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Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF).

Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. 62 index cases with a pre‐existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWFsequencing, comparative genomic hybridization and predictive computational programs. 75% of subjects (46) had central testing confirming type 3, while 25% were re‐classified as type 1‐Severe or type 1C. Candidate VWFvariants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co‐dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co‐dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWFgenetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

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EssentialsPatients with von Willebrand disease were enrolled in our study.Type 2 VWD diagnoses were based on original test results.Repeat evaluation resulted in many patients receiving a different type 2 diagnosis.Some genetic variants were particularly likely to move type 2 subcategories. Patients with von Willebrand disease were enrolled in our study.Type 2 VWD diagnoses were based on original test results.Repeat evaluation resulted in many patients receiving a different type 2 diagnosis.Some genetic variants were particularly likely to move type 2 subcategories. Type 2 von Willebrand disease (VWD) refers to patients with a qualitative defect in von Willebrand factor. Accurate diagnosis of type 2 VWD subtypes can be challenging. To compare the historical diagnosis of type 2 VWD with current laboratory testing. Subjects were enrolled in the Zimmerman Program either because of a preexisting diagnosis of VWD (retrospective cohort) or from evaluation for bleeding symptoms or suspected VWD (prospective cohort). Original diagnosis was assigned by the local center and central diagnosis was based on central laboratory testing. Two hundred and seventeen index cases in the retrospective cohort and 35 subjects in the prospective cohort carried a local diagnosis of type 2 VWD (29% and 6% of enrolled index cases, respectively). In the retrospective cohort, the diagnosis was confirmed in 66% of cases with a preexisting diagnosis of 2A, 77% 2B, 54% 2M, and 72% 2N. In the prospective cohort, 31% were confirmed 2A, 60% 2B, 23% 2M, and 100% 2N. Several genetic variants were repeatedly implicated in subjects with changed diagnosis: p.M1304R, p.R1315C, p.R1374C, and p.R1374H. Both the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging.

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ABSTRACT:While comics have found a distinguished position in medicine through the work of graphic medicine, they also have a long, vexed history in other areas of the medical field, namely psychiatry. I explore one way superheroes have previously entered mental health discourse by lingering over the rhetoric of psychiatrists who have attempted to understand the superhero and the supervillain through analysis and diagnosis. The writings of psychiatrists invested in comics and superheroes provide insight into the psychiatric discipline, and the superhero genre supplies new ways to think about mental health practice. After considering a selection of psychiatric readings of the superhero (and villain), I offer my own interpretation of The Killing Joke. By placing The Killing Joke in the context of discussions of mental health, Alan Moore and Brian Bolland's text complicates questions of evil as well as empathy through the depiction of the villainous Joker in pain. The reader's identification with and connection to the character facilitates opportunities for both clinicians and laypeople to listen to and to witness the story of a villain, to know what he is, and to contend with the ambivalent feelings that emerge from such a situation of knowing both his sad history and his violent actions.

Rising anthropogenic CO2in the atmosphere is accompanied by an increase in oceanic CO2and a concomitant decline in seawater pH (ref. ). This phenomenon, known as ocean acidification (OA), has been experimentally shown to impact the biology and ecology of numerous animals and plants, most notably those that precipitate calcium carbonate skeletons, such as reef-building corals. Volcanically acidified water at Maug, Commonwealth of the Northern Mariana Islands (CNMI) is equivalent to near-future predictions for what coral reef ecosystems will experience worldwide due to OA. We provide the first chemical and ecological assessment of this unique site and show that acidification-related stress significantly influences the abundance and diversity of coral reef taxa, leading to the often-predicted shift from a coral to an algae-dominated state. This study provides field evidence that acidification can lead to macroalgae dominance on reefs.

Amiodarone may induce hyper- or hypothyroidism. Patients with β-Thalassemia Major (β-Thal) have an increased prevalence of primary hypothyroidism and often require amiodarone for hemosyderotic cardiomyopathy. Aim of this study was to retrospectively evaluate thyroid function in β-Thal adult patients on long-term amiodarone. The study group consisted of twenty-two (21 males, 1 female; age: 23-36 yr) β-Thal patients submitted to long-term (3-48 months) amiodarone therapy from January 1991 to July 1996. Controls included 73 β-Thal patients (23 males and 50 females aged 25-35 yr) not treated with amiodarone. In all cases serum free thyroid hormones, thyrotropin and thyroid autoantibodies were evaluated. A higher prevalence of overt hypothyroidism (5/22 [22.7%]) as compared to controls (3/73 [4.1%], p=0.02) was found in β-Thal patients ≤3 months after starting amiodarone, while the prevalence of subclinical hypothyroidism was similar in amiodarone-treated (18.2%) and untreated (15%) β-Thal patients. Overt hypothyroidism resolved spontaneously after amiodarone withdrawal in 1 case, while the remaining patients were maintained euthyroid on amiodarone by L-thyroxine administration. After 21-47 months of amiodarone therapy, 3 patients (13.6%) developed thyrotoxicosis (2 overt and 1 subclinical), which remitted shortly after amiodarone withdrawal. No case of hyperthyroidism was observed in β-Thal controls (p=0.012 vsamiodarone-treated patients). In conclusion, amiodarone administration is often associated in adult β-Thal patients to a rapid progression of the pre-existing subclinical hypothyroidism, but transient thyrotoxicosis may also be observed after a longer period of therapy. These findings should be carefully considered in the management of these patients.

