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Biomedical subjects

L Baker

Publications and source records attributed to L Baker.

At least 37 records · Page 2Linked to original sources
PubMed1999

Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.

Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disorder of pancreatic beta-cell function, characterized by inadequate suppression of insulin secretion despite severe recurrent fasting hypoglycemia. Subtotal pancreatectomy is frequently required to prevent permanent neurologic sequelae. The incidence of HI in the Caucasian population is estimated at 1:50,000, however an apparent increased incidence among Ashkenazi Jews and Saudi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 600509, SUR1) and the potassium channel, inwardly rectifying, subfamily J member 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K(ATP) channel, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations in the SUR1 gene are present on approximately 88% of HI-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By contrast, the second, more common mutation (3992-9g-->a) was associated with nine different intergenic haplotypes and has been reported in non-Jewish HI patients as well. In this study, we evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9g-->a mutation by assessing haplotypes defined by nine common single nucleotide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 gene. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a mutation in the Jewish patients appear to have originated from one founder mutation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications concerning the HI-associated chromosomes on which no mutation has been identified.

ATP-Binding Cassette Transporters↗
PubMed1999

Detection of bursts of microneurographic activity and estimation of burst parameters.

Microneurograms are used to study the neural control of the autonomic nervous system. We developed a technique for automatically detecting the times of occurrence of bursts of microneurographic activity and their durations. It involves cross-correlating a rectified and smoothed microneurogram with a triangular shaped waveform as the signal template. Parameters of the derivative of this cross-correlation indicate the times of occurrence and the durations of the bursts of activity. The accuracy of the technique was assessed by comparing its results with those of four experienced investigators and showed significant agreement between the automated technique and the investigators.

Adrenergic Fibers↗
PubMed1999

Congenital hyperinsulinism and the surgeon: lessons learned over 35 years.

BACKGROUND/PURPOSE: Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS: The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS: Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION: Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

Female↗
PubMed1999

Trained nurses can obtain satisfactory bone marrow aspirates and trephine biopsies.

AIMS: To assess the feasibility of training nurse practitioners to perform bone marrow aspiration and trephine biopsy, and to compare the quality of these samples with those obtained by medical staff. METHODS: A retrospective audit was undertaken of nurse practitioner and medical staff performance in bone marrow procedures in a busy haematology day unit. RESULTS: Nurse practitioners fared favourably in comparison with medical staff in performing bone marrow trephine biopsies, with mean biopsy lengths of 11 mm and 10.7 mm respectively. However, only 78% of the smears obtained by the nurses were judged technically satisfactory, compared with 91% prepared by doctors. This discrepancy was thought to be due largely to the quality of slide spreading. CONCLUSIONS: With motivated staff and a structured educational and training programme it is possible for nurse practitioners to perform the techniques of bone marrow aspiration and biopsy, and obtain specimens of satisfactory quality, thus improving efficiency of the haematology day unit and increasing quality of patient care.

Biopsy, Needle↗
PubMed1999

Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants under 1 yr of age. HI is most often due to defective glucose-insulin coupling by the beta-cell sulfonylurea receptor (SUR1) or glutamate dehydrogenase. HI-induced hypoglycemia carries significant morbidity, and current therapies are suboptimal. Insulin-like growth factor I (IGF-I) decreases insulin secretion in vitro and in healthy adults in vivo. We postulated that recombinant human IGF-I (rhIGF-I) could benefit children with HI and hypoglycemia by decreasing insulin levels and improving fasting tolerance. We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1. All had suboptimal glycemic control and served as their own controls. Subjects underwent 24-h glucose monitoring under their home regimens, followed by a supervised fasting study. The controlled fast was terminated when the subject became hypoglycemic (blood glucose, <50 mg/dL) or developed symptoms consistent with hypoglycemia. The fast was repeated 2 days later with administration of rhIGF-I at 40 microg/kg, s.c., every 12 h. At the start of fasting rhIGF-I lowered the mean serum insulin level by 70% (21.0 +/- 11.1 vs. 6.3 +/- 2.2 microIU/mL; P < 0.04) and lowered the mean serum C peptide level by 43% (2.1 +/- 0.7 vs. 1.2 +/- 0.6 ng/mL; P < 0.04). rhIGF-I suppression of insulin and C peptide persisted throughout the fast. The duration of fasting did not change significantly with rhIGF-I treatment. We have directly demonstrated that rhIGF-I inhibits insulin oversecretion in children with HI due to defective SUR1. Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.

