The effect of the acute phase of infection on absorption of and exposure to orally administered antibiotics in non-critically ill, hospitalized patients.

OBJECTIVES: During the acute phase of infection, IV antibiotics are preferred to ensure adequate systemic exposure. To assess whether adequate exposure may also be achieved with oral antibiotics, we investigated exposure to oral antibiotics and PTA during the acute phase of infection and after defervescence. METHODS: We enrolled hospitalized, non-critically ill febrile patients treated with IV antibiotics other than amoxicillin or ciprofloxacin. The study consisted of two visits: when patients had received <24 h IV treatment; and when patients had become afebrile. On both visits, patients received one additional dose of 750 mg amoxicillin, or 500 mg ciprofloxacin, depending on the presumed infection, after which serial blood samples were obtained. The primary endpoint was the ratio of the AUC during the febrile and the afebrile phase. The AUCs were considered to be equivalent when the ratio of the mean AUCs and its 90% CI was contained within the acceptance interval of 80%-125%. The secondary endpoint was PTA. RESULTS: Forty-four patients (15 amoxicillin, 29 ciprofloxacin) completed both study visits. The median time between the two study visits was 65.8 h (range 33.8-427.4). The ratio of the mean AUCs (study visit 1/study visit 2) was 97% (90% CI of 80%-117%) for amoxicillin and 112% (90% CI of 108%-116%) for ciprofloxacin. The PTA for amoxicillin and ciprofloxacin did not differ between the two phases and was adequate to treat common pathogens. CONCLUSIONS: The acute phase of infection in non-critically ill febrile patients does not influence the exposure to, or PTA of, orally administered amoxicillin and ciprofloxacin. This might justify earlier IV-to-oral switching.

Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics.

BACKGROUND: In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies have revealed that tumor types can be predicted based on distinct patterns of somatic variants and other genomic characteristics. Moreover, actionable genomic events are present in almost half of CUP patients. This study investigated the clinical value of whole genome sequencing (WGS) in terms of primary tumor identification and detection of actionable events, in the routine diagnostic work-up of CUP patients. PATIENTS AND METHODS: A WGS-based tumor type 'cancer of unknown primary prediction algorithm' (CUPPA) was developed based on previously described principles and validated on a large pan-cancer WGS database of metastatic cancer patients (>4000 samples) and 254 independent patients, respectively. We assessed the clinical value of this prediction algorithm as part of routine WGS-based diagnostic work-up for 72 CUP patients. RESULTS: CUPPA correctly predicted the primary tumor type in 78% of samples in the independent validation cohort (194/254 patients). High-confidence predictions (>95% precision) were obtained for 162/254 patients (64%). When integrated in the diagnostic work-up of CUP patients, CUPPA could identify a primary tumor type for 49/72 patients (68%). Most common diagnoses included non-small-cell lung (n = 7), gastroesophageal (n = 4), pancreatic (n = 4), and colorectal cancer (n = 3). Actionable events with matched therapy options in clinical trials were identified in 47% of patients. CONCLUSIONS: Genome-based tumor type prediction can predict cancer diagnoses with high accuracy when integrated in the routine diagnostic work-up of patients with metastatic cancer. With identification of the primary tumor type in the majority of patients and detection of actionable events, WGS is a valuable diagnostic tool for patients with CUP.

[Adaptation to changing needs in mental health care: mental health centers]. / Aanpassing aan veranderende zorgbehoefte in de ggz: mentale gezondheidscentra.

BACKGROUND: The increasing healthcare needs in the Netherlands lead to increasing healthcare costs and waiting lists and warrants sufficient (staff-)capacity. The current market-driven organization of care affects qualitative, accessible, and affordable care. Whether the Dutch mental healthcare system can adapt efficiently is questioned in this article. AIM: Gaining insight into the developments and bottlenecks that can contribute to the realization of appropriate care in mental health. METHOD: An overview of literature is given regarding developments and necessary adjustments in mental healthcare. RESULTS: Appropriate care is value-driven, focused on health (instead of the absence of illness), based on management of health of the client and his network, is accessible, affordable and is offered at the right time and place. The collaborative innovation of Mental Healthcare Centers, in which GGz Breburg (specialized mental health care), Indigo Brabant (general mental health care), and health insurance company, form a sustainable coalition which is presented as a solution for manageability of the mental healthcaresystem. This coalition aims to improve the public values of mental healthcare as a response to the required paradigm shift and future model of mental healthcare. CONCLUSION: As a regional network model, the Mental Healthcare Centers offer a desirable answer to the demand for an appropriate and future-proof mental healthcare. w.