Shedding of membrane gangliosides is characteristic of human and experimental tumors. Because some shed tumor gangliosides have potent tumor-enhancing properties, significant ganglioside shedding could influence tumor progression. We examined this possibility in a human tumor, neuroblastoma. Ganglioside shedding, measured as circulating tumor-derived GD2 ganglioside, and the outcome of 74 patients with advanced stage (III and IV) disease were studied. Progression-free survival (PFS) was inversely related to circulating GD2 levels at the time of diagnosis (P = .018). By Kaplan-Meier analysis, the quartile of patients having the highest circulating GD2 levels (greater than or equal to 568 pmol/mL) had a strikingly different outcome from the quartile of patients with the lowest (less than or equal to 103 pmol/mL) GD2 levels (P = .013): median PFS was shorter (9 v 28 months), and the long-term survival rate lower (2-year PFS of 24% v 70%). We conclude that more rapid disease progression and lower survival rate are associated with high circulating GD2 levels at diagnosis and speculate that shed neuroblastoma tumor gangliosides play a role in accelerating tumor progression.

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.

The four stereoisomers of the 2-hydroxy derivatives of digitoxigenin and 3-epidigitoxigenin have been synthesized, their structures established by NMR, and their binding affinity for the digitalis receptor on Na+, K+-ATPase evaluated. These derivatives showed lower affinities than the parent compounds. The hydrophilic hydroxy groups in the alpha position are more detrimental to the affinity than hydroxy groups in the beta position.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family (hence the alternative designation FGF-7). It is produced by stromal cells, but acts as a mitogen for epithelial cells. We examined the effects of topically applied KGF on healing of wounds in a porcine model. In partial-thickness wounds, KGF stimulated the rate of reepithelialization (p < 0.0002), associated with a thickening of the epidermis (p < 0.0001). Epidermis from KGF-treated full-thickness wound sites was significantly thicker (0.31 +/- 0.22 mm) compared with mirror image control sites (0.18 +/- 0.12 mm) (p < 0.0001). Moreover, the majority (77%) of KGF-treated wounds exhibited epidermis with a deep rete ridge pattern as compared with control sites. These effects were observed as early as 14 d and persisted for at least 4 wk. KGF treatment also increased the number of serrated basal cells associated with increased deposition of collagen fibers in the superficial dermis adjacent to the acanthotic epidermis. Electron microscopy revealed better developed hemidesmosomes associated with thicker bundles of tonofilaments in the serrated cells. The pattern of epidermal thickening observed in KGF-treated wounds resembled psoriasis. Psoriasis is a disease associated with epidermal thickening, parakeratosis as well as hyperproliferation that extends beyond the basal layer. In striking contrast to psoriasis, KGF-treated wounds exhibited normal orthokeratotic maturation, and proliferation was localized to the basal cells. Our present findings have significant implications concerning the role of KGF as a paracrine modulator of epidermal proliferation and differentiation.

The reasons why the most gifted physics students generally choose to become theorists in preference to an experimental career are analyzed. Some remedies to this deplorable fact are suggested. Four brilliant, but comparatively little known measurements are described to illustrate the intellectual content of experimental physics.

Aim. To review the outcome of cases of left dorsal displacement of the large colon (LDDLC) treated with phenylephrine HCl and mild exercise.Methods. Physical parameters, laboratory data, ultrasonographic findings and outcome were analysed in a retrospective study of 12 horses with a confirmed diagnosis of LDDLC which were treated with phenylephrine HCl and mild exercise.Results. Administration of phenylephrine HCl and mild exercise resulted in the resolution of LDDLC in 11 of 12 treated horses. One horse failed to resolve the entrapment and required surgical correction.Conclusion. Administration of phenylephrine HCl appears to be an effective treatment for horses with confirmed diagnosis of LDDLC presented with mild to moderate colonic distention.

