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Biomedical subjects

A Schwartz

Publications and source records attributed to A Schwartz.

At least 73 records · Page 4Linked to original sources
PubMed2000

Chronic relapsing thrombocytopenic purpura with severe neurological manifestations and full recovery.

Neurological complications in thrombotic thrombocytopenic purpura (TTP) are associated with poor prognosis and/or permanent damage. We report a young woman in whom the diagnosis of TTP was difficult because cardinal manifestations were absent at presentation. The patient relapsed, showing severe and dramatic neurological manifestations, including coma. She was treated with multiple therapeutic modalities and recovered fully with no neurological sequelae. The difficulties involved in the management of chronic relapsing TTP are discussed. In the absence of clear guidelines, patients are still subjected to different treatment modalities according to the personal opinions and approaches of physicians. Clearly, well-controlled clinical trials to address this problem are required.

Adult↗
PubMed2000

Role of the leucine-rich domain of platelet GPIbalpha in correct post-translational processing--the Nancy I Bernard-Soulier mutation expressed on CHO cells.

The mechanisms governing the biosynthesis and surface expression of platelet adhesive receptors on parent megakaryocytes are as yet poorly understood. In particular, the assembly and processing of the multisubunit glycoprotein (GP) Ib-IX-V complex, a receptor for von Willebrand factor (vWf) is not fully understood. In the present work, these questions were addressed by reproducing a natural mutation of GPIbalpha found in a variant case of Bernard-Soulier syndrome (Nancy I), due to the deletion of leucine 179 in the seventh leucine-rich repeat of the polypeptide. Wild type and mutated GPIbalpha were transfected into CHO cells expressing GPlbbeta and GPIX. Flow cytometry showed surface expression of the three subunits of both GPIb-IX complexes, but GPlbalphadeltaLeu was present at lower levels (20-40%) and was recognized only by a sub class of monoclonal antibodies which epitopes were not modified by the mutation. These properties reproduce the defect found in the patient's platelets, demonstrating the causative nature of the mutation and validate the use of the CHO cells model. Biochemical studies were performed in an attempt to elucidate the mechanism of the conformational change of GPIbalphadeltaLeu. They unexpectedly revealed a major glycosylation deficiency of the mutated GPIbalpha leading to a 40% decrease in molecular weight. The other two subunits of the complex were however normal and present at the plasma membrane. The deletion led to complete functional deficiency with lack of vWf binding of CHOalphadeltaLeu transfected cells in the presence of botrocetin and defective adhesion to a vWf coated surface under static conditions. Finally, in contrast to normal CHOalphabetaIX cells, which displayed rolling and deceleration when perfused over a vWf surface, CHOalphadeltaLeubetaIX cells were unable to roll over or attach to a vWf substratum. These results show that the integrity of the leucine-rich region of GPIbalpha is essential for normal processing and function of the GPIb-IX complex. In addition, these results obtained in a cellular system supported the suspected role of the macroglycopeptide region of GPIbalpha in maintaining a suitable conformation of this multisubunit receptor to perform its adhesive function.

Adolescent↗
PubMed2000

Black thyroid adenoma. Clinical, histochemical, and ultrastructural features.

A 22-year-old woman with a "hot" thyroid nodule who was being treated with minocycline for severe acne vulgaris is presented. A partial thyroidectomy specimen revealed a black adenoma. Microscopically, the black pigment was found in the follicular cells and the colloid of the adenoma. The pigment was bleached with potassium permanganate and was Fontana-Masson stain positive. It was negative for iron, periodic acid-Schiff, and acid-fast Ziehl-Neelsen stains. All these feature suggest a melanin-like pigment. However, electron microscopic examination revealed a dense osmophilic material present within the lysosomes of the follicular cells. No melanosomes were present. Twenty-six previously reported cases are reviewed, and the possible mechanisms for the deposition of the pigment in the adenoma and its relation to minocycline degradation products are discussed.