Short-term prednisolone therapy has minimal impact on calcium metabolism in dogs with atopic dermatitis.

Glucocorticoids (GCs) are a large group of drugs used to treat a range of inflammatory, autoimmune and neoplastic diseases in dogs. Glucocorticoids have been linked to disturbances in calcium metabolism and skeletal disorders in humans, yet their effects at therapeutically effective dosages in dogs with spontaneous diseases are poorly understood. Serum concentrations of calcium, phosphate, vitamin D metabolites and plasma concentrations of parathyroid hormone and ionised calcium together with urinary fractional excretion of calcium and phosphate, were measured in 16 dogs with atopic dermatitis before and 6 weeks after standard dosage prednisolone treatment (0.93-1.06 mg/kg) every other day after 7 days of treatment with the same dosage once daily. The severity of their physical signs, as assessed by the canine atopic dermatitis extent and severity index version 3 (CADESI-03) and the Edinburgh Pruritus Scale (EPS), decreased in all dogs following prednisolone treatment. There was no significant difference in any of the biochemical parameters measured following prednisolone treatment. This study indicates that prednisolone, used at a therapeutically effective dose, has minimal impact on calcium metabolism in dogs with atopic dermatitis.

Mental health recovery: evaluation of a recovery-oriented training program.

AIM: This study investigates the effectiveness of a recovery-oriented training program on knowledge and attitudes of mental health care professionals towards recovery of people with serious mental illness. METHODS: Using data from a longitudinal study of recovery, changes in knowledge and attitudes of 210 mental health care professionals towards recovery were explored using the Recovery Attitude Questionnaire and the Recovery Knowledge Inventory. The study uses a two-group multiple intervention interrupted time-series design which is a variant of the stepped-wedge trial design. A total of six measurements occasions took place. RESULTS: This study shows that professionals' attitudes towards recovery from mental illness can improve with training. After two intensive recovery-oriented training sessions, mental health care professionals have a more positive attitude towards recovery in clinical practice. CONCLUSION: A recovery-oriented training program can change attitudes of mental health care professionals towards recovery of serious mental illness.

Evaluation of a human generic formulation of ciclosporin in the treatment of canine atopic dermatitis with in vitro assessment of the functional capacity of phagocytic cells.

To compare the efficacy, tolerability and safety of a generic formulation of ciclosporin for human beings with prednisone in the treatment of canine atopic dermatitis), human generic ciclosporin A (hgCsA) (5 mg/kg daily) and prednisone (1 mg/kg daily for seven days, followed by 1 mg/kg every second day) were administered to 13 and seven dogs with atopic dermatitis, respectively, for 42 days. Skin changes were assessed using a modified canine atopic dermatitis extent and severity index (mCADESI-01) and a pruritus intensity scale system. The in vitro functional capacity of phagocytic cells was assessed using the tetrazolium reductase activity and zymosan-stimulated tetrazolium reductase activity tests, as well as measurements of the percentage phagocytic activity and the ingestion capacity of phagocytic cells. Haematological and biochemical parameters were also monitored. There was a greater than or equal to 50 per cent reduction from the baseline in mCADESI-01 scores in 84.6 and 100 per cent of dogs, and a greater than or equal to 50 per cent reduction from the baseline in pruritus scores in 76.9 and 85.7 per cent of dogs, treated with hgCsA and prednisone, respectively. No important adverse physical, haematological or biochemical effects occurred with either drug and no statistically significant changes were detected in any of the four tests assessing the functional activity of phagocytes. The generic formulation of ciclosporin was effective in reducing the severity of physical signs of canine atopic dermatitis and was well tolerated.

Infestation of sheep with Psoroptes ovis, the sheep scab mite, results in recruitment of Foxp3(+) T cells into the dermis.

Regulatory T cells (Tregs) play a central role in maintenance of immune homeostasis by controlling harmful immune responses to inappropriate antigens and are thought to play a key role in modulating hypersensitivity reactions. Infestation of sheep with Psoroptes ovis results in a pronounced cutaneous hypersensitivity-type response, which appears to be crucial for mite survival. We hypothesize that (i) Tregs are involved in sheep scab lesions and (ii) Treg responses may crucially affect lesion development and subsequent mite survival. Foxp3 is a key transcription factor required for generation and maintenance of Tregs in rodents and humans, and is the most widely used marker for Tregs in these species. In this study, we sequence ovine foxp3 and show that it exhibits a high degree of homology with foxp3 from other species. Using a validated immunohistochemical staining technique, we demonstrate that infestation of sheep with P. ovis results in an influx of Foxp3(+) T cells into the skin. Future work will investigate the regulatory function of ovine Foxp3(+) T cells and determine whether the quality of the Treg response to P. ovis plays a role in individual susceptibility to the mite.

