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Biomedical subjects

H Schulman

Publications and source records attributed to H Schulman.

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

Developmental expression of the CaM kinase II isoforms: ubiquitous gamma- and delta-CaM kinase II are the early isoforms and most abundant in the developing nervous system.

CaM kinase II constitutes a family of multifunctional protein kinases that play a major role in Ca2+-mediated signal transduction. As a first step in understanding their possible function in mouse development we characterized the expression patterns of all CaM kinase II isoforms (alpha, beta, gamma and delta) starting in prenatal development. Remarkably, only the ubiquitous gamma- and delta-CaM kinase II are expressed during early development. Their distribution suggests a special role in the developing nervous system and in mature excitable tissues. Additionally, we describe the murine betaM-CaM kinase II, a variant of the 'brain-specific' beta-CaM kinase II, which is highly expressed in skeletal muscle.

Amino Acid Sequence↗
PubMed1999

Calcium/calmodulin-dependent phosphorylation and activation of human Cdc25-C at the G2/M phase transition in HeLa cells.

The human tyrosine phosphatase (p54(cdc25-c)) is activated by phosphorylation at mitosis entry. The phosphorylated p54(cdc25-c) in turn activates the p34-cyclin B protein kinase and triggers mitosis. Although the active p34-cyclin B protein kinase can itself phosphorylate and activate p54(cdc25-c), we have investigated the possibility that other kinases may initially trigger the phosphorylation and activation of p54(cdc25-c). We have examined the effects of the calcium/calmodulin-dependent protein kinase (CaM kinase II) on p54(cdc25-c). Our in vitro experiments show that CaM kinase II can phosphorylate p54(cdc25-c) and increase its phosphatase activity by 2.5-3-fold. Treatment of a synchronous population of HeLa cells with KN-93 (a water-soluble inhibitor of CaM kinase II) or the microinjection of AC3-I (a specific peptide inhibitor of CaM kinase II) results in a cell cycle block in G2 phase. In the KN-93-arrested cells, p54(cdc25-c) is not phosphorylated, p34(cdc2) remains tyrosine phosphorylated, and there is no increase in histone H1 kinase activity. Our data suggest that a calcium-calmodulin-dependent step may be involved in the initial activation of p54(cdc25-c).

Benzylamines↗
PubMed1999

Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood.

The idiopathic hypereosinophilic syndrome (HES) is a leukoproliferative disorder marked by a sustained overproduction of eosinophils and a distinct predilection to damage specific organs, especially the cardiovascular system. It is primarily a disease of middle-aged people. Occasional cases have been encountered in children. We report a case of an 11-year-old boy affected by idiopathic HES with an unusual rapidly fatal course. In addition to eosinophilic cellulitis, cerebral straight and superior sagittal sinus vein thrombosis (CVT) was evident on cranial CT. In our review of the English literature we were unable to find an association between idiopathic HES and CVT.

Cellulitis↗
PubMed1999

Intrathoracic rib demonstrated by helical CT with three-dimensional reconstruction.

Intrathoracic rib is a rare congenital anomaly. An unusual location with atypical pleural tenting is reported. Helical CT with three-dimensional reconstruction seems the best modality for demonstrating the origin and location of these abnormal ribs. The importance of the diagnosis of intrathoracic rib is to rule out pulmonary lesions and prevent unnecessary investigations.

Adolescent↗
PubMed1999

Maggot therapy for the treatment of intractable wounds.