ATP-Binding Cassette Transporters↗
PubMed1999

Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene.

Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic beta-cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of beta-cell proliferation (focal HI). Seventy HI probands in whom at least one SUR-1 mutation was identified were studied. Clinical data from patients with two SUR-1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was available and showed focal beta-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR-1 mutation within the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (TUNEL) reaction, apoptotic beta-cells were identified exclusively within the focal region. At diagnosis, disease severity was similar in patients with paternally inherited mutations and those with two mutations. For patients who did not undergo surgery, those with only paternal mutations entered clinical remission within 16 +/- 6.2 months, compared with 48 +/- 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HI and provide evidence to suggest that this entity may be self-limiting, since affected beta-cells undergo apoptosis.

ATP-Binding Cassette Transporters↗
PubMed1999

Cotherapy with recombinant human insulin-like growth factor I and insulin improves glycemic control in type 1 diabetes. RhIGF-I in IDDM Study Group.

OBJECTIVE: To study the effects of 12 weeks of cotherapy with recombinant human IGF-I (rhIGF-I) and insulin on glycemic control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study population consisted of 223 patients who ranged in age from 11-66 years and were randomized in a double-blind study to receive 12 weeks of treatment with twice-daily subcutaneous injections of placebo (n = 54), or rhIGF-I at a dose (A.M/P.M) of 40/40 micrograms/kg (n = 56), 80/40 micrograms/kg (n = 57), or 80/60 micrograms/kg (n = 56), while continuing to receive standard insulin therapy. Patients were instructed to test blood glucose levels four times daily and adjust insulin doses to optimize blood glucose control. HbAlc, insulin requirements, body weight, and parameters of the IGF-IGF-binding protein axis were assessed before and during treatment. RESULTS: All groups were comparable at baseline with respect to mean age, gender distribution, duration of diabetes, HbAlc, and BMI. Cotherapy with rhIGF-I/insulin produced a mean decrease in HbAlc of 1.2%, compared with a 0.7% decrease in HbAlc for patients receiving intensified insulin therapy alone (P < or = 0.01). Subjects receiving rhIGF-I/insulin cotherapy also decreased their daily insulin usage by 11-19%, compared with a 7% increase in insulin usage reported by the placebo group. Moreover, the incidence of hypoglycemia was similar in subjects treated with rhIGF-I/Insulin cotherapy compared with those treated with insulin alone, despite the better glycemic control of the former group. The 40/40 dose of rhIGF-I was well tolerated. Higher doses of rhIGF-I did not further improve efficacy yet were associated with unacceptable levels of adverse events, including edema, jaw pain, and early worsening of retinopathy. CONCLUSIONS: These results demonstrate that rhIGF/insulin cotherapy improves glycemic control in patients with type 1 diabetes better than optimized insulin management alone; longer-term trials would be required to determine an acceptable benefit-risk profile.

Adult↗
PubMed1998

In vitro inhibition of Ras-Raf association by short peptides.

