Index of suspicion. Case 3. Congenital sucrase-isomaltase deficiency.
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Carbohydrate Metabolism, Inborn Errors↗
Biomedical subjects
J Friedman
Publications and source records attributed to J Friedman.
Evaluation of the role of the D2 dopamine receptor in myoclonus dystonia.
A novel Val154-->Ile mutation in the D2 dopamine receptor (DRD2) on chromosome 11q23 has recently been shown to be associated with myoclonus dystonia (M-D) in one large family. Sequence analysis of the DRD2 gene in 5 M-D patients from different families did not reveal any mutations, nor was there evidence of linkage to the 11q23 region in the DRD2 gene in four other families. Receptor binding and signal transduction assays of the DRD2 mutant and wild-type receptors revealed identical agonist and antagonist affinities and functional responses. These studies suggest that M-D is genetically heterogeneous. The molecular mechanisms through which the Val-->Ile mutation may contribute to M-D remain to be determined.
Adolescent↗
Altered ligand rebinding kinetics due to distal-side effects in hemoglobin chico (Lysbeta66(E10) --> thr).
Hb Chico is an unusual human hemoglobin variant that has lowered oxygen affinity, but unaltered cooperativity and anion sensitivity. Previous studies showed these features to be associated with distal-side heme pocket alterations that confer increased structural rigidity on the molecule and that increase water content in the beta-chain heme pocket. We report here that the extent of nanosecond geminate rebinding of oxygen to the variant and its isolated beta-chains is appreciably decreased. Structural alterations in this variant decrease its oxygen recombination rates without significantly altering rates of migration out of the heme pocket. Data analysis indicates that one or more barriers that impede rebinding of oxygen from docking sites in the heme pocket are increased, with less consequence for CO rebinding. Resonance Raman spectra show no significant alterations in spectral regions sensitive to interactions between the heme iron and the proximal histidine residue, confirming that the functional differences in the variant are due to distal-side heme pocket alterations. These effects are discussed in the context of a schematic representation of heme pocket wells and barriers that could aid the design of novel hemoglobins with altered ligand affinity without loss of the normal allosteric responses that facilitate unloading of oxygen to respiring tissues.
Binding Sites↗
Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis.
FIP-3 (14.7K interacting protein) was discovered during a search for cell proteins that could interact with an adenovirus protein (Ad E3-14.7K) that had been shown to prevent tumor necrosis factor (TNF)-alpha-induced cytolysis. FIP-3, which contains leucine zippers and a zinc finger domain, inhibits both basal and induced transcriptional activity of NF-kappaB and causes a late-appearing apoptosis with unique morphologic manifestations. Ad E3-14.7K can partially reverse apoptotic death induced by FIP-3. FIP-3 also was shown to bind to other cell proteins, RIP and NIK, which previously had been described as essential components of TNF-alpha-induced NF-kappaB activation. In addition, FIP-3 inhibited activation of NF-kappaB induced by TNF-alpha, the TNFR-1 receptor, RIP, NIK, and IKKbeta, as well as basal levels of endogenous NF-kappaB in 293 cells. Because the activation of NF-kappaB has been shown to inhibit apoptosis, FIP-3 appears both to activate a cell-death pathway and to inhibit an NF-kappaB-dependent survival mechanism.
Adenoviridae↗
Treatment of acute neonatal vascular injuries--the utility of multiple interventions.