BACKGROUND: Fly maggots have been known for centuries to help debride and heal wounds. Maggot therapy was first introduced in the USA in 1931 and was routinely used there until the mid-1940s in over 300 hospitals. With the advent of antimicrobiols, maggot therapy became rare until the early 1990s, when it was re-introduced in the USA, UK, and Israel. The objective of this study was to assess the efficacy of maggot therapy for the treatment of intractable, chronic wounds and ulcers in long-term hospitalized patients in Israel. METHODS: Twenty-five patients, suffering mostly from chronic leg ulcers and pressure sores in the lower sacral area, were treated in an open study using maggots of the green bottle fly, Phaenicia sericata. The wounds had been present for 1-90 months before maggot therapy was applied. Thirty-five wounds were located on the foot or calf of the patients, one on the thumb, while the pressure sores were on the lower back. Sterile maggots (50-1000) were administered to the wound two to five times weekly and replaced every 1-2 days. Hospitalized patients were treated in five departments of the Hadassah Hospital, two geriatric hospitals, and one outpatient clinic in Jerusalem. The underlying diseases or the causes of the development of wounds were venous stasis (12), paraplegia (5), hemiplegia (2), Birger's disease (1), lymphostasis (1), thalassemia (1), polycythemia (1), dementia (1), and basal cell carcinoma (1). Subjects were examined daily or every second day until complete debridement of the wound was noted. RESULTS: Complete debridement was achieved in 38 wounds (88.4%); in three wounds (7%), the debridement was significant, in one (2.3%) partial, and one wound (2.3%) remained unchanged. In five patients who were referred for amputation of the leg, the extremities was salvaged after maggot therapy. CONCLUSIONS: Maggot therapy is a relatively rapid and effective treatment, particularly in large necrotic wounds requiring debridement and resistant to conventional treatment and conservative surgical intervention.

Adult↗
PubMed1998

Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II.

Autophosphorylation of Thr286 in Ca2+/calmodulin-dependent protein kinase II occurs within each holoenzyme by an intersubunit reaction and is essential for kinase function in vivo. In addition to a kinase-directed function of calmodulin to activate the kinase, a second calmodulin is required for the autophosphorylation of each Thr286 (Hanson, P. I., Meyer, T., Stryer, L., and Schulman, H. (1994) Neuron 12, 943-956). We have engineered heteromeric holoenzymes comprising distinct "kinase" and "substrate" subunits to test for kinase- and substrate-directed functions of calmodulin. The obligate kinase subunits have aspartate residues substituted for threonine at positions 286, 305, and 306 (the autophosphorylation and calmodulin-binding sites), making it constitutively active but unable to bind calmodulin. Obligate substrate subunits are catalytically inactive (K42M mutation) but are able to bind calmodulin. Phosphorylation of substrate subunits occurs specifically at Thr286 and is completely dependent upon the presence of calmodulin. Blocking the ability of the substrate subunit to bind calmodulin, either with inhibitor KN-93 or by mutagenesis of the calmodulin-binding domain of the substrate subunit, prevents its phosphorylation, consistent with a substrate-directed function of calmodulin that requires its direct binding to the subunit being phosphorylated.

Calcium Signaling↗
PubMed1998

alphaKAP is an anchoring protein for a novel CaM kinase II isoform in skeletal muscle.

Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) is present in a membrane-bound form that phosphorylates synapsin I on neuronal synaptic vesicles and the ryanodine receptor at skeletal muscle sarcoplasmic reticulum (SR), but it is unclear how this soluble enzyme is targeted to membranes. We demonstrate that alphaKAP, a non-kinase protein encoded by a gene within the gene of alpha-CaM kinase II, can target the CaM kinase II holoenzyme to the SR membrane. Our results indicate that alphaKAP (i) is anchored to the membrane via its N-terminal hydrophobic domain, (ii) can co-assemble with catalytically competent CaM kinase II isoforms and target them to the membrane regardless of their state of activation, and (iii) is co-localized and associated with rat skeletal muscle CaM kinase II in vivo. alphaKAP is therefore the first demonstrated anchoring protein for CaM kinase II. CaM kinase II assembled with alphaKAP retains normal enzymatic activity and the ability to become Ca2+-independent following autophosphorylation. A new variant of beta-CaM kinase II, termed betaM-CaM kinase II, is one of the predominant CaM kinase II isoforms associated with alphaKAP in skeletal muscle SR.

Amino Acid Sequence↗
PubMed1998

Phosphorylation at the nuclear localization signal of Ca2+/calmodulin-dependent protein kinase II blocks its nuclear targeting.