A review of the current literature on management of halitosis.

Halitosis is an unpleasant or offensive odour, emanating from the oral cavity. In approximately 80% of all cases, halitosis is caused by microbial degradation of oral organic substrates. Major degradation products are volatile sulphur-containing compounds. In this review, the available management methods of halitosis and their effectiveness and significance are presented and discussed. Undoubtedly, the basic management is mechanically reducing the amount of micro-organisms and substrates in the oral cavity. Masking products are not, and antimicrobial ingredients in oral healthcare products are only temporary effective in reducing micro-organisms or their substrates. Good short-term results were reported with chlorhexidine. Triclosan seems less effective, essential oils and cetylpyridinium chloride are only effective up to 2 or 3 h. Metal ions and oxidizing agents, such as hydrogen peroxide, chlorine dioxide and iminium are active in neutralizing volatile sulphur-containing compounds. Zinc seems to be an effective safe metal at concentrations of at least 1%. The effectiveness of active ingredients in oral healthcare products is dependent on their concentration and above a certain concentration the ingredients can have unpleasant side effects. Tonsillectomy might be indicated if (i) all other causes of halitosis are managed properly; (ii) halitosis still persists and (iii) crypts in tonsils are found to contain malodorous substrates.

Focal metatarsal sinus tracts in a Weimaraner successfully managed with ciclosporin.

Focal metatarsal sinus tracts ('fistulation') are, to the authors knowledge, reported for the first time in a Weimaraner. The six-year-old, entire male had a five-month history of two symmetrical, well-demarcated sinuses on the plantar aspect of each metatarsus. The area surrounding each pair of sinuses was slightly fluctuant and a serosanguineous discharge could be expressed. Cytological examination of the discharge was characteristic of pyogranulomatous inflammation. Bacterial culture showed the material to be sterile. Examination of a skin biopsy revealed a severe inflammatory reaction involving the dermal collagen, with an infiltrate of neutrophils, macrophages, lymphocytes, plasma cells and multi-nucleated giant cells, with some micro-pustule formation. Treatment with ciclosporin induced total remission. Reduction of the dose of ciclosporin resulted in recurrence of the physical signs with further remission on re-introduction of the original dosage. This is the first report of the use of ciclosporin to control this condition.

Significance of donor anuria differs between monoamniotic and diamniotic twin-twin transfusion syndrome.

Development of severe twin-twin transfusion syndrome (TTTS) in diamniotic-monochorionic twins includes five stages of increasing severity, i.e. recipient polyhydramnios and donor oligohydramnios, donor anuria, abnormal umbilical flow velocities in either twin, hydrops in the recipient, and intrauterine fetal death (IUFD) in either or both twins. In a severe case of TTTS in monoamniotic twins we observed donor anuria to appear after hydrops in the recipient. We conclude that donor anuria is a late and serious symptom in monoamniotic TTTS.

Immune responses to Staphylococcus aureus and Psoroptes ovis in sheep infected with P. ovis--the sheep scab mite.

In sheep, lesions caused by Psoroptes ovis, the sheep scab mite, may become colonized by Staphylococcus aureus. The present study compares clinical signs, lesional area and the immune response to P. ovis and S. aureus in P. ovis-infested sheep with and without secondary S. aureus infection. No differences were detected in the clinical signs or lesional areas in the S. aureus-positive and -negative sheep. However, 6 weeks after infestation an IgG but not IgE isotype antibody response to S. aureus was detected in the S. aureus-positive but not the S. aureus-negative group of sheep. This response targeted S. aureus antigens with molecular weights of approximately 36, 38, 50 and 65 kDa. In addition, 6 weeks after infestation an IgE response to P. ovis was detected in the S. aureus-positive but not the S. aureus-negative group of sheep.

[Late presentation of congenital diaphragmatic hernia]. / Late presentatie van aangeboren hernia diaphragmatica.

