Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib.

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.

Colistin Reduces LPS-Triggered Inflammation in a Human Sepsis Model In Vivo: A Randomized Controlled Trial.

The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1ß concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system.

Fy phenotype and gender determine plasma levels of monocyte chemotactic protein.

BACKGROUND: In vitro studies indicate that the Fy blood group system antigens serve as receptors for chemokines such as monocyte chemotactic protein-1 (MCP-1) and RANTES. However, it is unclear whether subjects with the Fy(a-b-) phenotype exhibit altered clearance and hence altered plasma levels of chemo-kines, because they still express Fy on endothelial cells. STUDY DESIGN AND METHODS: To clarify a possible in vivo role of Fy on RBCs in the regulation of chemo-kine levels, healthy young volunteers of common Fy phenotypes were compared in a cross-sectional study. RESULTS: More than 90 percent of the 34 subjects of African origin were Fy(a-b-), one black volunteer was Fy(a+b-), and two were Fy(a-b+). As expected, all 65 white volunteers were positive for either Fy(a) and/or Fy(b). Unexpectedly, persons expressing either Fy(a) and/or Fy(b) had significantly higher plasma levels of MCP-1 than Fy(a-b-) volunteers (women: 154 vs. 110 ng/L, p<0.01; men: 179 vs. 169 ng/L, p = 0.03). Surprisingly, plasma levels of MCP-1 were found to be sex-dependent: median MCP-1 levels averaged 180 ng per L in men but only 139 ng per L in women (p<0.001). Further, MCP-1 levels decreased significantly throughout the menstrual cycle of 18 women studied longitudinally. CONCLUSION: MCP-1 levels are about 30 percent higher in men than in premenopausal women, and MCP-1 levels are also higher in persons with RBCs expressing Fy antigens than in Fy(a-b-) persons. These findings have direct implications for the concept and interpretation of clinical studies measuring MCP-1 levels; the role of the observed differences in MCP-1 levels for the pathogenesis of MCP-1-dependent diseases, such as atherosclerosis, merits further investigation.

Paroxetine decreases platelet serotonin storage and platelet function in human beings.

BACKGROUND: Serotonin is a platelet agonist and potent vasoconstrictor that has recently received attention concerning its potential role in acute coronary artery thrombosis. Selective serotonin-reuptake inhibitors, such as paroxetine, are widely used antidepressant agents. We sought to characterize the potential inhibitory effect of paroxetine on platelet function. METHODS: Healthy male volunteers received 20 mg/d paroxetine for 2 weeks in a randomized, double-blind, placebo-controlled, two-way cross-over trial. RESULTS: Paroxetine decreased intraplatelet serotonin concentrations by -83% (P < .01). This inhibited platelet plug formation as reflected by a 31% prolongation of closure time measured with the platelet function analyzer-100 (P < .05). Furthermore, paroxetine lowered expression of the platelet activation marker CD63 in response to two different concentrations of thrombin receptor-activating peptide (P < .01). Plasma concentrations of prothrombin fragment, von Willebrand factor antigen, and circulating P-selectin remained unchanged in either period, indicating that paroxetine does not increase activation of coagulation, endothelium, or platelets in vivo, underlining a favorable safety profile. CONCLUSIONS: Paroxetine substantially decreases intraplatelet serotonin content and thereby reduces platelet plug formation under shear stress, and responsiveness to thrombin receptor activating peptide-induced platelet activation. Further studies will reveal whether these pharmacodynamic effects can be exploited for treatment of thrombotic artery disease.

Temporalis muscle for facial reanimation. A 13-year experience with 224 procedures.

A procedure for temporalis muscle transposition was used to reanimate the paralyzed face in 219 patients. In most cases, facial paralysis had followed an operation to remove an acoustic tumor. Analysis of the results showed this procedure to be highly successful and the method of choice, alone in cases of long-standing facial paralysis or to augment the effects of facial nerve grafting or hypoglossal-facial nerve anastomosis, in reanimating the mouth. It was successful in restoring a smile to 80% of the 219 patients and provided overall improvement in mouth function in 96%. Complications occurred in 21% of patients, with the most common being infection (12% of patients). Since one of us began to use the procedure to reanimate the eye and mouth, results of temporalis muscle transposition have been improved by the following: (1) using the procedure to reanimate the mouth only; (2) performing revision surgery, most often tightening the corner of the mouth (25% of patients), as indicated; (3) transposing only the midsection of the muscle; (4) implanting a prefabricated Silastic prosthesis to fill the muscle defect; (5) when indicated, lengthening the muscle with polytef (Gore-Tex+); and (6) placing the muscle in a tunnel lateral to the superficial musculoaponeurotic system to avoid injuring the underlying facial nerve should some spontaneous recovery of facial nerve function be possible.

