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Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM. © 2016 by The American Society of Hematology.

The direct effect of clarithromycin and azithromycin on human polymorphonuclear leukocyte (PMN) functions and their intracellular activity against Staphylococcus aureus, phagocytosed by human monocytes, were studied. The presence of both antibiotics, in the range of concentrations from 0.25 to 20 micrograms/ml, did not affect chemotaxis, opsonized-zymosan phagocytosis, respiratory burst measured by nitroblue tetrazolium reduction and phorbol myristate acetate-induced superoxide production, or the microbicidal activity of human PMNs against Candida albicans. Both macrolides were bactericidal against staphylococci in the monocyte system, while bacteriostatic activity was found in cell free system. At concentrations equal to the minimum inhibitory concentrations (MICs) (0.75 and 0.1 respectively for azithromycin and clarithromycin) more than 99% of intraphagocytic S. aureus were killed after 24 h incubation. Increasing the concentrations of each drug above the MICs (5 and 10 MICs) did not alter the killing rate of intracellular bacteria. Moreover, no differences between the intracellular bioactivity of these antibiotics were demonstrated, despite their different uptake kinetics.

The influence of aging on some parameters of systemic host defense mechanisms, i.e. white cell counts, lymphocyte subpopulations, delayed-type hypersensitivity (DTH), polymorphonuclear and mononuclear leukocyte functions, was evaluated. One hundred and forty-six healthy volunteers (60 men and 86 women), aged 25-100 years, were enrolled. None of the subjects had taken any drug in the month before the study. Subjects were divided into three age groups: 25-45, 46-65 and 66-100 years. Groups were comparable in size, and sex distribution was similar throughout all age groups. Elderly people were 51 healthy volunteers between the ages of 66 and 100 years (mean age 79.2). Younger people were 41 subjects between the ages of 46 and 65 years (mean age 54.3) and 53 between the ages of 25 and 45 years (mean age 32.7). As for the comparison between sexes, no significant differences in the values of the studied parameters were found between males and females (p0.05). Only quantitative DTH data, i.e. the number of antigens producing positive reactions and the score (sum of positive reaction diameters), were significantly (p0.05) reduced in responsive females when compared to males. Aging did not affect white cell counts, lymphocyte subsets and many phagocytic functions, i.e. phagocytosis frequency and index, nitroblue tetrazolium reduction, superoxide production, microbicidal activity against bacteria and yeasts. A significant decrease (p0.05) in the chemotactic response to serum-derived chemotactic factors was observed in aged people in comparison to younger subjects. Anergy was more frequent in older (about 29%) than in younger (5-9.4%) healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

The immunological and clinical effects of two oral treatment schedules of RU 41740 (standard for 3 months vs. long-term for 6 months) were assessed in 40 patients with chronic bronchitis by a controlled, double-blind, randomized trial. Both treatments significantly improved phagocytosis index of both neutrophils and monocytes, and the phagocytosis frequency and the candidacidal activity of neutrophils, showing the maximum stimulation at the end of the third course of treatment. Both treatment schedules reduced the number and the duration of infectious exacerbations of chronic bronchitis with respect to those observed in the corresponding period of the previous year. However, no significant difference between standard and long-term treatment with RU 41740 was found with respect to the immunological and clinical effect and tolerability.

Long-term PUVA-treated psoriatic patients given maintenance therapy (UVA doses greater than 1,000 J/cm2) have been demonstrated to undergo lymphopenia and a decrease in the total number of circulating CD3+ and CD4+ T cells. The aim of this study was to assess whether the impairment of T cells is detectable also in psoriatic patients after long-lasting PUVA discontinuation. A group of 34 psoriatic patients (25 males, 9 females; mean age 52.7 +/- 12.82 years), who had previously been treated by PUVA therapy (average cumulative dose 1,898.48 +/- 1,207.12 J/cm2), was studied 1 year or more after discontinuation of PUVA therapy. The patients studied failed to show any impairment in CD3+ and CD4+ cells. Nevertheless, a significant increase (p less than 0.05) in circulating CD8+ cells (both in the percentage and the total number) was detectable in PUVA patients as compared to appropriate controls. The significance and implications of this finding are not known and need further investigations.

Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymorphonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL. The uptake kinetics of AZ were time-dependent over an 18 h period, while those of CL were similar to erythromycin (ER) kinetics, with a maximum level of incorporation being obtained after a 60 min incubation. The accumulation of both drugs was influenced by extracellular antibiotic-concentrations, PMN viability, extracellular calcium, physiological environmental temperature and pH. The uptake was not modified by inhibitors of cell metabolism or activators of cell membranes. After removal of extracellular antibiotic, the release of AZ from PMNs was very slow: nearly 50% of the drug remained cell-associated after 24 h incubation. The efflux of this derivative was significantly enhanced when drug-loaded PMNs were stimulated by phorbol-myristate acetate (PMA). The kinetics of CL release indicated that this macrolide behaved like ER. Nevertheless, about 10% of the initial cell-associated antibiotic showed a prolonged retention. On the whole, these data suggest that diffusion through cell membranes and trapping into acidic compartments of PMNs are important events in CL and AZ uptake.

Summary. Some measures of systemic host defences, i.e. white cell counts, lymphocyte subsets, delayed-type hypersensitivity and polymorphonuclear leucocyte functions, were evaluated in 42 patients suffering from cutaneous superficial mycoses and in 35 healthy volunteers. Patients were divided according to the extent of their lesions into two groups: group A (30 patients) with skin involvement ≥30% and group B (12 patients) with skin involvement ≤1%. No significant abnormalities in systemic defence mechanisms were observed in group B patients, whereas multiple alterations of polymorphonuclear phagocyte activities, i.e. chemotaxis, phagocytosis, mitogeninduced superoxide anion production, were observed in patients with extensive lesions. The values of these phagocytic functions remained significantly reduced (P

The in vitro effects of cefixime and cefdinir (CI 983), two so-called third-generation oral cephalosporin derivatives, on human polymorphonuclear and mononuclear phagocyte functions (random migration and chemotaxis, specific and nonspecific phagocytosis, nitroblue tetrazolium reduction, superoxide production, microbicidal activity) were studied. Neither antibiotic, in the range of its attainable therapeutic concentration, exhibited any toxic effect on random migration, chemotaxis, metabolic activation and microbicidal mechanisms of phagocytic cells. Cefixime did not interfere in phagocytosis while cefdinir enhanced both phagocytosis frequency and index. The modulating effect on phagocytosis exerted by cefdinir was achieved at very low antibiotic concentrations (0.06 mg/l for polymorphonuclear leukocytes and 0.03 mg/l for monocytes) when non-opsonized zymosan particles were used as phagocytic challenge. Moreover, the effect was demonstrated both in the presence of cefdinir and after pretreatment of cells with the antibiotic and its removal by washings. As for specific phagocytosis, parameters were slightly increased by cefdinir but only the phagocytosis index was significantly improved in the presence of 2 mg/l of antibiotic.

We investigated the effects of aging on some functional activities (chemotaxis, phagocytosis, nitroblue tetrazolium reduction and candidacidal activity) of peripheral polymorphonuclear and mononuclear phagocytes in 96 healthy subjects and 89 patients with chronic bronchitis, aged 40 to 100 years. The subjects were divided according to age into younger (40–65 years) and older (66–100 years) individuals. No subject was taking any drug known to affect phagocytic functions. A few abnormalities in PMN and monocyte functions were observed in aged healthy subjects, in comparison to the younger ones; in fact, only the chemotactic response to complement-derived chemotactic factors was significantly impaired in elderly healthy individuals. On the contrary, multiple alterations of phagocyte activities, i.e., chemotaxis, phagocytosis, and candidacidal activity were observed in aged subjects with chronic bronchitis, compared to healthy adults. However, the results obtained in older and younger patients with chronic bronchitis were superimposable. The present data suggest that the decline in functional activities of phagocytes in the aged could depend on the effect of the underlying chronic bronchitis on the cellular components of the non-specific host defense system, rather than a direct effect of the aging process.(Aging Clin. Exp. Res. 5: 357-361, 1993)