A boy aged 6 months and a girl aged 9 months were admitted due to vomiting, among others, and a boy aged 11 months due to pneumonia. It turned out that they had a congenital diaphragmatic hernia. Primary operative repair was performed successfully in all patients, followed by recovery. The older boy experienced a relapse nearly 1 year later, which was treated by surgical correction. Most congenital diaphragmatic hernias present directly after birth, with cyanosis and respiratory distress. However, 10-20% of the cases are discovered after this period. In these children diagnosis can be difficult because of the diverse symptoms such as vomiting, feeding difficulties, tachypnoea or recurrent respiratory tract infections. Physical signs include the absence of breath sounds or the presence of bowel sounds in the chest. Chest X-ray, contrast upper gastrointestinal series or ultrasound imaging confirms the diagnosis. Delay in treatment can lead to complications such as necrosis of the bowel. In young children with acute or chronic respiratory infections or gastrointestinal complaints, a congenital diaphragmatic defect should be considered.

Characterisation of lesional infiltrates of dendritic cells and T cell subtypes during primary infestation of sheep with Psoroptes ovis, the sheep scab mite.

Earlier studies of cattle and sheep have demonstrated that Psoroptes ovis infestations provoke an intense immunoinflammatory response dominated by eosinophils accompanied by a substantial infiltrate of lymphocytes. However, the kinetics of the lymphocyte response and the subtypes involved have not been characterised. We employed two groups of sheep to investigate the early (1-21 days) and later (21-63 days) infiltration of lymphocyte subpopulations and dendritic cells in primary infestations of sheep with P. ovis. Immunohistochemistry indicated that by 4 days after infestation numbers of CD4+ and CD45RA+ cells in lesional skin had increased significantly (P<0.03 and P<0.005, respectively) and that a significant increase in gammadelta T cells and dendritic cells (CD1b+) had occurred by 8 days (P<0.02 and P<0.01, respectively). Numbers of lymphocyte and dendritic cells declined from 49 to 63 days after infestation. Our observations suggest that mite-derived products exert a profound influence on the early recruitment of lymphocytes that may significantly influence the genesis of the adaptive immune response.

Early innate and longer-term adaptive cutaneous immunoinflammatory responses during primary infestation with the sheep scab mite, Psoroptes ovis.

Clinical observation has indicated that Psoroptes ovis mites provoke cutaneous inflammation within hours of experimental infestation, but the nature of this reaction has not been described. After infestation of naive sheep with ovigerous P. ovis mites, significant influxes of eosinophils (P<0.004) and neutrophils (P<0.001) were detected within 24 h. A significant (P<0.001) increase in mast cell numbers was observed by 96 h post-infestation. In addition, marked degenerative and proliferative epidermal lesions were evident 24 and 96 h, respectively, after infestation. The influence of the later, adaptive response on the cellular infiltrate at the advancing margin of the lesion and the original site of infestation was also monitored. Mast cell numbers were greatest at 21 days while recruitment of eosinophils and neutrophils was maximal 63 days after infestation. Lesional severity was particularly pronounced from 42 to 63 days after infestation, but significant resolution had occurred by 84 days. Pathological changes at the advancing margin of the lesion were more severe than at the initial site of infestation, and this was reflected by the numbers of mites present. These data suggest that P. ovis elicits an early innate cutaneous response that is subsequently augmented by the development of an adaptive immune response, the intensity of which corresponds to the local population density of mites.

Dermatitis and lymphadenitis resembling juvenile cellulitis in a four-year-old dog.

A four-year-old, entire male toy poodle was presented with a two-and-a-half-week history of ocular discharge progressing to periorbital alopecia, depigmentation, alopecia and ulceration around the muzzle. There was also a haemorrhagic discharge from the ears, pyrexia, lethargy and generalised lymphadenopathy. The clinical, cytological, bacteriological and histopathological findings were consistent with a diagnosis of dermatitis resembling juvenile cellulitis in an adult dog. Glucocorticoid therapy led to rapid resolution of the clinical signs and the dog has remained in remission for two years after cessation of treatment.

Identification of tropomyosin, paramyosin and apolipophorin/vitellogenin as three major allergens of the sheep scab mite, Psoroptes ovis.