Acne Vulgaris↗
PubMed1999

Predictors of proximal aortic dissection at the time of aortic valve replacement.

BACKGROUND: Type I aortic dissection develops in 0.6% of patients late after aortic valve replacement (AVR), and 13% of patients with type I aortic dissections have a history of AVR. Predictors of aortic dissection at AVR, however, have not been characterized. METHODS AND RESULTS: A study group of 33 patients with type I aortic dissection had aortic surgery 49+/-55 months after routine AVR. A group of 101 controls, who did not have morphological progression of aortic diameters >/=6 years after AVR, was used to identify predictors of postsurgical dissection. Multivariate analysis identified aortic regurgitation (P<0.002) and fragility (P<0.001) or thinning of the aortic wall (P<0.007) at AVR as predictors, associated with a 14%, 22%, and 7% probability of late aortic dissection, respectively. Clamping times, types of valve prostheses, concomitant coronary artery bypass grafting, and mean ascending aortic diameters of 43+/-10 mm at AVR did not predict late dissection. A separate analysis of 29 nondissecting aneurysms of the ascending aorta developing 104+/-64 months after routine AVR revealed younger age at AVR (P<0.003) and congenitally bicuspid aortic valves (P<0.03) as predictors of late aneurysm formation. CONCLUSIONS: Aortic regurgitation combined with fragile and thinned aortic walls in patients with moderate aortic dilation may reflect aortic root disease, with a high risk for postsurgical aortic sequelae if it is treated incompletely by isolated valve replacement.

Adult↗
PubMed1999

Cardiac-specific overexpression of the alpha(1) subunit of the L-type voltage-dependent Ca(2+) channel in transgenic mice. Loss of isoproterenol-induced contraction.

The L-type voltage-dependent calcium channel (L-VDCC) regulates calcium influx in cardiac myocytes. Activation of the beta-adrenergic receptor (betaAR) pathway causes phosphorylation of the L-VDCC and that in turn increases Ca(2+) influx. Targeted expression of the L-VDCC alpha(1) subunit in transgenic (Tg) mouse ventricles resulted in marked blunting of the betaAR pathway. Inotropic and lusitropic responses to isoproterenol and forskolin in Tg hearts were significantly reduced. Likewise, Ca(2+) current augmentation induced by iso- proterenol and forskolin was markedly depressed in Tg cardiomyocytes. Despite no change in betaAR number, isoproterenol-stimulated adenylyl cyclase activity was absent in Tg membranes and NaF and forskolin responses were reduced. We postulate an important pathway for regulation of the betaAR by Ca(2+) channels.

Adenylyl Cyclases↗
PubMed1999

Inotropy, calcium, and heart failure: a personal perspective.

The medical treatment of heart failure has improved significantly in the last decade, yet despite the reduction of morbidity and mortality, heart attacks and stroke cause 15 million deaths each year. Cardiovascular disease (CVD) constitutes 50% of all deaths worldwide. Indeed, heart disease represents a continuing global burden, despite all the advances. When considering the major objective of medical treatment of heart failure, the paradigm has shifted from increasing cardiac output of the failing heart by augmenting contractility to a decrease in afterload and inhibition of neurohumors affecting heart muscle. Nevertheless, a direct increase in contractility is still appropriate in some conditions of heart failure for a short-term beneficial effect. This article reviews certain aspects of cellular and molecular mechanisms to provide a framework for problem solving in this vital field.

Animals↗
PubMed1999

Morphological transformation induced by activation of the mitogen-activated protein kinase pathway requires suppression of the T-type Ca2+ channel.

