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Richter's transformation of chronic lymphocytic leukaemia (CLL) to high-grade B-cell Non-Hodgkin lymphoma occurs in < 5% of CLL cases. Transformation of CLL to Hodgkin Lymphoma is a much rarer event and here we describe a patient who developed Richter's transformation into a Hodgkin Lymphoma presenting as rapidly progressive hepatosplenomegaly.

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Background: Moderate alcohol consumption reduces the risk of cardiovascular diseases, especially coronary heart disease (CHD). Because of the presence of polyphenols in red wine, this type of beverage may be superior to other alcoholic drinks in the prevention of CHD. Inhibition of platelet aggregation is thought to be one of the mechanisms underlying this favorable effect. The present study analyzes the direct effect of alcohol and red wine polyphenols on platelet aggregation. Methods: Unfractionated red wine, a red wine polyphenolic extract, and alcohol were added in different concentrations to a standardized quantity of blood platelets 2 min before aggregation was induced by different concentrations of ADP. Aggregation was measured in an aggregometer and results were compared to a control 0.9% NaCl solution. Results: Alcohol in concentrations up to 0.24 percent did not inhibit platelet aggregation in vitro initiated with ADP The polyphenolic red wine extract inhibited aggregation dose-dependently and significantly from concentrations of 45 mg/l ( [Formula: see text] ) or more. Red wine only inhibited platelet aggregation at very high concentrations ( approximately 0.24 and 0.48 alcohol%). Conclusions: Consumption of red wine has an inhibitory effect on platelet aggregation, which is caused by the polyphenolic compounds in the wine. Alcohol itself does not have a direct inhibitory effect within a range up to 0.24 percent. Since this effect is only observed at very high concentrations, it is unlikely to be of clinical relevance in a moderate drinking pattern. The results do not exclude platelet inhibition by wine in vivo. However, this must be related to metabolic changes rather than to direct blockade.

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A series of neurotensin (NT)(8-13) analogs featuring substitution of the Arg8 and/or Arg9 residues with non-natural cationic amino acids was synthesized and evaluated for binding to the human NT receptor-1 (hNTR-1). The modifications were designed to probe specific steric and electrostatic requirements in the N-terminal cationic region of NT(8-13) for receptor binding as a general evaluation of the feasibility of incorporating minor structural changes into a peptide at a crucial polar receptor binding site. Many of the non-natural amino acids are more or less isosteric to Arg but more lipophilic as a result of addition of alkyl groups or through removal or replacement of NH character with methylene or methyl substituents, whereas others vary the distance between the cation and the alpha-amino acid carbon. Substitution of Arg8 with N(G)-alkylated Arg derivatives or homolysine (Hlys) maintained the subnanomolar affinity of NT(8-13) to the hNTR-1. Position 8 incorporation of Hlys produced the most favorable primary amine side-chain substitution to date. Moderate losses in affinity observed with position 9 substitutions were attributed to adverse steric effects. Doubly substituted [Hlys8, DAB9]NT(8-13), in which DAB is 2,4-diaminobutyric acid, was also prepared and tested as the shorter side-chain of DAB is known to be favored in position 9 of NT(8-13). This analog maintained 60% of NT(8-13) binding affinity making it the most favored des-guanidinium-containing analog known. These results demonstrate that adequate receptor binding affinity can be maintained over a structural range of Arg analogs, thus providing a range of peptides expected to exhibit altered pharmacokinetic properties. From the standpoint of the hNTR-1 cationic binding sites, these results help to map out the structural stringency inherent in the formation of a tight binding complex with NT(8-13) and related analogs.