Translocation of protein kinases with broad substrate specificities between different subcellular compartments by activation of signaling pathways is an established mechanism to direct the activity of these enzymes toward particular substrates. Recently, we identified two isoforms of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), which are targeted to the nucleus by an alternatively spliced nuclear localization signal (NLS). Here we report that cotransfection with constitutively active mutants of CaM kinase I or CaM kinase IV specifically blocks nuclear targeting of CaM kinase II as a result of phosphorylation of a Ser immediately adjacent to the NLS of CaM kinase II. Both CaM kinase I and CaM kinase IV are able to phosphorylate this Ser residue in vitro, and mutagenesis studies suggest that this phosphorylation is both necessary and sufficient to block nuclear targeting. Furthermore, we provide experimental evidence that introduction of a negatively charged residue at this phosphorylation site reduces binding of the kinase to an NLS receptor in vitro, thus providing a mechanism that may explain the blockade of nuclear targeting that we have observed in situ.

Amino Acid Sequence↗
PubMed1998

Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations.

The transduction of many cellular stimuli results in oscillations in the intracellular concentration of calcium ions (Ca2+). Although information is thought to be encoded in the frequency of such oscillations, no frequency decoder has been identified. Rapid superfusion of immobilized Ca2+- and calmodulin-dependent protein kinase II (CaM kinase II) in vitro showed that the enzyme can decode the frequency of Ca2+ spikes into distinct amounts of kinase activity. The frequency response of CaM kinase II was modulated by several factors, including the amplitude and duration of individual spikes as well as the subunit composition and previous state of activation of the kinase. These features should provide specificity in the activation of this multifunctional enzyme by distinct cellular stimuli and may underlie its pivotal role in activity-dependent forms of synaptic plasticity.

Animals↗
PubMed1998

CT findings in neonatal hypothermia.

BACKGROUND: Newborn infants are particularly prone to hypothermia, a condition with a high mortality. OBJECTIVE: To study the CT brain patterns in infants with hypothermia and neurological symptoms. MATERIALS AND METHODS: We reviewed the brain CT of nine infants with neonatal hypothermia, multiple organ failure, seizures and coma. RESULTS: Two infants had normal CT scans, acutely and at follow-up, and were clinically normal at follow-up. In seven infants, CT showed diffuse cerebral oedema, with reversal of the normal density relationship between grey and white matter and a relative increased density of the thalami, brainstem and cerebellum - the 'reversal sign'. In six surviving infants with severe developmental delay, follow-up CT revealed cerebral atrophy with multicystic encephalomalacia. CONCLUSIONS: The 'reversal sign' has been described in the abused child, birth asphyxia and anoxia due to drowning. Neonatal hypothermia is offered as a further cause.

Brain↗
PubMed1998

Ganglioneuroma: an 'incidentaloma' of childhood.

In adults clinically silent adrenal masses can be discovered incidentally in imaging studies. Most of these 'incidentalomas' are benign, non-functioning adenomas. In contradistinction, in infancy and childhood the most common adrenal mass is the neuroblastoma, a malignant neural crest tumour. Four children are described, each with a benign neural crest tumour - ganglioneuroma - incidentally discovered by conventional radiography or sonographic examination. Complete surgical excision resulted in total recovery of all the children.

Adrenal Gland Neoplasms↗
PubMed1998

Chronic intussusception in childhood.

A rare case of chronic intussusception is reported. Radiological investigation including ultrasound, CT and barium enema provided the correct diagnosis. Ultrasound revealed a solid mass near the transverse colon in the right lower abdomen. CT demonstrated the real nature of the solid mass as being the classical 'coiled spring' of intussusception. The barium enema was unsuccessful as an attempt at hydrostatic reduction, but confirmed the diagnosis by a 'crescent-shaped' filling defect in the ascending colon. The patient was discharged after an uneventful surgery and recovery. No organic lesion that precipitated the chronic intussusception was discovered at operation. Radiological findings, the typical clinical picture and adequate treatment are discussed.

Chronic Disease↗
PubMed1998

Simple cyst in the postmenopausal patient: detection and management.