Transformation of fibroblasts by various oncogenes, including ras, mos, and src accompanies with characteristic morphological changes from flat to round (or spindle) shapes. Such morphological change is believed to play an important role in establishing malignant characteristics of cancer cells. Activation of the mitogen-activated protein kinase (MAPK) pathway is a converging downstream event of transforming activities of many oncogene products commonly found in human cancers. Intracellular calcium is known to regulate cellular morphology. In fibroblasts, Ca2+ influx is primarily controlled by two types of Ca2+ channels (T- and L-types). Here, we report that the T-type current was specifically inhibited in cells expressing oncogenically activated Ras as well as gain-of-function mutant MEK (MAPK/extracellular signal-regulated kinase (ERK) kinase, a direct activator of MAPK), whereas treatment of ras-transformed cells with a MEK-specific inhibitor restored T-type Ca2+ channel activity. Using a T-type Ca2+ channel antagonist, we further found that suppression of the T-type Ca2+ channel by the activated MAPK pathway is a prerequisite event for the induction and/or maintenance of transformation-associated morphological changes.

3T3 Cells↗
PubMed1999

A region in IVS5 of the human cardiac L-type calcium channel is required for the use-dependent block by phenylalkylamines and benzothiazepines.

Mutations in motif IVS5 and IVS6 of the human cardiac calcium channel were made using homologous residues from the rat brain sodium channel 2a. [3H]PN200-110 and allosteric binding assays revealed that the dihydropyridine and benzothiazepine receptor sites maintained normal coupling in the chimeric mutant channels. Whole cell voltage clamp recording from Xenopus oocytes showed a dramatically slowed inactivation and a complete loss of use-dependent block for mutations in the cytoplasmic connecting link to IVS5 (HHT-5371) and in IVS5 transmembrane segment (HHT-5411) with both diltiazem and verapamil. However, the use-dependent block by isradipine was retained by these two mutants. For mutants HHT-5411 and HHT-5371, the residual current appeared associated with a loss of voltage dependence in the rate of inactivation indicating a destabilization of the inactivated state. Furthermore, both HHT-5371 and -5411 recovered from inactivation significantly faster after drug block than that of the wild type channel. Our data demonstrate that accelerated recovery of HHT-5371 and HHT-5411 decreased accumulation of these channels in inactivation during pulse trains and suggest a close link between inactivation gating of the channel and use-dependent block by phenylalkylamines and benzothiazepines and provide evidence of a role for the transmembrane and cytoplasmic regions of IVS5 in the use-dependent block by diltiazem and verapamil.

Amino Acid Sequence↗
PubMed1999

Critical role of conserved proline residues in the transmembrane segment 4 voltage sensor function and in the gating of L-type calcium channels.

The fourth transmembrane segment (S4) has been shown to function as a voltage sensor in voltage-gated channels. On membrane depolarization, a stretch of S4 moves outward and initiates a number of conformational changes that ultimately lead to channel opening. Conserved proline residues are in the middle of the S4 of motifs I and III in voltage-dependent Ca2+ channels. Because proline often introduces a "kink" into a helical structure of proteins, these residues might have an intrinsic function in the voltage sensor. Here, we report that the removal of S4 prolines results in a dramatic shortening of channel open time whereas the introduction of extra prolines to the corresponding positions in motif IIS4 and IVS4 lengthens channel open time. The number of S4s with a proline residue showed a clear positive correlation with the mean open time of the channel. The mean open time was >11-fold longer for a channel mutagenized to have prolines in all four S4s compared with a channel that had no prolines in the S4 region. Additionally, prolines in the S4s slowed activation kinetics and shifted the voltage dependence of activation and inactivation in a hyperpolarized direction. Our results strongly suggest that proline residues in the S4s are critical for stabilizing the open state of the channel. Moreover, it is suggested that motif IS4 and IIIS4 contribute to the channel opening more efficiently than motif IIS4 and IVS4.

Amino Acid Sequence↗
PubMed1999

[Echo-planar diffusion-weighted MRI in the diagnosis of acute ischemic stroke: characterisation of tissue abnormalities and limitations in the interpretation of imaging findings].