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In order to evaluate the nature and frequency of adverse reactions associated with Therapeutic Apheresis (TA), database information from two large mobile apheresis services was analyzed. A total of 17,940 procedures performed on 3,583 patients were studied using an Access Database. Seventy percent (12,558) of the procedures were performed on a Fresenius AS104 blood cell separator and 30% (5,382) were performed on a COBE Spectra. The five most commonly treated diseases were Guillain-Barre Syndrome (25%), thrombotic thrombocytopenic purpura (20%), myasthenia gravis (18%), the hyperviscosity syndrome (12%), and chronic inflammatory demyelinating polyneuropathy (9%). All patients received calcium gluconate supplement during the procedures. Cardiac monitoring was used during 80% of the procedures and blood pressure monitoring was used during all procedures. All procedures were supervised by a physician. Both apheresis services fully comply with the ASFA Guidelines for Therapeutic Apheresis Providers. Adverse reactions occurred in 3.9% of all procedures. The following adverse reactions were documented: reactions related to ACD toxicity (3%), vasovagal reactions (0.5%), vascular access related complications (0.15%), reactions related to FFP (0.12%), hepatitis B from FFP (0.06%), arrhythmias (0.01%), hemolysis due to inappropriate dilution of 25% albumin (0.01%), and one death (from underlying disease) during a TA procedure (0.006%). These data demonstrate that therapeutic apheresis is associated with a low rate of side effects when performed by well-trained and certified nurses under the direction of experienced physicians, even in the diverse setting of large mobile therapeutic apheresis programs.

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1. P-Glycoprotein is a 170-kDa transmembrane glycoprotein active efflux system that confers multidrug resistance in tumors, as well as normal tissues including brain. 2. The classical model of multidrug resistance in brain places the expression of P-glycoprotein at the luminal membrane of the brain microvascular endothelial cell. However, recent studies have been performed with human brain microvessels and double-labeling confocal microscopy using (a) the MRK16 antibody to human P-glycoprotein, (b) an antiserum to glial fibrillary acidic protein (GFAP), an astrocyte foot process marker, or (c) an antiserum to the GLUT1 glucose transporter, a brain endothelial plasma membrane marker. These results provide evidence for a revised model of P-glycoprotein function at the brain microvasculature. In human brain capillaries, there is colocalization of immunoreactive P-glycoprotein with astrocytic GFAP but not with endothelial GLUT1 glucose transporter. 3. In the revised model of multidrug resistance in brain, P-glycoprotein is hypothesized to function at the plasma membrane of astrocyte foot processes. These astrocyte foot processes invest the brain microvascular endothelium but are located behind the blood-brain barrier in vivo, which is formed by the brain capillary endothelial plasma membrane. 4. In the classical model, an inhibition of endothelial P-glycoprotein would result in both an increase in the blood-brain barrier permeability to a given drug substrate of P-glycoprotein and an increase in the brain volume of distribution (VD) of the drug. However, in the revised model of P-glycoprotein function in brain, which positions this protein transporter at the astrocyte foot process, an inhibition of P-glycoprotein would result in no increase in blood-brain barrier permeability, per se, but only an increase in the VD in brain of P-glycoprotein substrates.

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Thoracic trauma causes one of every four trauma deaths in this country, and many of these deaths could have been prevented with prompt diagnosis and treatment. Injuries to the thorax range from a superficial wound such as contusions and abrasions to life-threatening tension pneumothorax. Being aware of the mechanism of injury and pathophysiology of the chest cavity will alert the nurse to suspected injuries. A brief description of common injuries is discussed in this article.

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PURPOSE: To evaluate the need for obtaining postdischarge chest radiographs for trauma patients who were treated with a thoracostomy tube. METHODS: A retrospective medical record review was conducted for all patients treated with a thoracostomy tube while admitted to the trauma service at Saint Louis University Hospital over a 12-month period. Patients who died during their hospital stay were excluded. RESULTS: During the 12-month study period, 155 trauma patients who were treated with a thoracostomy tube were discharged from the hospital. The indications for the thoracostomy tube were pneumothorax (n = 79, 51% of study population), hemopneumothorax (n = 34, 22%), hemothorax (n = 28, 18%), diaphragmatic rupture/laceration (n = 8, 5%), post thoracotomy (n = 4, 3%), and iatrogenic pneumothorax (n = 2, 1%). A follow-up clinic visit was scheduled for 1 to 2 weeks after discharge. Forty patients (26%) were lost to follow-up. Two patients called to report they had no symptoms and canceled their appointments. A total of 113 patients returned for follow-up appointments. Fifty-two patients had a predischarge chest radiograph that was negative for pneumothorax or hemothorax, had no symptoms, had normal results of a physical examination at the time of their clinic visit, and did not have a postdischarge chest radiograph. A total of 61 (54%) had postdischarge chest radiographs. Of that number, 56 (92%) were negative for pneumothorax. Three patients (5%) had a small pneumothorax, and 2 patients (3%) were noted to have a resolving hemothorax. All 5 patients were without symptoms and were released from the trauma service. CONCLUSION: A postdischarge chest radiograph is not indicated for an asymptomatic trauma patient who was treated with a tube thoracostomy and had a predischarge chest radiograph that was negative for pneumothorax or hemothorax.