The aims of our study were to determine the prevalence of simple ovarian cysts in asymptomatic postmenopausal patients and to investigate the natural history of these cysts by ultrasonographic follow-up examinations. Three thousand five hundred and eighty-five women participated in the volunteer pelvic cancer screening program. Entry criteria were as follows: postmenopausal, no clinical symptoms, and no previous gynecologic pathology. An anechoic, small cyst less than 5 cm in greatest diameter was classified as a simple ovarian cyst. A scoring system to determine malignant potential had been established previously. All simple cysts had a score of 2 or less and had a morphology typical of benign lesions. In the case of a positive finding, the patient would be seen at 3 to 6 month intervals. The decision for surgical intervention was made by a private gynecologist or patient or if an interval change was noted. One thousand seven hundred and sixty-nine postmenopausal women (49.34% of all patients from the screening program) participated in this study. One hundred and sixteen simple cysts were found, with a prevalence of 6.6% in our population. Among those patients, 27 (23.28%) simple cysts resolved spontaneously, 69 (59.48%) have persisted, and 20 (17.24%) have been lost to follow-up study. Eighteen women (26.09%) with persistent simple ovarian cyst underwent surgery. No malignant ovarian conditions were identified. In conclusion, simple ovarian cysts are more common in postmenopausal women than previously was thought. This condition is very unlikely to be malignant and can be followed conservatively.

Adult↗
PubMed1998

KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart.

The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are favored by CaM kinase activation EADs were induced with clofilium in isolated rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92 (0.5 microM) for 10 min before clofilium exposure. EADs were significantly suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs present in 10/11 hearts) (P =.024). There were no significant differences in parameters favoring EADs such as monophasic action potential duration or heart rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased 37% in hearts with EADs compared to hearts without EADs (P =.015). This increase in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93 potently inhibited rabbit myocardial CaM kinase activity (calculated Ki </= 2.58 microM), but the inactive analog KN-92 did not (Ki > 100 microM). The actions of KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain preferential EAD suppression by KN-93. These data show a novel association between CaM kinase activation and EADs and are consistent with the hypothesis that the ICa and CaM kinase activation both contribute to EADs in this model.

Animals↗
PubMed1997

The nuclear deltaB isoform of Ca2+/calmodulin-dependent protein kinase II regulates atrial natriuretic factor gene expression in ventricular myocytes.

Cultured neonatal ventricular myocytes display features of myocardial hypertrophy including increased cell size, myofilament organization, and reexpression of the embryonic gene for atrial natriuretic factor (ANF). KN-93, an inhibitor of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase II), blocked the induction of these responses by the alpha1-adrenergic receptor agonist phenylephrine, whereas its inactive analog KN-92 did not. To directly determine whether CaM kinase II could regulate ANF gene expression, we transiently expressed each of three isoforms of CaM kinase II (alpha, deltaB, and deltaC) along with an ANF promoter/luciferase reporter gene. The deltaB isoform markedly increased luciferase gene expression, whereas comparable levels of the deltaC and alpha isoforms were ineffective. Expression of deltaB-CaM kinase II also potentiated phenylephrine-mediated ANF gene expression, and this effect was blocked by KN-93 but not by KN-92. The ability of deltaB-CaM kinase II to transactivate a truncated ANF promoter, containing a serum response element (SRE) required for phenylephrine-inducible gene expression, was lost when this SRE was mutated. The deltaB isoform of CaM kinase II has been shown to exhibit nuclear localization. Coexpression of the non-nuclear deltaC or alpha isoforms, which can form multimers with the deltaB isoform, prevented the nuclear localization of deltaB-CaM kinase II and also blocked its effects on ANF reporter gene and protein expression. In addition, a chimeric alpha-CaM kinase II which contains the nuclear localization signal of the deltaB isoform was able to induce ANF reporter gene expression, albeit to a lesser extent than deltaB-CaM kinase II. These data are the first to assign a function to the deltaB isoform of CaM kinase II and to link its nuclear localization to subsequent activation of cardiac gene expression.

Animals↗