Optimal dosing to prevent excessive surgical bleeding in VWD is being investigated in an ongoing prospective, uncontrolled, open-labeled study to establish the safety and efficacy of replacement therapy with a VWF/FVIII concentrate (Humate-P®). This protocol-defined interim analysis describes the results in the first eighteen (18) patients (6 males, 12 females) of a total of 30 planned. Seven patients had Type 1 VWD, 6 had Type 2 (2 with 2A, 3 with 2B, 1 with 2M), and 5 had Type 3. All patients had pre-operative pharmacokinetic assessments to individualize the loading and maintenance doses of VWF/FVIII concentrate utilized for surgery. Fourteen patients had major surgical procedures including neurosurgery, joint replacement, tonsillectomy and complete oral restoration; three had minor procedures; and one had oral surgery. Hemostatic efficacy was assessed by investigators on a four-point scale (excellent, good, moderate/poor, none) immediately after surgery, 24 hours after the last VWF/FVIII concentrate infusion, and 14 days post-op. Good and excellent efficacy were combined into one endpoint of effective hemostasis. Expected estimated blood loss (EBL) was defined prior to the procedure, and actual EBL was recorded post-op. Adverse events were collected throughout the trial until follow-up 4 weeks post-op. Hemostasis was effective in 17/18 patients (94.4%) immediately after surgery; in 17/17 patients (100%) 24 hours after the last VWF/FVIII conc infusion; and in 18/18 (100%) patients 14 days after surgery. Median actual EBL did not exceed expected EBL in any surgery category. Four patients received transfusions (one for pre-existing anemia, three for serious adverse events). Loading doses of VWF/FVIII concentrate ranged from 36 to 135 IU/kg. Maintenance doses were determined by daily monitoring of plasma coagulation factor levels. Median durations of treatment were 2 days for oral surgery, and 4 days for both minor and major surgery. Post-op nausea (n=5) and fever (n=3) were the most commonly reported adverse events. Nausea, headache, and dizziness were considered possibly related to VWF/FVIII concentrate in one patient each; these events were mild in severity and resolved without sequelae. Bleeding-related serious adverse events were reported in three patients: one with GI bleeding post-laparoscopic gastro-jejunal bypass; one with post-craniotomy subdural and intracranial bleeding; and one with post-hysteroscopy/dilatation & curettage hemorrhage followed by hysterectomy. Hemostasis was considered effective in these 3 by the investigators, and in 2 patients by an independent DSMB review; hemostasis was considered ineffective by the DSMB only in the patient with post-hysteroscopy bleeding. No thromboembolic complications or changes in viral titers were observed. This analysis supports VWF/FVIII concentrate safety and efficacy to prevent excessive bleeding during and after a range of surgical procedures in patients with VWD. Enrollment in the trial continues.

The VWF/FVIII concentrate Humate-P® (ZLB Behring) was studied in a prospective, uncontrolled, open-label clinical trial in VWD patients undergoing elective surgery. An interim analysis was performed after 24 patients (18 female, 6 male) with the following types of VWD had been included into the study: type 1 (n=11), type 2A (n=2), type 2B (n=4), type 2M (n=2) and type 3 (n=5). All patients underwent the pre-operative PK assessment to individualize the loading and maintenance doses of Humate-P® and 18 patients had completed surgery. The primary objective of the study - to demonstrate safety and hemostatic efficacy - was achieved in 100% of the patients. All patients received at least two infusions: a single infusion of 60 IU VWF:RCo per kg b.w. for a pharmacokinetic (PK) assessment prior to surgery and a PK guided loading dose before start of surgery. In addition, all patients received more infusions for further treatment after surgery. PK results: VWF:RCo: The overall median IVR was 2.1 [% per IU/kg] (range 1.1–4.2). The overall median response was 75.3% (range 37.0–169.4). Type 3 VWD patients had a slightly lower median response of 73.4% (range 63.7–96.1). Median value of Cmax was 142 IU/dL (range 84–330). Median effective half-life was 6.7 h (range 0.2–74.9), median clearance 3.6 [mL/kg/h] (range 1.0–16.6). FVIII:C: The median IVR was 2.8 [% per IU/kg] (range 1.4–4.9). Type 3 VWD patients had a median IVR of 3.4 [% per IU/kg] (range 1.7–4.9). The median response was 96.4% (range 63.0–164.8). Type 3 VWD patients had a median response of 104.5% (range 63.0–155.3). Dose-linearity: Graphical presentation of the relation between IVR and dose administered demonstrated the dose linearity of the VWF concentrate within a wide dose range. IVR of VWF:RCo versus the amount of VWF:RCo administered (all doses) IVR of VWF:RCo versus the amount of VWF:RCo administered (all doses) Statistical modeling using all doses (loading dose and maintenance infusions) supported this finding. Using the log-transformed IVR plotted against the dose administered the slope was 0.0004 (95% confidence interval: −0.0045 to 0.0053. Conclusion: The PK results are comparable to PK data from other clinical studies with Humate-P®/Haemate P® and given the interindividual variability underline the importance of pharmacokinetic studies prior to surgical interventions. Dose linearity of VWF:RCo with Humate-P® has been shown over a wide range of dosages (10–135 IU/kg b.w.). These results increase our confidence in the treatment of VWD patients with Humate-P®.