Seven amino acid peptides were tested as in vitro inhibitors of oncogenic Ras-Raf association. The sequences of these peptides were derived from the H-Ras effector region (amino acids 25 to 51) and the Ras binding domain of Raf-1 (amino acids 64 to 105). Eleven out of the twenty-one Ras 7-mers tested inhibited formation of the Ras-Raf complex by at least 20% at 100 microM. The most potent of these inhibitory peptides contained the effector residues 32 to 37 or 40 to 45. Of the Raf-1 peptides tested, only the 94-ECCAVFR-100 and 95-CCAVFRL-101 peptides were significant inhibitors of Ras-Raf binding. The 95-101 Raf peptide had an IC50 value of 7 microM and also inhibited Ras-RalGDS binding. Analysis of the 95-101 peptide showed that its inhibitory activity required at least one cysteine followed by several hydrophobic residues. Our results demonstrate the feasibility of using small molecules as inhibitors of Ras protein-protein interactions.

Amino Acid Sequence↗
PubMed1998

Adjustment to residential placement in Alzheimer disease patients: does premorbid personality matter?

AIM: To evaluate the influence of premorbid personality on adaptation to placement in a long-term care facility. SUBJECTS: Twenty-eight persons with probable Alzheimer disease (AD) residing in an academically affiliated nursing home for 6-9 months. METHODS: Premorbid personality was described retrospectively by two informants for each resident using the revised NEO Personality Inventory (NEO-PI-R). Standardized tests and rating scales were used on admission to the facility to assess cognition, mood state, physical dependency and general health. Nurses rated each AD resident's social behaviour, participation in activities and quality of sleep. RESULTS: Poorer adjustment was associated with more severe dementia but better physical health. None of the NEO-PI-R domain scores predicted adjustment. CONCLUSIONS: Contrary to popular belief, premorbid personality is relatively inconsequential for an AD patient's adaptation to a long-term care facility.

Adaptation, Psychological↗
PubMed1998

Using client satisfaction surveys to evaluate and improve services in locked and unlocked adult inpatient facilities.

This article describes the implementation, in five inpatient subacute treatment facilities, of a satisfaction survey designed especially for adults with serious and persistent mental illnesses. The survey measures not only global satisfaction but also client perceptions about different treatment modalities and services, important treatment goals, and the philosophy of treatment. Data are presented from 770 completed surveys, illustrating patterns of satisfaction across facilities and services and patterns over time of stability and change in satisfaction. Data are also presented showing how the surveys were used to facilitate and measure improvements in clinical services. Finally, the implications for mental health services delivery are summarized.

Adult↗
PubMed1998

Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.

Adolescent↗
PubMed1998

Linkage-disequilibrium mapping without genotyping.

Genomic mismatch scanning (GMS) is a technique that enriches for regions of identity by descent (IBD) between two individuals without the need for genotyping or sequencing. Regions of IBD selected by GMS are mapped by hybridization to a microarray containing ordered clones of genomic DNA from chromosomes of interest. Here we demonstrate the feasibility and efficacy of this form of linkage-mapping, using congenital hyperinsulinism (HI), an autosomal recessive disease, whose relatively high frequency in Ashkenazi Jews suggests a founder effect. The gene responsible (SUR1) encodes the sulfonylurea receptor, which maps to chromosome 11p15.1. We show that the combination of GMS and hybridization of IBD products to a chromosome-11 microarray correctly maps the HI gene to a 2-Mb region, thereby demonstrating linkage-disequilibrium mapping without genotyping.

ATP-Binding Cassette Transporters↗
PubMed1998

Relationship of cognitive and functional impairment to depressive features in Alzheimer's disease and other dementias.

Patients with clinical diagnoses of Alzheimer's disease, vascular dementia, or undifferentiated dementia were rated on standardized measures of depression, cognitive impairment, and functional impairment. Logistic regression was used to evaluate the relationship between functional or cognitive impairment, as well as their interaction, and depressive features in each group. This analysis revealed notable differences by type of dementia. The results imply that the mechanisms underlying depression in Alzheimer's disease may be different from those in vascular and other types of dementia. These results also provide indicators to the clinician for further evaluation of depression in different dementia subtypes.

Aged↗
PubMed1998

Dual regulation of insulin-like growth factor binding protein-1 levels by insulin and cortisol during fasting.

