Effect of care transfer model led by the hospital clinical pharmacist on reduction of hospital readmissions in the elderly.

Transfer of care is a critical point for patient safety and requires an optimal care transfer model in order to ensure safe pharmacotherapy transfer. Polypharmacy among elderly is associated with adverse health consequences such as hospital readmissions. Hospital readmissions represent priorities in health care research and are one of the measures for assessing patient safety. Medication-related problems among elderly are associated with polypharmacy. The aim of the study was to show the impact of a developed model of care transfer led by a hospital clinical pharmacist on the number of hospital readmissions in the 12-months period in the elderly. A randomized controlled study of patients aged 65 or more was conducted at Dubrava University Hospital, Community Health Centre Zagreb - East and community pharmacies in the City of Zagreb and Zagreb County, Croatia. An intervention group received specially designed care transfer led by the hospital clinical pharmacist. Model included high-intensity pharmacotherapy interventions delivered at admission, during hospital stay and discharge, transition to primary care and post-discharge and cooperation between all healthcare professionals. In all, 182 patients in the intervention and 171 in the control group were analysed. The total number of hospital readmissions and emergency readmissions, within one year from the hospital discharge, was lower in the intervention group than in the control group (41.7% vs. 58.3%, p=0.005; 40.8% vs. 59.2%, p=0.008). The model of the health care transfer applied in this research thus significantly reduced hospital readmissions in the 1-year period in elderly patients. Therefore, the hospital clinical pharmacists should design and coordinate the transfer between hospital and primary care.

PRIMARY HYPERPARATHYROIDISM DETECTED BY PARATHYROID INCIDENTALOMA: CLINICAL FEATURES, WORK-UP AND MANAGEMENT.

CONTEXT: With the widespread use of neck ultrasound, parathyroid incidentaloma (PI) emerges as an additional opportunity for incidental detection of primary hyperparathyroidism (PHPT). OBJECTIVE AND DESIGN: This study aimed to investigate PHPT cases detected by PI and to compare them with other PHPT patients. A retrospective analysis of newly diagnosed PHPT patients between 2014 and 2020 was conducted in our hospital. SUBJECTS AND METHODS: The cohort of 124 subjects was divided in two groups: 22 (17.7%) PHPT patients detected by PI (PI PHPT group) and the rest of 102 PHPT patients (non-PI PHPT group). Overall, 21 PIs were discovered on ultrasound and one was found during thyroid surgery. Clinical features, work-up and management of two study groups were compared. RESULTS: The PI PHPT group had lower ionized calcium at diagnosis (p=0.034), lower peak serum calcium during follow-up (p<0.01), less fractures (p=0.022) and was less likely to meet the international criteria for parathyroidectomy (p<0.01). Positive sestamibi scan (p=0.022) and confirmed concordant localization in at least two different parathyroid imaging techniques (p=0.033) were more likely in the PI PHPT group. The frequency of surgical management did not differ between groups. CONCLUSIONS: PHPT detected by PI is clinically relevant and mostly comparable to PHPT in other patients with some features that correspond more often to a mild disease. Higher rate of positive preoperative localization in PHPT detected by PI might encourage parathyroidectomy even without the international criteria met.

Incidence of potential drug interactions in co-prescription of statins and macrolide antibiotics in Croatia during the 14 year period.

The objective of this study was to determine the number of patients on the national level that took macrolide antibiotics along with chronic statin therapy in Croatia in the period from 2002 to 2015, and to analyse prescription patterns. In 2002, statins were used in the treatment of 2.6% of the total number of insured persons in Croatia. By 2015, this number increased to 8.4%. In the period studied, on average 15.3% of the patients on statin therapy were co-prescribed macrolide antibiotics. Erythromycin was combined with different statins on average in 1.4% of cases, clarithromycin in 25.5% and azithromycin in 73.2% of the cases. Relative frequency of combining statins with macrolides was similar for all statins. On average, 11.5% of patients on concomitant statin-macrolide therapy were taking high-dose statins. On average, 90% of these co-prescriptions can lead to potentially clinically significant DDIs (X, D, C). The co-prescription of statins and macrolide antibiotics in the Republic of Croatia is increasing. The greatest number of co-prescriptions with macrolides were with atorvastatin and simvastatin.