The intracellular activity of flurithromycin, erythromycin, roxithromycin and miocamycin against susceptible clinical isolates of Staphylococcus aureus, phagocytosed by human monocytes, was investigated. Intracellular bioactivity was studied in a 24-hour assay, using experimental conditions which allowed the intracellular growth of bacteria. A colony counting method was used to differentiate between intracellular bacteriostatic and bactericidal activity of antibiotics. Moreover, the effect of macrolides against extracellular staphylococci was assessed. All agents showed higher intracellular than extracellular activity against staphylococci. At low concentration (0.1 mg/l) they had intracellular bacteriostatic activity. At concentrations higher than the minimal inhibitory ones (1 and 5 mg/l), miocamycin only still produced a bacteriostatic effect while flurithromycin, erythromycin and roxithromycin also showed intracellular bactericidal activity.

The ability of flurithromycin and erythromycin to enter human polymorphonuclear phagocytes were studied and compared by a velocity centrifugation gradient technique. Both macrolides were markedly concentrated by human cells and attained cellular to extracellular concentration ratios (C/E)or = 10. The incorporation was rapid and essentially complete after 60 min incubation. When PMNs were pretreated with formaldehyde, or incubated at low temperatures (4-25 degrees C) or at low pH, the transport ratios of both molecules were reduced. Sodium fluoride and 2,4-dinitrophenol, which decreased erythromycin uptake, did not affect flurithromycin penetration. Perturbation of cell membrane by phorbol myristate acetate, but not by formyl methionyl leucyl peptide, affected C/E ratios of both antibiotics. The addition of amino acids or nucleosides did not influence their transfer into PMNs.

Apical root resorption is a frequent phenomenon observed in pre-surgical orthodontic; the reason is double: we deal with adult patients and we often move the teeth in the opposite direction compared to the position obtained in previous inefficacious orthodontic treatments. Notwithstanding the amount of apical root resorption we couldn't record an hyper-mobility of the teeth and a long term evaluation of occlusal stability didn't show any significant change.

The close examination of the central osseous and/or parosteal lesions of the jaws must be reconducted to the study of the main fundamental embryonal processes that take place in the primordial stomodeus. Some pathological lesions can arise from the rests that survive after the disgregation of various odontogenic epithelial structures destined to disappear with growth: the epithelial root sheath, the dental lamina and the external epithelium of the enamel organ. Some osseous lesions can also originate from the nonodontogenic epithelial rests: this tissue comes from the uncompleted obliteration of the ectodermic layer during the processes of union and fusion of the various embryonal components of the maxillary structures.

The Authors presented the clinical report of an apical scar because of the rareness of the case and because of the interesting differential diagnosis: this lesion has a cystic radiological aspect and must be differentiated from the real odontogenic cysts of the jaws; the apical scar does not belong to the cystic pathology and represents just a defect of the healing process: no treatment is requested as the apical scar mustn't be considered a pathology.

Discussing the central intraosseous developmental odontogenic cysts of the jaws the Authors have followed the classification suggested by Hoffman et Al. that lists the lesions according to their biological activity. After a short foreword about the most important stages of the embryological dental development, grouped in six phases, the Authors referred to the principal concepts emerging from the literature about the most aggressive developmental odontogenic cysts of the jaws: the primordial cyst and the odontogenic keratocyst of which they have outlined a definition, and referred to the clinical, radiological, ethiological and microscopical data, the treatment and the differential diagnosis.

The Authors conclude the chapter about the central intraosseous developmental odontogenic cysts. Some of them are very rare, others are very similar histogenetically with other more frequent cystic lesions of the jaws. Notwithstanding the radiographic and macroscopic aspect apparently similar, these lesions are very different between each other in their biological activity. The classification, suggested by Hoffman, Jacoway and Krolls lists these lesions from the least to the most aggressive. We have here considered the multiple nevoid basal cell carcinoma syndrome, also known as Gorlin-Goltz syndrome, associated to one or more keratinized maxillary cysts, the calcifying odontogenic cyst, the more frequent and well known dentigerous cyst, the lateral periodontal cyst with its uncertain etiology and the harmless eruption cyst.