BACKGROUND/PURPOSE: Vascular injuries in neonates are a rare complication of the varied invasive procedures performed in these small children. Unfortunately there remains a reluctance to repair these injuries early, often because of the relative small size of the affected vessels and the nature of the patient's underlying medical condition. The authors report a consecutive series of patients treated for arterial and venous injuries early in their course using a variety of microsurgical techniques. METHODS: A retrospective chart review was performed of consecutive patients (n = 7) treated over a 2-year period. All had injury as a result of invasive procedures performed in the neonatal period. Both arterial and venous injuries that required some form of intervention were included. RESULTS: Five arterial and two venous injuries were identified. Surgical thrombectomy and microvascular repair was required in two patients. Primary healing occurred despite prolonged (>13 hours) warm ischemia time. Pseudoaneurysms of the brachial artery and radial artery were controlled with surgical ligation, and one patient required bilateral fasciotomies for compartment syndromes related to severe spasm of the common femoral arteries. Phlegmasia cerulea dolens of the lower extremity (n = 2) was treated with leech therapy. All patients healed without tissue loss or functional deficit. CONCLUSIONS: A variety of microvascular interventions have application to the treatment of acute vascular injuries in neonates. Early, aggressive use of these techniques can provide effective therapy for these potentially devastating injuries and allow for complete limb recovery without tissue loss.
Aneurysm, False↗
Genetic testing for early-onset torsion dystonia (DYT1): introduction of a simple screening method, experiences from testing of a large patient cohort, and ethical aspects.
Early-onset, generalized primary torsion dystonia (PTD) is an autosomal dominantly inherited disorder, characterized by involuntary movements and abnormal postures. The majority of cases are caused by a 3-bp deletion in the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We developed a simple, reliable, and cost-effective, PCR-based screening method for this mutation. Testing results from a cohort of 550 cases, including patients with different forms of dystonia and unclassified movement disorders, revealed that 72.2% of the patients with typical early-onset generalized PTD carried the GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of the patients with an unclassified movement disorder were GAG positive. Our results confirm a genotype/phenotype correlation in early-onset PTD and show that application of strict clinical criteria leads to accurate prediction of carrier status in more than two-thirds of patients with this type of dystonia. Currently, we suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early-onset PTD. Testing is not recommended in patients with onset of symptoms after 30 years or in asymptomatic individuals under the age of 18.
Adult↗
Metabolism of fatty acids and glucose.
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Fatty Acids↗
Regulation of tyrosine phosphorylation in isolated T cell membrane by inhibition of protein tyrosine phosphatases.
Jurkat T cells activated by the phosphotyrosine phosphatase inhibitors H2O2 or vanadate were found to have a similar pattern of tyrosine phosphorylation when compared with T cells stimulated by anti-CD3 Ab cross-linking, suggesting that protein tyrosine phosphatase (PTP) inhibitors affect the early steps of TCR signaling. To study the role of PTPs in the most proximal membrane events of tyrosine phosphorylation, subcellular fractions of T cells were treated with the PTP inhibitors in the presence of ATP. In the membrane fraction, tyrosine phosphorylation of Lck, Fyn, and CD3 zeta can be induced by PTP inhibitors, but not by anti-CD3. Detailed characterization of this cell-free system showed that the pattern and the order of induced tyrosine phosphorylation is similar to that induced in intact cells. Upon removal of the PTP inhibitor, the tyrosine-phosphorylated proteins, including Lck, Fyn, Syk, Zap70, and CD35 zeta are rapidly dephosphorylated. Preliminary characterizations indicate that a PTP distinct from CD45, SHP1, and SHP2 is present in T cell membranes and the inhibition of this yet unidentified PTP is most likely responsible for the Lck-dependent tyrosine phosphorylation triggered by PTP inhibitors.
Animals↗
Desensitization of beta2-adrenergic receptors with mutations of the proposed G protein-coupled receptor kinase phosphorylation sites.