Impact of ceftriaxone de-restriction on the occurrence of ESBL-positive bacterial strains and antibiotic consumption.

As a cost-saving measure, the Drug and Therapeutics Committee (DTC) removed ceftriaxone from the list of restricted antibiotics in May, 2008, which permitted its use as a first-line antibiotic. To evaluate the impact of this change, the occurrence of extended-spectrum beta-lactamase (ESBL)-positive bacterial strains and antibiotic consumption were monitored for 2 years before and after the intervention. In the post-intervention period, ceftriaxone utilization increased, while total antibiotic utilization did not change significantly. The utilization of all restricted antibiotics decreased (p <0.05) in the post-intervention period. Utilization of carbapenems increased (p <0.05), while utilization of quinolones increased nonsignificantly. The density of resistant ESBLs increased (p = 0.001) from 0.99 to 1.34 per 1000 bed-days from the pre- to the postintervention period. Ceftriaxone use was significantly correlated with ESBL occurrence (p <0.005). It can be concluded that ceftriaxone de-restriction increased the occurrence of ESBLs and the utilization of carbapemens.

Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis.

Wegener's granulomatosis (WG) is a life-threatening autoimmune vasculitis that affects lungs, kidneys and other organs. A hallmark of WG is the presence of classic anti-neutrophil cytoplasmic antibodies (c-ANCA) against self-proteinase 3 (PR3). Little is known about the role of these antibodies and PR3-specific immune responses in disease development. In this study, we demonstrate that PR3-specific autoimmune responses are pathogenic in non-obese diabetic (NOD) mice with an impaired regulatory arm of the immune response. Immunization of autoimmunity prone NOD mice with rmPR3 (recombinant mouse PR3) in complete Freund's adjuvant (CFA) resulted in high levels of c-ANCA, without detectable disease development. However, when splenocytes from these immunized mice were transferred into immunodeficient NOD-severe combined immunodeficiency (SCID) mice, the recipient mice developed vasculitis and severe segmental and necrotizing glomerulonephritis. No disease developed in NOD-SCID mice that received splenocytes from the CFA-alone-immunized donors (controls), indicating that disease development depends upon PR3-specific immune responses. In contrast to the pathology observed in NOD-SCID mice, no disease was observed when splenocytes from rmPR3-immunized C57BL/6 mice were transferred into immunodeficient C57BL/6-RAG-1(-/-) mice, suggesting that complex and probably multi-genetic factors play a role in the regulation of disease development.

Leukocytoclastic vasculitis associated with insulin aspart in a patient with type 2 diabetes.

OBJECTIVE: To report a case of leukocytoclastic vasculitis associated with insulin aspart therapy. CASE SUMMARY: A 56-year-old man was admitted to the Department of Endocrinology because of a poorly controlled Type 2 diabetes. In an attempt to reach a tight blood glucose control, an intensive diabetes management consisting of one evening dose of intermediate-acting NPH insulin and three preprandial doses of short-acting insulin aspart was introduced. Two weeks following insulin aspart introduction the patient developed palpable purpura on distal parts of the upper and lower limbs. Four days after the onset of purpura, a skin biopsy was preformed. Histological examination showed vasculitis with perivascular infiltrates of lymphocytes and erythrocyte extravasation. Direct immunofluorescence was negative. On the day the purpuric eruptions appeared, insulin aspart was substituted with regular human insulin. All skin lesions disappeared spontaneously within 8 days. Insulin aspart was not re-administered. DISCUSSION: Other possible causes of vasculitis in this case were excluded by diagnostic tests. The temporal relationship between the insulin aspart administration and the occurrence of purpura, with no further episodes of skin eruptions after discontinuation of the drug, support the hypothesis of an insulin aspart caused vasculitis. Based on the Naranjo's algorithm, the adverse drug reaction could be considered possible. CONCLUSION: Clinicians should be aware of the possibility of leukocytoclastic vasculitis occurring during insulin aspart treatment.

The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK.

MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

Differential expression of inducible costimulator-ligand splice variants: lymphoid regulation of mouse GL50-B and human GL50 molecules.

The process of immunological costimulation between APC and T cells is mediated by protein ligand:receptor interactions. To date, costimulatory receptors known to be expressed by T cells include the structurally related proteins CD28 and the inducible costimulator (ICOS). The ligands to human and mouse ICOS, human GL50 (hGL50), and mouse GL50 (mGL50) were recently cloned and demonstrated to have sequence similarity to the CD28 ligands B7-1 and B7-2. Examination of mGL50 cDNA transcripts by 3'RACE revealed an alternatively spliced form, mGL50-B, that encoded a protein product with a divergent 27-aa intracellular domain. Both mGL50- and mGL50-B-transfected cells exhibited binding to human and mouse ICOS-Ig fusion protein, indicating that the alternate cytoplasmic domain of mGL50-B does not interfere with extracellular interactions with ICOS receptor. Flow cytometric and RT-PCR analysis of BALB/c and RAG1(-/-) mice splenocytes demonstrate that freshly isolated B cells, T cells, macrophages, and dendritic cells express both splice variant forms of ICOS ligand. Comparative analyses with the human ICOS ligand splice variants hGL50 and B7-H2 indicate that differential splicing at the junction of cytoplasmic exon 6 and exon 7 may be a common method by which GL50-ICOS immunological costimulatory processes are regulated in vivo.

Monoclonal antibodies against maternal major histocompatibility complex class I molecules induce rapid abortion in mice.

PROBLEM: The role of antibodies against fetal or maternal antigens in maintaining or losing pregnancy is not clear. METHOD OF STUDY: Term-pregnant mice were injected with monoclonal antibodies against only fetal or fetal and maternal major histocompatibility complex class I molecules. The development of pregnancy was then followed. RESULTS: Antibodies against maternal, but not fetal, major histocompatibility complex class I molecules induced abortion in mice. The abortion occurred 6-8 hr after the administration of autoreactive antibodies. The abortion could only be induced after the formation of placenta. Antibodies against tumor necrosis factor-alpha could not prevent or postpone the abortion. Extensive bleeding has been detected in the placenta of aborting mice 3 hr after the administration of the antibodies. CONCLUSIONS: This study indicates that autoreactive antibodies present risk for pregnancy and that the damage leading to abortion induced by such antibodies most likely occurs at the maternal side of placenta.

Anthropological aspects of alcohol consumption and alcohol related problems.

Authors believe that drinking alcoholic beverages can be associated with customs and habits specific to small communities, societies and even entire nations. The primary family, as the foundation of customs and habits of the first generation, has a role in stimulating drinking and alcoholism. The authors have examined some sociocultural factors, mostly taking into consideration relations in the primary family, by means of a questionnaire filled out by alcoholics (N = 200) and non-alcoholics (N = 100). The alcoholics usually have their first drink earlier, start drinking regularly earlier, and in the primary family there is a high tolerance towards the use of alcoholic beverages. The authors believe that the prevention should be directed primary towards the primary family with a view to changing their customs and habits as well as attitudes towards the use of alcoholic beverages.

Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide.

Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is an animal model of paralyzing human disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alphabeta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paralysis is inhibited by prior intraperitoneal injection of the same peptide in incomplete Freund's adjuvant (IFA). In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA. Tolerance induction is equally efficient in Fas-deficient and IL-4-deficient TCR-transgenic mice, suggesting that neither activation-induced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells. We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.

Humoral stimulating activities in post-cyclophosphamide rat sera and their purified fractions.