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A novel series of indolebutyric acids with varying benzoyl substituents were synthesized to develop nonsteroidal inhibitors of steroid 5 alpha-reductase. We previously reported the discovery of a novel nonsteroidal 5 alpha-reductase inhibitor, FR119680, which had an IC50 value of 5.0 nM against the rat prostatic enzyme. However, this compound was not strongly active against the human prostatic enzyme. By further study of the structure-activity relationships we succeeded in producing the strongly active compound, FK143, 4-[3-[3-[bis(4-isobutylphenyl)-methylamino]benzoyl]-1H-indol-1-yl] butyric acid, with an IC50 value of 1.9 nM against the human enzyme. FK143 also has in vivo inhibitory activity against the castrated young rat model and it should therefore be an extremely useful agent for the treatment of benign prostatic hyperplasia.

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Sites of immunoreactive P-glycoprotein associated with human brain microvasculature were identified by labeling of unfixed isolated human brain capillaries, allowing visualization of the three-dimensional capillary structure by confocal microscopy. Capillaries isolated from human autopsy brain were dual-labeled with the MRK16 mouse monoclonal antibody (against human P-glycoprotein) and rabbit polyclonal antisera against the human brain microvascular glucose transporter (GLUT1), or glial fibrillary acidic protein (GFAP) on astrocyte foot processes. MRK16 and GLUT1 dual-labeling showed no signal overlap, identical to the staining pattern observed for dual-labeling with anti-GFAP and anti-GLUT1 antibodies: both GFAP and MRK16 labeling were discrete, discontinuous, and not co-localized with continuous GLUT1 labeling of capillary endothelium. In contrast, complete overlap of MRK16 and GFAP labeling demonstrated P-glycoprotein localization on astrocyte foot process remnants at the abluminal face of the brain microvasculature.

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Leptin is a 16-kDa protein synthesized in adipose tissue that produces a satiety effect in the CNS. Leptin may gain access to the brain via receptor-mediated transport through the blood-brain barrier (BBB), and the BBB leptin receptor (OBR) may regulate the availability of circulating leptin to brain cells. The aim of the present study was twofold: first, to identify the OBR isoform expressed at the BBB, i.e., short, or "a," and long, or "b," form; and second, to compare the abundance of the BBB OBR mRNA and protein between control and high fat-fed rats. RT-PCR with isoform-specific primers showed that OBRa is the most abundant isoform at the BBB. BBB OBRa transcript content was markedly increased in high fat-fed rats compared with controls (11-fold), and no changes were observed in the expression of the internal standard control actin. The high fat feeding induction of OBR mRNA was correlated with an increase in the immunoreactive BBB OBR determined by immunocytochemistry using an all-isoform reactive antibody in high fat-fed obese rats. This investigation demonstrates (a) the OBRa is the principal leptin receptor expressed at the BBB and (b) this BBB OBR isoform is up-regulated by a high fat diet.