Tentative identification of the G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5) sites of phosphorylation of the beta2-adrenergic receptor (betaAR) was recently reported based on in vitro phosphorylation of recombinant receptor (Fredericks, Z. L., Pitcher, J. A., and Lefkowitz, R. J. (1996) J. Biol. Chem. 271, 13796-13803). Phosphorylated residues identified for GRK2 were threonine 384 and serines 396, 401, and 407. GRK5 phosphorylated these four residues as well as threonine 393 and serine 411. To determine if mutation of these sites altered desensitization, we have constructed betaARs in which the threonines and serines of the putative GRK2 and GRK5 sites were substituted with alanines. These constructs were further modified to eliminate the cAMP-dependent protein kinase (PKA) consensus sites. Mutants betaARs were transfected into HEK 293 cells, and standard kinetic parameters were measured following 10 microM epinephrine treatment of cells. The mutant and wild type (WT) receptors were all desensitized 89-94% after 5 min of 10 microM epinephrine stimulation and 96-98% after a 30-min pretreatment. There were no significant changes observed for any of the mutant betaARs relative to the WT in the extent of 10 microM epinephrine-induced internalization (77-82% after 30 min). Epinephrine treatment for 1 min induced a rapid increase in the phosphorylation of the GRK5 and PKA- mutant betaARs as well as the WT. We conclude that sites other than the GRK2 and GRK5 sites identified by in vitro phosphorylation are involved in mediating the major effects of the in vivo GRK-dependent desensitization of the betaAR.
Adenylyl Cyclases↗
Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
BACKGROUND: The incremental prognostic value of stress single photon emission computed tomography (SPECT) for the prediction of cardiac death as an individual end point and the implications for risk stratification are undefined. METHODS AND RESULTS: We identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or myocardial infarction. Over a mean follow up of 642+/-226 days, 119 cardiac deaths and 158 myocardial infarctions occurred (3.0% cardiac death rate, 2.3% myocardial infarction rate). Patients with normal scans were at low risk (< or =0.5%/y), and rates of both outcomes increased significantly with worsening scan abnormalities. Patients who underwent exercise stress and had mildly abnormal scans had low rates of cardiac death but higher rates of myocardial infarction (0.7%/y versus 2.6%/y; P<.05). After adjustment for prescan information, scan results provided incremental prognostic value toward the prediction of cardiac death. The identification of patients at intermediate risk of nonfatal myocardial infarction and low risk for cardiac death by SPECT may result in significant cost savings when applied to a clinical testing strategy. CONCLUSIONS: Myocardial perfusion SPECT yields incremental prognostic information toward the identification of cardiac death. Patients with mildly abnormal scans after exercise stress are at low risk for cardiac death but intermediate risk for nonfatal myocardial infarction and thus may benefit from a noninvasive strategy and may not require invasive management.
Adenosine↗
Effects of thrombospondin-1 on disease course and angiogenesis in rat adjuvant-induced arthritis.
Leukocyte extravasation into the synovium is important in rheumatoid arthritis (RA). Thrombospondin (TSP)-1 mediates cell adhesion and migration and inhibits angiogenesis, and it has been implicated in RA. However, little information is available on the role of TSP-1 in arthritis-associated inflammation and neovascularization. Therefore, we analyzed the effects of TSP-1 in adjuvant-induced arthritis (AIA), a rat model for RA. Hydron pellets containing TSP-1 were implanted in one ankle of AIA rats post-adjuvant injection, while the contralateral ankle received sham implants. Body weight loss and joint swelling were determined in comparison to nonimplanted AIA controls. In addition, synovial vessel counts were obtained in TSP-1-versus sham-implanted ankles of the same rat. The implantation of TSP-1 pellets into one ankle resulted in an enhancement of swelling in both ankles. Furthermore, TSP-1 exhibited a biphasic modulatory effect on synovial vessel counts (P < 0.05). In conclusion, TSP-1 implanted into one ankle of AIA rats may augment the severity of the disease. One possible explanation, among others, for the modulating effect of TSP-1 on inflammation may be its effect on arthritis-related angiogenesis.
Animals↗
Selective speech motor, syntax and cognitive deficits associated with bilateral damage to the putamen and the head of the caudate nucleus: a case study.
Deficits in speech production, sentence comprehension and abstract reasoning occurred in a subject having profound bilateral damage to the putamen and the caudate nucleus. Acoustic analyses indicated that the subject's speech was degraded due to inappropriate sequencing of articulatory gestures that involve different articulatory structures. Transitions between sounds were slow and often did not achieve target configurations. The subject had a 14% error rate comprehending distinctions in meaning conveyed by syntax in English sentences; normal controls make virtually no errors in this test. Cognitive deficits involving impaired sequencing occurred: the subject had a 70% error rate on the Odd Man Out test when making decisions within a single category. Cognitive perseveration occurred when the subject was asked to shift categories. In contrast, performance was within normal ranges in tests of lexical access and memory. The pattern of deficits provides evidence for basal ganglia involvement in the regulation of sequencing across modalities.