INTRODUCTION: An accurate diagnosis is frequently difficult in early stroke. Diffusion-weighted (DW) magnetic resonance imaging (MRI) allows visualization of ischemic parenchyma and quantitative assessment of tissue changes before unequivocal abnormalities appear on T(2)-weighted MRI. METHODS: We analyzed 105 MRI examinations of patients with acute stroke (<24 h) with regard to patterns of abnormalities in T(2)-weighted and DW MRI. Furthermore we assessed the influence of artifacts related to DW echo-planar single-shot MRI on image interpretation. RESULTS: Depending on the time of patient assessment there were three partly overlapping T(2)/DW patterns: (1) in the very early phase (</=1.5 h after symptom onset) there was no T(2) abnormality and no definite abnormality of diffusion; (2) no T(2) abnormality and restricted diffusion (1.5-4 h); (3) T(2) hyperintensity and restricted diffusion (>/=3 h). Typical artifacts (susceptibility distortions, N/2 artifact, chemical shift artifact and eddy currents artifact) had to be considered when interpreting images. CONCLUSIONS: Provided typical artifacts are taken into consideration, echo-planar DW MRI allows a more precise diagnostic assessment in acute stroke.

Acute Disease↗
PubMed1999

Responses of primate spinomesencephalic tract cells to intradermal capsaicin.

The responses of 32 spinomesencephalic tract cells to intradermal capsaicin were examined in anesthetized monkeys. Wide dynamic range (n = 20) and nociceptive specific (n = 6) cells showed two types of excitatory responses to intradermal injection of capsaicin. The first excitatory response shown by the majority of wide dynamic range (n = 13) and nociceptive specific (n = 4) cells was consistent with their sensitization by capsaicin. The cells showed an acute and prolonged increase in ongoing activity with capsaicin injection. Responses to mechanical stimuli were substantially increased after capsaicin and an expansion of receptive field was often observed. The responses of the same cells to excitatory amino acid agonists applied locally by iontophoresis also increased. All cells showing sensitization were antidromically activated from periaqueductal gray regions dorsal to the sulcus limitans. Electrical stimulation at these sites did not affect the ongoing or evoked discharges of these cells. The second excitatory response of wide dynamic range (n = 5) and nociceptive specific (n = 1) cells was a novel pattern not consistent with sensitization. These cells nevertheless showed an acute and prolonged increase in background activity after capsaicin injection. Yet, there was no change or a decrease in responses to cutaneous stimuli, no evidence for change in receptive field size and no increase in responses to locally released excitatory amino acids. These cells projected to regions in the periaqueductal gray ventral to the sulcus limitans. Electrical stimulation at these sites produced a decrease in spontaneous activity of the same cell. Low threshold mesencephalic-projecting neurons (n = 6) showed a single inhibitory pattern (n = 4) of responses to capsaicin. The injection produced an acute decrease in spontaneous activity that was sustained for at least 30 min after injection. The responses to cutaneous stimuli and to excitatory amino acids were also substantially reduced. Low threshold cells were found that projected to both dorsal-lateral and ventral-lateral regions of the periaqueductal gray. In summary, three patterns of responses shown by primate spinomesencephalic tract cells to intradermal capsaicin appear dependent on the functional regions of the periaqueductal gray to which they project. These results suggest that inputs of spinomesencephalic tract neurons to the periaqueductal gray may evoke important components of the systemic response to the neurogenic hyperalgesia produced by intradermal capsaicin.

Animals↗
PubMed1999

Characteristics of injuries to the cervical spine and spinal cord in polytrauma patient population: experience from a regional trauma unit.

