown origin by nucleotide sequence analysis of the cDNA derived from the viral S RNA segment.

The genetic characterization of a serologically Hantaan-like virus but of unknown origin (termed DX) was carried out by molecular cloning and nucleotide sequencing of the corresponding cDNA of the viral S RNA segment. The S RNA was found to be 1765 nucleotides long with 3' and 5' termini being complementary for 24 bases. The virus messenger-sense RNA contains one major open reading frame (ORF) encoding 428 amino acids or a 50 kD polypeptide. A comparison of the DX S RNA segment to those of Sapporo rat, Hantaan, Puumala/Hällnäs B1, and Prospect Hill viruses reveals 95.4, 71.3, 55.3, and 60.9% homology at the nucleotide sequence level, and 94.7, 80.1, 58.4, and 59.8% at the deduced amino acid sequence level. Thus Hantavirus strain DX is very closely related to Sapporo rat virus. We also analyzed the S RNA segments of these Hantaviruses for the presence of a second ORF encoding a potential nonstructural NSs protein. All potential second ORFs detected in the different S RNA segments differ substantially in length and position among the viruses, despite the high conservation of the nucleotide sequences and the overall structure of the nucleocapsid proteins. This suggests that the nucleocapsid protein is the only polypeptide encoded by Hantavirus S RNA segments, setting them apart from the other members of the Bunyaviridae family.

Expression of human immunodeficiency virus type 1 gag gene using genetically engineered herpes simplex virus type 1 recombinants.

Infectious herpes simplex virus type 1 (HSV-1) recombinants were constructed by inserting the cDNA sequence of the human immunodeficiency virus type 1 (HIV-1) gag gene (from nucleotide position 675 [SacI] to 3859 [Asp718] of the cDNA sequences of HIV-1 strain BH-10) within the DNA sequences of the BamHI DNA fragment B of the genome of an apathogenic HSV-1 strain HFEM. This HSV-1 strain possesses a 4.1-kbp deletion within the BamHI DNA fragment B between 0.762 and 0.789 map units of the viral genome, which allows the insertion of at least 4 kbp of foreign genetic material into this particular region. The DNA sequences of the immediate early promoter (IE4) of HSV-1 that were inserted upstream from the gag gene were used as a promoter. The screening of 205 virus stocks derived from individual plaques revealed that 46 recombinant viruses harbor HIV-1 gag-specific DNA sequences. However, it was found that only six of the recombinant viruses are able to express the gag gene product of HIV-1. This indicates that the ratio of the positive recombination events is about 2.9%.

Echovirus 11 infections of newborns with mortality during the 1979 enterovirus season in Milwaukee, Wis.

Echovirus serotype 11 (ECHO-11) was implicated in three neonatal deaths during an enterovirus outbreak from July through October 1979 in Milwaukee. The deaths followed congenital infections acquired in the community during late pregnancy. Two of the three ECHO-11 and one Coxsackie B4 deaths of infants occurred after cesarean section deliveries. Of 225 confirmed echovirus infections, 30 to 45 percent occurred in infants under 60 days old, 54 to 67 percent in the first year of life, and 13 to 25 percent in the over-10 age groups. In 13 cases with onset of symptoms in the first week of life. 8 (including the 4 fatalities) were acquired congenitally; 6 of the 8 were associated with ECHO-11, 2 with ECHO-7, and 1 with Coxsackie B4. ECHO-7 and 30 other predominant strains were isolated during the outbreak, but none was associated with mortality or severe disease in neonates. At a Milwaukee hospital, a temporal association was observed between echovirus infection, particularly ECHO-11, and increased numbers of stillbirths.