Adult↗
Human antibodies elicited by a pneumococcal vaccine express idiotypic determinants indicative of V(H)3 gene segment usage.
Human immunodeficiency virus (HIV)-infected persons manifest decreased antibody responses to pneumococcal polysaccharide vaccines. Since human antibody responses to polysaccharides are often restricted, the molecular structure of antibodies elicited by a 23-valent pneumococcal vaccine was analyzed. Anti-idiotypic reagents were used to detect V(H)1, V(H)3, and V(H)4 gene usage by antibodies to pneumococcal capsular polysaccharides in HIV-uninfected and HIV-infected subjects by ELISA. HIV-uninfected persons generated beta-mercaptoethanol-sensitive and -resistant antibodies to pneumococcal capsular polysaccharides expressing V(H)3 determinants recognized by the D12, 16.84, and B6 monoclonal antibodies; antibodies expressing V(H)1 determinants were not detected, and V(H)4 determinants were expressed by beta-mercaptoethanol-sensitive antibodies only; and HIV-infected subjects had significantly lower capsular polysaccharide-specific and V(H)3-positive antibody responses. These findings confirm decreased antibody responses to pneumococcal vaccination in HIV-infected persons and suggest that their poor responses may result from HIV-associated depletion of restricted B cell subsets.
Adult↗
An unusual case of polydactyly of the thumb.
We present an unusual case of polydactyly of the thumb. The patient, despite having a fully developed nail bed, had a duplication at the metacarpophalangeal level consisting of a single bony phalanx. The Wassel classification of polydactyly, which is the most commonly cited classification scheme, does not include this particular anomaly. In addition, there has been no reference to this type of polydactyly in the literature.
Bone Wires↗
Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease.
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Aged↗
Spontaneous intracranial hypotension resulting in stupor caused by diencephalic compression.
A 51-year-old man had a 4-month history of progressive headache and gradual onset of somnolence. MRI suggested spontaneous intracranial hypotension (SIH) with diencephalic compression, but he did not improve after three epidural blood patches. He became alert following intrathecal saline infusion that normalized his CSF pressure. A CSF leak was noted on spinal MRI and confirmed with CT contrast myelography. Surgical ligation of a torn dural root sleeve isolating a ruptured Tarlov's cyst resulted in permanent cure.
Brain↗
Increased sensitivity of IL-6-deficient mice to carbon tetrachloride hepatotoxicity and protection with an IL-6 receptor-IL-6 chimera.
Interleukin-6 (IL-6)-deficient mice were found to be much more sensitive to liver injury by carbon tetrachloride (CCl4) than mice with an intact IL-6 system. At doses of CCl4 ranging from 2 to 3.5 ml/kg body weight, mean mortality in the IL-6 gene knockout (IL-6-/-) mice was 71% at 24 hours versus 12% in normal IL-6+/+ mice. At sublethal doses, there was extensive parenchymal necrosis in the livers of IL-6-deficient mice, which was not seen in the control animals. Lipid peroxidation induced by CCl4 was up to 10-fold higher in the IL-6-/- mice. Injections of a chimeric protein containing IL-6 fused to its soluble receptor (IL-6R-IL-6 chimera) induced hepatocyte protection against CCl4 damage in both IL-6-/- and IL-6+/+ mice. Treatment with IL-6R-IL-6 restored the survival of the IL-6-/- mice to the level of IL-6+/+ animals. Free IL-6 was not effective in reducing CCl4-induced liver toxicity, but was as effective as IL-6R-IL-6 in reducing death from metastases in a murine melanoma model. Hence the IL-6R-IL-6 chimera appears to be particularly effective against chemical hepatotoxic injury.
Aldehydes↗