The VWF/FVIII concentrate Humate-P® (ZLB Behring) was studied in a prospective, uncontrolled, open-label clinical trial in VWD patients undergoing elective surgery. An interim analysis was performed after 24 patients (18 female, 6 male) with the following types of VWD had been included into the study: type 1 (n=11), type 2A (n=2), type 2B (n=4), type 2M (n=2) and type 3 (n=5). All patients underwent the pre-operative PK assessment to individualize the loading and maintenance doses of Humate-P® and 18 patients had completed surgery. The primary objective of the study - to demonstrate safety and hemostatic efficacy - was achieved in 100% of the patients. All patients received at least two infusions: a single infusion of 60 IU VWF:RCo per kg b.w. for a pharmacokinetic (PK) assessment prior to surgery and a PK guided loading dose before start of surgery. In addition, all patients received more infusions for further treatment after surgery. PK results: VWF:RCo: The overall median IVR was 2.1 [% per IU/kg] (range 1.1–4.2). The overall median response was 75.3% (range 37.0–169.4). Type 3 VWD patients had a slightly lower median response of 73.4% (range 63.7–96.1). Median value of Cmaxwas 142 IU/dL (range 84–330). Median effective half-life was 6.7 h (range 0.2–74.9), median clearance 3.6 [mL/kg/h] (range 1.0–16.6). FVIII:C: The median IVR was 2.8 [% per IU/kg] (range 1.4–4.9). Type 3 VWD patients had a median IVR of 3.4 [% per IU/kg] (range 1.7–4.9). The median response was 96.4% (range 63.0–164.8). Type 3 VWD patients had a median response of 104.5% (range 63.0–155.3). Dose-linearity: Graphical presentation of the relation between IVR and dose administered demonstrated the dose linearity of the VWF concentrate within a wide dose range.

Optimal dosing to prevent excessive surgical bleeding in VWD is being investigated in an ongoing prospective, uncontrolled, open-labeled study to establish the safety and efficacy of replacement therapy with a VWF/FVIII concentrate (Humate-P®). This protocol-defined interim analysis describes the results in the first eighteen (18) patients (6 males, 12 females) of a total of 30 planned. Seven patients had Type 1 VWD, 6 had Type 2 (2 with 2A, 3 with 2B, 1 with 2M), and 5 had Type 3. All patients had pre-operative pharmacokinetic assessments to individualize the loading and maintenance doses of VWF/FVIII concentrate utilized for surgery. Fourteen patients had major surgical procedures including neurosurgery, joint replacement, tonsillectomy and complete oral restoration; three had minor procedures; and one had oral surgery. Hemostatic efficacy was assessed by investigators on a four-point scale (excellent, good, moderate/poor, none) immediately after surgery, 24 hours after the last VWF/FVIII concentrate infusion, and 14 days post-op. Good and excellent efficacy were combined into one endpoint of effective hemostasis. Expected estimated blood loss (EBL) was defined prior to the procedure, and actual EBL was recorded post-op. Adverse events were collected throughout the trial until follow-up 4 weeks post-op. Hemostasis was effective in 17/18 patients (94.4%) immediately after surgery; in 17/17 patients (100%) 24 hours after the last VWF/FVIII conc infusion; and in 18/18 (100%) patients 14 days after surgery. Median actual EBL did not exceed expected EBL in any surgery category. Four patients received transfusions (one for pre-existing anemia, three for serious adverse events). Loading doses of VWF/FVIII concentrate ranged from 36 to 135 IU/kg. Maintenance doses were determined by daily monitoring of plasma coagulation factor levels. Median durations of treatment were 2 days for oral surgery, and 4 days for both minor and major surgery. Post-op nausea (n=5) and fever (n=3) were the most commonly reported adverse events. Nausea, headache, and dizziness were considered possibly related to VWF/FVIII concentrate in one patient each; these events were mild in severity and resolved without sequelae. Bleeding-related serious adverse events were reported in three patients: one with GI bleeding post-laparoscopic gastro-jejunal bypass; one with post-craniotomy subdural and intracranial bleeding; and one with post-hysteroscopy/dilatation & curettage hemorrhage followed by hysterectomy. Hemostasis was considered effective in these 3 by the investigators, and in 2 patients by an independent DSMB review; hemostasis was considered ineffective by the DSMB only in the patient with post-hysteroscopy bleeding. No thromboembolic complications or changes in viral titers were observed. This analysis supports VWF/FVIII concentrate safety and efficacy to prevent excessive bleeding during and after a range of surgical procedures in patients with VWD. Enrollment in the trial continues.