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Ingestion of strong oxidant substances may result in acquired methemoglobinemia, a clinical condition in which the oxidized blood hemoglobin is incapable of delivering oxygen to the tissues, and the patient becomes cyanotic. Traditional first-line therapy consists of infusion of methylene blue, whose action depends on the availability of reduced nicotinamide adenine nucleotide phosphate (NADPH) within the red blood cell (RBC). Some patients, particularly those who are deficient in glucose-6-phosphate dehydrogenase (G6PD), will not benefit from methylene blue. In these patients, and in some patients who have ingested very strong oxidants, methylene blue may also precipitate Heinz body hemolytic anemia. We present a case of severe, acquired methemoglobinemia in a 26-month-old, 9.8-kg boy with G6PD deficiency. He was cyanotic, in respiratory failure, intubated in a pediatric intensive care unit. In typical fashion, he did not respond to methylene blue. Manual exchange of two whole blood volumes, performed over 4 1/2 hr, also failed to resolve his severe methemoglobinemia. An automated RBC exchange (1.3 RBC volume), lowered his methemoglobin content from 31.8% to 7% in a single 40-min procedure. Thereafter his methemoglobin level continued to decrease rapidly and spontaneously. He was discharged home 2 days later, with 0.4% methemoglobin. To our knowledge, this is the first report to demonstrate the (potentially superior) effectiveness of automated RBC exchange for treatment of patients with high-risk acquired methemoglobinemia, that is, those with G6PD deficiency or who have ingested strong oxidants.

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Various methods of optimizing brain exposure to polar compounds have been examined. However, direct comparisons of the potential efficacy of these methods have not been forthcoming. The present study utilized a mathematical approach to compare the efficacy of two pharmacologic methods of improving brain drug distribution: uptake enhancement and efflux blockade. In the present simulation study, the pharmacokinetics of a hypothetical marker and modifier were described by differential equations. The relationship between modifier effect on marker uptake into, or efflux from, the brain and modifier concentration in serum (uptake enhancement) or brain tissue (efflux blockade) was described by the Hill equation. Uptake enhancement increased both the rate and extent of marker penetration into the brain. Efflux blockade resulted in delayed attainment of maximum marker concentration, and prolonged marker residence, in brain tissue. Under all conditions and doses examined, uptake enhancement was more effective than efflux blockade in maximizing brain tissue exposure to the marker. Although development of agents that enhance uptake of polar compounds may be limited by the potential deleterious effects of blood-brain barrier disruption, use of this approach in theory could represent a significant advancement in the treatment of brain disorders.

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A novel series of indole-3-alkanoic acids with varied N-benzyl substituents were synthesized as nonsteroidal inhibitors of steroid 5 alpha-reductase. The structure-activity relationships in this series were studied and the optimum carboxylic acid side chain was butyric acid. Furthermore, compounds with a diaryl substituent at the 1-position of the indole ring displayed strong inhibitory activities in vitro. Amongst these derivatives, 4-[1-(6,6-dimethyl-6H-dibenzo[b,d]pyran-3-yl)methylindol-3-yl]b uty ric acid (FR119680) displayed very high inhibitory activity in vitro against rat prostatic 5 alpha-reductase (IC50 = 5.0 nM) and good in vivo activity in the castrated young rat model.

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Previous work on the effects of sterically stabilized liposomes on the growth of experimental solid tumors used protocols that began drug treatment when tumor volume was small (<0.01 mL). The goal of the present work was to compare the antitumor efficacy of daunomycin-loaded sterically stabilized liposomes versus free daunomycin in animals with large (>0.5 mL) experimental tumors. BALB/c nude mice were transplanted with 2.3 x 10(6) 3T3 cells transfected with an activated HER2 gene. After 8 days, when mean tumor volume was 0.52 mL, mice were treated with intraperitoneal daunomycin-loaded polyethylene glycol-stabilized liposomes (daunomycin 6 mg/kg, including tracer [(3)H]daunomycin), free daunomycin (6 mg/kg), or vehicle. Both control and free daunomycin-treated mice survived an average of 15 days after tumor cell inoculation (and 7 days after treatment), while mice receiving daunomycin-loaded sterically stabilized liposomes survived for 32 days. Tumors were well vascularized and contained no necrotic centers. These studies demonstrate that sterically stabilized daunomycin-loaded liposomes are more effective in prolonging life span than an equivalent dose of free daunomycin even when therapy is initiated after the tumor volume reaches 2% of body weight.