The apical granuloma, the periapical abcess and the radicular cyst are the most frequent between the inflammatory odontogenic lesions of the jaws. These three lesions are caused by the necrosis of the pulp but are very different between each other from an histological point of view and they can correspond to different stages of the same pathological process considering the fact that from a granuloma can arise a periapical abcess or a radicular cyst and from a radicular cyst and abcess can originate. About these three pathological processes we discuss in this article the clinical, radiographical, ethiological, microscopical features, we suggest the treatment and the differential diagnosis.

An irradiation device for the continuous and accurate in-pile measurement of fission enhanced creep in ceramic nuclear fuels has been designed and operated. The specimen stack was a hollow cylinder of 0.7 by 1 cm diameter and 2 cm gauge length, doubly contained, with sodium bonding in the inner container. The operational parameters were variable up to a fission rate of 5 × 10 13 cm −3 sec −1 , a temperature of 1100°C and a compressive stress of 70 MNm−2. The strain was measured differentially on the gauge length by an inductive transducer. The device performed satisfactorily during one year of inpile operation. Deformations due to creep and swelling were measured at different stresses and temperatures on uranium nitride specimens. Routine measurements of deformations due to thermal expansion, and elastic strain at ambient and high temperature have proven the reliability and accuracy of the measuring and loading systems.

This paper presents a study of the natural circulation heat transfer to water flowing under supercritical pressures. Flow oscillations occurred when crossing the critical state, both from the compressed liquid region and from the supercritical vapour region. The threshold was found to correspond to the outlet film temperature, being close to the transposed critical value. Differential pressure fluctuations with frequencies of 25–60 Hz were encountered. These vibrations are generated in the heated section and propagate in the system when resonance occurs. The heat transfer data, when compared with available forced circulation correlations, showed the need for a new correlation having smaller exponents of Reynolds and Prandtl numbers. This was attributed to the power-dependence of flow rate.

Adrenal feminizing tumours are rare but frequently malignant. A case of adrenal feminizing tumour in a 35-year-old man, which presented with gynaecomastia and infertility due to azoospermia, without loss of libido and sexual potency is reported in this paper. Our patient represents a relatively unusual case. The long free interval from the excision allows us to consider the patient cured as despite the pathological malignant features of the neoplasm.

The literature on the medical management of pancreatitis is reviewed. Reference is made to successful results obtained in 30 personal cases with a semimedicamentous protocol, in which an antipancreatitic activity in the true sense was obtained by administering aprotinine and glucagon. Eight subjects presented acute or recrudescent chronic forms, 12 pancreatitis combined with cholelithiasis, 5 secondary forms following penetrating duodenal ulcers, and 5 forms arising after stomach, duodenal or bile duct surgery. The evaluation of each case is described and the conclusion is drawn that intensive, timely medical therapy will secure resolution in the majority of cases.

A double-blind trail was performed to investigate the effects of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, on host defenses and its efficacy in reducing the number of exacerbation in 29 evaluable patients with chronic bronchitis, out of 36 patients who entered the study. The drug enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes. Increased candidacidal activity of monocytes was also observed. These effects, already detectable after one course of therapy and during the entire period of treatment, were no longer detectable when tested 6 months after the end of treatment. A significantly (p less than 0.05) larger number of patients in the treated group than in the placebo group had no exacerbations during drug administration (0-3 months). Moreover, patients treated with RU 41740 had significantly fewer and shorter episodes of acute exacerbation. The positive decreases in these two parameters persisted throughout the follow-up.

We studied the effects of rifamycin SV, rifampicin and rifapentine on human phagocyte functions. Rifamycins inhibited in vitro neutrophil chemotaxis in the range of their therapeutic levels, and they significantly affected the survival of a rifamycin-sensitive strain of Staphylococcus aureus inside human monocytes. Both effects were related to the intraphagocytic penetration of these antibiotics. For the ex vivo studies, 600 mg of rifampicin were orally administered to five subjects with defective S. aureus killing. A significant reduction of neutrophil chemotaxis and increased activity against S. aureus were shown 150 and 210 min after administration of the drug.