Analysis by one-dimensional (1-D) SDS-PAGE/Western blotting of whole mite extract (larval and adult stages) with sheep sera taken 0-84 days after infection with the sheep scab mite, Psoroptes ovis revealed a progressive IgE antibody response, with a dominant high molecular weight allergen (MW 180 kDa) detected early during infection. Further analysis by two-dimensional (2-D) SDS-PAGE/Western blotting with post-infection sera, revealed a more complex picture with numerous (> 20) IgE reactive spots. Trypsin digest and Maldi-ToF analyses of these spots identified two house dust mite allergen homologues, namely tropomyosin (Der p 10) and paramyosin (Der p 11), and analysis of a third spot indicated an apolipoprotein-like IgE reactive protein (Der p 14). Further 1-D and 2-D SDS/Western blotting, with specific antibodies to the house dust mite allergens Der p 10, 11, and to the IgE reactive peptide of the high molecular weight house dust mite allergen, Der p 14 (vitellogenin/apolipophorin), provided firm evidence for the presence of these three allergens in extracts of the Psoroptes mite. These studies show for the first time that homologues of the house dust mite 10, 11 and 14 group allergens are represented as immunodominant allergens of the sheep scab mite, and may represent important vaccine candidates.

Cutaneous hypersensitivity reactions to Psoroptes ovis and Der p 1 in sheep previously infested with P. ovis--the sheep scab mite.

We have previously shown that infestation with Psoroptes ovis induces an IgE response and intense tissue eosinophilia, typical of a Type I hypersensitivity response [Parasite Immunol. 22 (2000) 407]. Intradermal tests (IDSTs) suggest that there are also delayed and Arthus-type responses to this parasite. In order to study the nature of ovine cutaneous reactions to P. ovis, naïve controls and experimentally infested sheep (n = 5) were challenged intradermally with mite antigen. Challenge elicited immediate (P < 0.001) and delayed (P < 0.005) wheal reactions in sensitised sheep. At 6 (P < 0.02) and 30 h (P < 0.001) the predominant infiltrating cells were eosinophils. To explore the role of circulating antibodies, naïve sheep (n = 5) were subjected to Prausnitz-Kustner (PK) tests. These elicited immediate (P < 0.02) but not delayed wheal reactions. At 6 h eosinophils (P < 0.001) dominated the infiltrate. These results suggest that P. ovis allergens provoke an IgE-dependent immediate and late phase response and a cell-mediated eosinophil-rich delayed-type hypersensitivity response (ER-DTH).

Temporal pattern of isotype-specific antibody responses in primary and challenge infestations of sheep with Psoroptes ovis--the sheep scab mite.

In sheep Psoroptes ovis provokes an allergic dermatitis with significant P. ovis antigen-specific IgE responses. The kinetics of the IgE response to primary and challenge infestations of P. ovis were reported earlier [Parasite Immunol. 22 (2000) 407]. The present study examines IgG, IgM and IgA responses to primary and challenge infestations of P. ovis and the profile of antigens/allergens reacting with IgG and IgE antibodies. Antigen-specific enzyme-linked immunosorbent assays (ELISAs) demonstrate that primary infestations elicited significant increases in levels of IgG and IgM but not IgA antibodies. IgG and IgM responses to primary and challenge infestations were not significantly different. Western blots of reduced P. ovis proteins indicate that IgG antibodies reacted with five major antigens following primary infestation and only three of these after challenge infestation. IgE antibodies bound to three major and five minor allergens after primary infestation and two additional minor allergens after challenge infestation. Immunodominant antigens >100 and <15 kDa and allergens >100 kDa were most consistent in stimulating substantial IgG and IgE antibody responses, respectively. These antigens/allergens may be exploited in immunodiagnosis and modulation of the host immune response.

Treatment of fibroadenomatous hyperplasia in cats with aglépristone.

Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of mammary stroma and duct epithelium of 1 or more glands and predominantly affects younger female cats. Endogenous progesterone and exogenous progestogens play an important role in the genesis of FAH. The presence of progesterone receptors in fibroadenomatous tissue allows for targeted endocrine therapy with progesterone receptor blockers. We report on 22 young cats with FAH, none of which had responded to the withdrawal of progestogens or ovariectomy. The common signs were tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16 cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with subcutaneous injections of the progesterone receptor blocker aglépristone on 1 (7 cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but 1 cat responded with a complete and lasting remission of signs after 1-4 weeks of treatment. Two cats had a short-term skin irritation at the site of the aglépristone injection. Two pregnant cats with FAH aborted after treatment with aglépristone and subsequently developed endometritis. In conclusion, the results of this study demonstrate that FAH in cats can be treated successfully with the progesterone receptor blocker aglépristone.