Enhanced humoral, stimulating activities (HSAs) of post-cyclophosphamide (CY) sera and their purified fractions, acting on mitogen activated T-lymphocytes, were detected in Wistar rats after treatment by high single doses of the aplasia producing alkylating cytostatic drug CY. These activities, monitored in vitro, were partially purified from post-CY sera, collected 2, 4, and 7 days after treatment, yielding fractions with higher humoral stimulating activity. The preliminary purification included molecular cutting by Amicon-Diaflo filters (1-30 kDa pore size range) and gel-filtration on Sephadex G-50 and G-75. Results show that post-CY sera partially purified fraction (10-20 kDa), enhances the proliferation of hydrocortisone resistant (HCR) T-lymphocytes up to threefold under microculture conditions (P << 0.001); partially purified post-CY sera fraction (10-20 kDa) increases the proliferative response of T-cells in microcultures to the mitogenic 145-2C11 monoclonal antibody (mAb) up to tenfold (P << 0.001). These results show that the activity of stimulating factors is localized in the molecular weight range of 10-20 kDa.

The development and analysis of species specific and cross reactive monoclonal antibodies to leukocyte differentiation antigens and antigens of the major histocompatibility complex for use in the study of the immune system in cattle and other species.

We examined the potential of developing a set of species specific and cross reactive monoclonal antibodies (MoAbs) for use in the study of the phylogenetic and functional relation of class I and class II antigens of the major histocompatibility complex (MHC) and leukocyte differentiation antigens in cattle and other species. Comparing immunization strategies demonstrated the number of hybrids producing cross reactive antibodies can be increased by hyperimmunization of mice with lymphoid cells from multiple species. Comparing various methods of assay (antibody-complement mediated cytotoxicity [CT], enzyme linked immunosorbent assay [ELISA] and flow microfluorimetry [FMF]), revealed FMF is the most useful technique for the primary assay of hybridomas producing MoAbs of potential interest. By using dual parameter and dual fluorescence analysis, we could determine whether a given MoAb reacted with mononuclear cells (lymphocytes and monocytes) and/or granulocytes, and also whether any two MoAbs of different isotype and specificity recognized antigens present on identical or separate populations of leukocytes. Comparing the patterns of MoAb reactivity with leukocytes obtained from cows, goats, sheep, pigs, horses and humans, as well as comparing the patterns of reactivity with a panel of lymphoid cell lines derived from cattle (with enzootic bovine leukemia) and humans (with various forms of leukemia), revealed sets of MoAbs reactive with unique antigenic determinants present on BoLA class I (15 MoAbs) and class II (9 MoAbs) antigens, and also MoAbs reactive with determinants present on leukocyte differentiation antigens (36 MoAbs). Dual fluorescence analysis demonstrated the antigens detected by some MoAbs are predominantly expressed on one lineage of leukocytes while others are expressed on two or more lineages of leukocytes. Dual and single fluorescence analysis also demonstrated the PNA receptor(s) is: expressed on T cells, granulocytes and class II antigen monocytes and absent or expressed in low amount on sIgM+ B cells and a newly defined Non T/Non B population of cells. The strategies described for identifying and analyzing the specificity of MoAbs demonstrate the feasibility of developing a set of cross reactive MoAbs for identifying homologous molecules in multiple species and delineating their functional and phylogenetic relation.

Autocrine tumour growth regulation by somatomedin C: an in-vitro model.

A human primary haemangiosarcoma was derived from a patient with severe hypoglycaemia. Cell line established from that tumour secreted somatomedin C in serum-free culture media. Immunoreactive somatomedin from the media eluted from Sephacryl S-200 in two peaks of 160 000 and 8000 molecular weights. Similar results were obtained when medium was acidified and chromatographed on Sephadex G-50. Binding of tracer concentrations of 125I-labelled somatomedin C to human haemangiosarcoma cells was much higher than that of 125I-labelled insulin. Half-maximal displacement of 125I-labelled somatomedin C binding occurred at an unlabelled somatomedin C concentration of 0.7 nmol/l. Insulin competed with 125I-labelled somatomedin for binding to this receptor, but 150-fold more insulin was required for half-maximal displacement. Somatomedin secreted by human haemangiosarcoma cells and purified from serum-free media strongly stimulated [methyl-3H]thymidine incorporation into the DNA of these cells. Inhibition of somatomedin C secretion by cortisol resulted in the inhibition of tumour cell proliferation but stimulation of somatomedin secretion by human GH stimulated the cell proliferation rate. It appears that production of somatomedin C in human haemangiosarcoma cells plays a part in the regulation of tumour growth by an autocrine mechanism.