STUDY DESIGN: Retrospective analysis of a prospectively collected trauma database of a Level 1 (tertiary) trauma center. OBJECTIVE: To define the features of the cervical spinal injuries in polytrauma population admitted to the regional trauma unit. SETTING: Canada, Ontario Province, Toronto, Sunnybrook Health Sciences Center. METHODS: All trauma admissions between 1987 and 1996 entered prospectively into a trauma registry database were studied for incidence, demographic and epidemiological details of cervical spine (cord and column) injuries. RESULTS: A total of 468 patients (66% male) with cervical spinal injury (CSI) from 1198 spinal injuries admitted to the regional trauma center were identified. Seventy-five per cent of the CSI involved were aged less than 50 years; nearly 30% were in the third decade alone. Overall, the commonest spinal level injured was C2 (27%) followed by C5 (22%). Older population (above 60 years of age) had C1 + 2 involved more often than the young (P=0.02). Motor vehicular crashes (MVC) accounted for 71%, followed by pedestrian trauma (10%), sport injuries (7%). Spinal cord injury (SCI) was noted in 27%; complete in 16% and incomplete in 11% and more frequently at C4 or C5 level compared with C1, C2 (P<0.00001); the former level had more often a complete SCI (P=0.06). Though MVC produced 74% of SCI, only 27% had neurological deficits. Recreational trauma produced SCI in 45%, motor cycle crashes (MCC) in 37% and a rear passenger in MVC in 34% that was complete in 78%, 71% and 73% respectively. Front seat passenger and driver in MVC had a C5 level injury while a rear seat passenger had at C4 (P<0.001). The C1 level injury had high association with severe and life threatening head and neck and facial injuries compared with the more frequently injured spinal levels; either C2 (P=0.03) or C5 (P=0.004). Similarly C1 injuries had higher ISS compared with C2 (P<0.0001) and C5 (P<0.008). CONCLUSIONS: C2 was the commonest fractured spine while SCI was more frequent at C5. Older and pedestrian population had higher incidences of injuries at C1 and C2. Sport and MCC resulted in severe SCI. The level of spine injured was different between a front and a rear seat occupant in MVC.

Adult↗
PubMed1999

An investigation into the possibility of transmission of tick-borne pathogens via blood transfusion. Transfusion-Associated Tick-Borne Illness Task Force.

BACKGROUND: Tick-borne illnesses were diagnosed in a group of National Guard members, including some who had donated blood a few days before the onset of symptoms. A voluntary recall of those blood components was issued and a multistate investigation was conducted to determine if transfusion-transmitted illness had occurred. STUDY DESIGN AND METHODS: Donors and recipients were asked to complete questionnaires regarding symptoms and risk factors for infection and to provide blood samples for laboratory analysis. RESULTS: Among National Guard personnel who donated blood, 12 individuals were found to have a confirmed or probable case of Rocky Mountain spotted fever or ehrlichiosis. A total of 320 units (platelets or packed red cells) from 377 donors were transfused into 129 recipients. Although 10 recipients received units from National Guard personnel with confirmed or probable infection, none became ill. CONCLUSION: Transfusion-transmitted illness did not occur. Despite the awareness of the risk for tick-borne diseases and the use of tick-preventive measures, many National Guard personnel reported exposure to ticks. In addition to augmenting current tick-preventive measures, scheduling blood drives before rather than after field exercises could further reduce the potential for transmission of tick-borne pathogens.

Adult↗
PubMed1999

Acceptable regret in medical decision making.

When faced with medical decisions involving uncertain outcomes, the principles of decision theory hold that we should select the option with the highest expected utility to maximize health over time. Whether a decision proves right or wrong can be learned only in retrospect, when it may become apparent that another course of action would have been preferable. This realization may bring a sense of loss, or regret. When anticipated regret is compelling, a decision maker may choose to violate expected utility theory to avoid regret. We formulate a concept of acceptable regret in medical decision making that explicitly introduces the patient's attitude toward loss of health due to a mistaken decision into decision making. In most cases, minimizing expected regret results in the same decision as maximizing expected utility. However, when acceptable regret is taken into consideration, the threshold probability below which we can comfortably withhold treatment is a function only of the net benefit of the treatment, and the threshold probability above which we can comfortably administer the treatment depends only on the magnitude of the risks associated with the therapy. By considering acceptable regret, we develop new conceptual relations that can help decide whether treatment should be withheld or administered, especially when the diagnosis is uncertain. This may be particularly beneficial in deciding what constitutes futile medical care.

Brain Ischemia↗