Sublingual contiguous thyroglossal and dermoid cysts in a neonate.

Thyroglossal duct cysts and dermoid cysts are two distinct lesions which can occur in the midline of the head and neck region. Different embryologic explanations for these two lesions have traditionally been accepted. Recent evidence, however, hints at an association between them. We present here a case in which both of these cysts occurred together in an unusual anatomic location, along with a discussion of the possible relationship between these two pathologic entities.

Nonsquamous tumors of the head and neck in the geriatric population.

Thyroid tumors, salivary gland tumors, and non-Hodgkin's lymphoma are described. Psychosocial issues involving the geriatric patient are discussed. Case reports of a number of geriatric tumor patients are included.

Chondrosarcoma of the sphenoethmoid complex.

Chondrosarcoma of the nose and paranasal sinuses is extremely rare. We report a case of a child with a massive chondrosarcoma of the sphenoethmoid complex who presented with a change of visual acuity. Clinical and histologic characteristics of this lesion are discussed, along with treatment options and factors affecting prognosis.

Malignant atrophic papulosis: response to antiplatelet therapy.

A patient with malignant atrophic papulosis (Degos' disease) is studied. Platelet function studies showed abnormalities of increased adhesiveness and aggregation. Treatment with dipyridamole and aspirin correlated with reversal of these abnormalities and cessation of new lesion development. When treatment was stopped, platelet function abnormalities and new skin lesions developed within 2 months. With reinstitution of therapy, the patient developed no new lesions in the 5 months he was followed. This is the second report of platelet function abnormality and apparent successful treatment with antiplatelet therapy in a patient with Degos' disease.

Acquired perforating dermatosis. Evidence for combined transepidermal elimination of both collagen and elastic fibers.

Patients with renal disease or diabetes mellitus often have an acquired perforating disease of the skin develop that is characterized by hyperkeratotic papules with transepidermal elimination of degenerated material, including collagen or elastic fibers. There is disagreement regarding the most appropriate name for this disease. The pathologic process has been identified by various authors as reactive perforating collagenosis, elastosis perforans serpiginosa, perforating folliculitis, or Kyrle's disease. We have seen four patients with renal disease and/or diabetes whose skin biopsy specimens demonstrated combined transepidermal elimination of both collagen and elastic fibers. This finding is not characteristically seen in any of the previously defined perforating diseases. Since the histologic findings vary greatly in different lesions from different patients with renal disease, we recommend referring to this process as "acquired perforating dermatosis." It is best not to create a new category of perforating disease or to say that a given patient has one of the other four diseases based on random sampling of only a few lesions.

Antiplatelet therapy in atrophie blanche and livedo vasculitis.

Seven patients with atrophie blanche or livedo vasculitis of the lower extremities showed abnormal platelet functions in vitro. Six of seven showed hyperaggregation with epinephrine and/or collagen, three showed increased platelet adhesiveness, three showed increased platelet count, and one showed increased microemboli. After treatment with dipyridamole and aspirin, all showed return to normal platelet function. Clinical improvement occurred in all patients, with significant alleviation of pain and decrease in new lesion formation. Although enhanced healing of lesions seemed evident to physician and patient, it was incomplete. In two patients, pain returned when dipyridamole and aspirin were stopped, but the patients improved again when the medicines were restarted. These preliminary findings indicate a possible beneficial effect of antiplatelet therapy in atrophie blanche and livedo vasculitis. A double-blind study is being undertaken to further study this effect.

Exfoliative dermatitis: presenting sign of internal malignancy.

Exfoliative dermatitis is most commonly associated with antecedent cutaneous disorders, medications, and lymphoreticular malignancies. Three patients with exfoliative dermatitis associated with internal carcinoma are described. The importance of thorough evaluation of all patients who present with exfoliative dermatitis is stressed.

Eye protection from light radiation.

It appears that green absorptive lenses are highly desirable for the purposes of shielding the eyes against light radiation from molten metal during the casting and soldering procedures. The dental laboratory technicians have experienced no after-images, less eye fatigue, and no adverse symptoms when using these lenses, as were reported previously. The lenses not only effectively protect the eyes from the injurious light wavelengths, but they also provide for enough normal (as well as individually corrected) vision to accomplish any procedure necessary in the dental laboratory. We propose that the green absorptive lenses, with individual corrections if needed, be considered for dental laboratory technicians during dental laboratory procedures when needed, such as during casting and soldering, to protect their eyes from light radiation.