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Computerized simulations have been used for many years for teaching principles of management in business schools. This paper describes the development of a computerized business simulation for use in dental school practice management courses. The simulation is in a competitive game format. It requires students to formulate strategies and to implement management decisions that reinforce and fulfill that strategy. Participants use the outcomes of these decisions to formulate new management decisions for the upcoming period. Student response to participation in the simulation has been positive, with students indicating that participation is valuable for developing better understanding of analytical business management techniques and interpersonal techniques such as group process and leadership skills.

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The hypothesis that P-glycoprotein plays a functional role at the brain capillary endothelium, which makes up the blood-brain barrier in vivo, is based largely on immunocytochemical studies showing immunoreactive P-glycoprotein localized to either isolated brain microvessels or microvessels within tissue sections. The present studies use the MRK16 monoclonal antibody to human P-glycoprotein to demonstrate that the pattern of immunolocalization of P-glycoprotein in microvessels of human or primate brain is similar to the pattern of immunolocalization of an astrocyte protein, glial fibrillary acidic protein. In contrast, the discontinuous staining pattern of MRK16 is not colocalized with the continuous immunostaining of the brain endothelial GLUT1 glucose transporter. The MRK16 antibody was radiolabeled with [125I]-iodine, and 125I-MRK16 avidly bound isolated human brain capillaries via a saturable mechanism. However, the 125I-MRK16 antibody was not taken up by primate brain capillaries in vivo following intravenous injection. In conclusion, these studies provide evidence that P-glycoprotein does not play a functional role at the luminal membrane of the brain capillary endothelium in vivo, and that a principal site of immunoreactive P-glycoprotein in brain microvasculature is localized to astrocyte foot processes.

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The peripheral production of leptin by adipose tissue and its putative effect as a signal of satiety in the central nervous system suggest that leptin gains access to the regions of the brain regulating energy balance by crossing the brain capillary endothelium, which constitutes the blood-brain barrier in vivo. The present experiments characterize the binding and internalization of mouse recombinant leptin in isolated human brain capillaries, an in vitro model of the human blood-brain barrier. Incubation of 125I-leptin with isolated human brain capillaries resulted in temperature-dependent binding: at 37 degrees C, approximately 65% of radiolabeled leptin was bound per milligram of capillary protein. Two-thirds of the bound radioactivity was resistant to removal by acid wash, demonstrating endocytosis of 125I-leptin into capillary cells. At 4 degrees C, binding to isolated capillaries was reduced to approximately 23%/mg of protein, the majority of which was acid wash resistant. Binding of 125I-leptin to brain capillary endothelial plasma membranes was saturable, described by a two-site binding model with a high-affinity dissociation constant of 5.1+/-2.8 nM and maximal binding capacity of 0.34+/-0.16 pmol/mg of membrane protein. Addition of porcine insulin or insulin-like growth factor at a final concentration of 100 nM had a negligible effect on leptin binding. These results provide evidence for a leptin receptor that mediates saturable, specific, temperature-dependent binding and endocytosis of leptin at the human blood-brain barrier.

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Operative laparoscopic techniques requiring placement of large-bore cannulas through the abdominal wall lateral to the midline result in increased numbers of injuries to abdominal wall vessels. Five cases of inferior epigastric artery hemorrhage were controlled by percutaneous transabdominal placement of polypropylene sutures, allowing the procedure to be completed with the cannula in place. In two patients the sutures were left in place for 72 to 96 hours, and cutaneous necrosis occurred requiring debridement and delayed primary closure. In the other three women, removal of the sutures less than 24 hours postoperatively resulted in satisfactory hemostasis and primary healing of the abdominal wound. Percutaneous placement of polypropylene sutures may provide effective hemostasis after inferior epigastric artery hemorrhage due to cannula injury. Early suture removal may avoid potential cutaneous necrosis.

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