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) gene transcription is known to be inhibited by insulin in vivo and in vitro. Levels of IGFBP-1 typically rise during fasting but also rise after acute hypoglycemia, including that induced by insulin, through an unknown mechanism that may involve counterregulatory hormones such as cortisol. To study the regulation of IGFBP-1 secretion during fasting, we measured IGFBP-1, insulin, cortisol, GH, and glucose during the course of standardized fasting studies in a total of 21 children. The fasting studies lasted 13-32 h and were terminated for a whole-blood glucose concentration of less than 50 mg/dL (2.8 mmol). Of the children studied, 9 children had no disorder, 8 had ketotic hypoglycemia, 2 had isolated GH deficiency, and 2 had fatty acid oxidation disorders. During fasting, IGFBP-1 rose above the mean baseline levels of 28+/-5 ng/mL to a mean level+/-SEM of 336+/-59 ng/mL at the time of hypoglycemia (P=0.001). IGFBP-1 was strongly associated with serum insulin and cortisol levels over the entire course of fasting (P < 0.0001)). The interaction of the 2 hormones across time was also strongly significant (P < 0.0001). There was no statistically significant association between IGFBP-1 and GH or glucose. At the time of hypoglycemia, insulin levels were suppressed to 1.7 microU/mL or less, and there was no correlation between IGFBP-1 levels at the end of fasting and final insulin level. In contrast, cortisol levels correlated with IGFBP-1 in the final hypoglycemic sample (r=0.56, P < 0.01). Partial correlation analysis revealed that the relationship between IGFBP-1 and cortisol was unchanged when the data was controlled for insulin levels. These data show that insulin and cortisol both regulate IGFBP-1 secretion during fasting; the effects of insulin and cortisol are strong during the course of fasting. Significant hypoglycemia stimulates a further rise in IGFBP-1, which seems to be regulated, in part, by cortisol. The cortisol-induced rise in IGFBP-1 during fasting and during hypoglycemia potentially serves to prevent the hypoglycemic effects of free IGFs.

Child↗
PubMed1998

End-of-life confusion in patients with cancer.

PURPOSE/OBJECTIVES: To review the literature on confusion at the end of life, provide accurate definitional and defining characteristics of confusion, and outline nursing strategies for its resolution. DATA SOURCES: Published articles, computerized databases, book chapters, reference lists from chapters and journal articles. DATA SYNTHESIS: As a major component of symptom distress in terminal care, confusion has not been defined clearly and therefore has not benefited from rigorous assessment and study as have other end-of-life symptoms. CONCLUSIONS: Increased knowledge about confusion that occurs in patients with widely metastatic cancer will assist in accurate symptom identification, early recognition, and timely management to reduce cognitive symptom distress at the end of life. Improved symptom resolution also can benefit family coping during terminal care. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can devise management protocols for confused patients that include screening criteria, pharmacologic interventions, environmental support, and prophylactic safety measures.

Confusion↗
PubMed1997

Characterization of the Ras binding domain of the RalGDS-related protein, RLF.

The Ras binding domain (RBD) of Rlf, a member of the RalGDS family of proteins, was characterized. Using an ELISA-based technique, the relative binding affinity of Rlf for a variety of mutant Ras proteins was determined. Rlf had significantly different binding characteristics than the Raf-1 RBD. The minimal effective Ras binding domain was defined as residues 657-778 using N- and C-terminal deletions of Rlf. Using the PHD algorithm, the secondary structure of this domain was predicted to be similar to the ubiquitin superfold previously identified in the Raf-1 RBD. When the predicted secondary structure of the Rlf-RBD was aligned with the known secondary structure of the Raf-RBD, amino acids in Raf-1 essential for Ras binding were found to also be conserved in Rlf. Consistent with this observation, alanine substitution of one of these residues (K687) in Rlf significantly reduced affinity for Ras-GTP.

Amino Acid Sequence↗