Phagosome-lysosome fusion is a calcium-independent event in macrophages.

Phagosome-lysosome membrane fusion is a highly regulated event that is essential for intracellular killing of microorganisms. Functionally, it represents a form of polarized regulated secretion, which is classically dependent on increases in intracellular ionized calcium ([Ca2+]i). Indeed, increases in [Ca2+]i are essential for phagosome-granule (lysosome) fusion in neutrophils and for lysosomal fusion events that mediate host cell invasion by Trypanosoma cruzi trypomastigotes. Since several intracellular pathogens survive in macrophage phagosomes that do not fuse with lysosomes, we examined the regulation of phagosome-lysosome fusion in macrophages. Macrophages (M phi) were treated with 12.5 microM bis-(2-amino-S-methylphenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethyl ester (MAPT/AM), a cell-permeant calcium chelator which reduced resting cytoplasmic [Ca2+]; from 80 nM to < or = 20 nM and completely blocked increases in [Ca2+]i in response to multiple stimuli, even in the presence of extracellular calcium. Subsequently, M phi phagocytosed serum-opsonized zymosan, staphylococci, or Mycobacterium bovis. Microbes were enumerated by 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining, and phagosome-lysosome fusion was scored using both lysosome-associated membrane protein (LAMP-1) as a membrane marker and rhodamine dextran as a content marker for lysosomes. Confirmation of phagosome-lysosome fusion by electron microscopy validated the fluorescence microscopy findings. We found that phagosome-lysosome fusion in M phi occurs noramlly at very low [Ca2+]i (< or = 20 nM). Kinetic analysis showed that in M phi none of the steps leading from particle binding to eventual phagosome-lysosome fusion are regulated by [Ca2+]i in a rate-limiting way. Furthermore, confocal microscopy revealed no difference in the intensity of LAMP-1 immunofluorescence in phagolysosome membranes in calcium-buffered vs. control macrophages. We conclude that neither membrane recognition nor fusion events in the phagosomal pathway in macrophages are dependent on or regulated by calcium

Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia

An open, randomized, multicenter study was conducted to compare the efficacy and safety of piperacillin/tazobactam and co-amoxiclav plus aminoglycoside in the treatment of hospitalized patients with severe community-acquired or nosocomial pneumonia. Of the 89 patients who entered the study, 84 (94%) were clinically evaluable. A favorable clinical response was observed in 90% of the piperacillin/ tazobactam group and in 84% of the co-amoxiclav/aminoglycoside group (not significant). The bacteriological efficacy was comparable in both groups (96% vs. 92%; not significant). There was only one fatal outcome in the piperacillin/tazobactam group compared to six in the co-amoxiclav/aminoglycoside group regimenP=0.058). The adverse event rate was non-significantly lower in the piperacillin/ tazobactam group compared to the co-amoxiclav/aminoglycoside group (2% vs. 7%;P=0.32). Piperacillin/tazobactam is safe and highly efficacious in the treatment of serious pneumonia in hospitalized patients. It compares favorably with the combination of co-amoxiclav/aminoglycosid

Successful Treatment of Disseminated Nocardiosis Complicated by Cerebral Abscess with Ceftriaxone and Amikacin: Case Report

We report the case of an 85-year-old female patient who suffered from disseminated Nocardia asteroides infection complicated by a cerebral abscess. Treatment with amikacin for 2 weeks and ceftriaxone for 6 weeks led to complete recovery, and there was no recurrence of disease over a follow-up period of 12 months after therapy. The use of ceftriaxone in combination with amikacin might significantly shorten the duration of treatment for patients with disseminated nocardiosis. This combination of antibiotics merits further investigation with use of a larger sample of patient

Der internistische Check-up

Zusammenfassung: Viele präventive Maßnahmen bei gesunden Erwachsenen werden in zunehmendem Maße durch Evidenz gestützt oder verworfen. Dabei sind v.a. die Beratung bezüglich Tabakabstinenz, indizierte Impfungen und das Screening in Bezug auf Übergewicht, hohen Blutdruck, Hyperlipidämie, Zervixkarzinom, kolorektales Karzinom und Mammakarzinom bewiesenermaßen wichtig und sinnvoll. Nicht empfohlen wird ein Screening für Bronchial-, Pankreas- und Ovarialkarzinom. Ein Screening für Diabetes mellitus beim jüngeren Erwachsenen, Schilddrüsenerkrankungen und Prostatakarzinom wird nicht routinemäßig empfohlen, sollte aber je nach persönlichem Risikoprofil im Sinne eines sog. "Case findings" erwogen werden. Aus ärztlicher Sicht ist es auch wichtig, auf mögliche nicht deklarierte Beweggründe für eine Check-up-Untersuchung einzugehen, um so mögliche "Hidden Agendas" der Konsultationen aufzudecke

Disseminated Tuberculosis Following Total Knee Arthroplasty in an HIV Patient

Skeletal tuberculosis is now uncommon in developed countries. In immunocompromised patients - particularly in the HIV-infected - who present with subacute or chronic joint pain refractory to conventional treatment, osteoarticular tuberculosis should still be included in the differential diagnosis. We report on a lethal case of disseminated tuberculosis in an HIV-infected subject. Dissemination may have resulted from the implantation of an articular prosthesis in a knee joint with unsuspected osteoarticular tuberculosis. The diagnosis was established months later when the patient presented with far-advanced tuberculous meningitis, miliary tuberculosis of the lungs, femoral osteomyelitis and extended cold abscesses along the femoral shaft. Failure to respond to a conventional four-drug regimen is explained by the resistance pattern of his multi-drug resistant strain of Mycobacterium tuberculosis, which was only reported after the patient's death. This case illustrates the diagnostic challenges of osteoarticular tuberculosis and the consequences of a diagnostic delay in an HIV-infected individua

Motivation and personality factors of Generation Z high school students aspiring to study human medicine

Background: A new generation of medical students, Generation Z (Gen Z), is becoming the predominant population in medical schools and will join the workforce in a few years’ time. Medicine has undergone serious changes in high-income countries recently. Therefore, it is unclear how attractive the medical profession still is for high school students of Gen Z. The aim of this study was to investigate what motivation leads Gen Z students in their choice to study human medicine, and how they see their professional future. Our study was guided by motivation theory and the influence of personality traits and other personal factors on students’ choice of university major. Methods: In a cross-sectional online survey, we included third- and fourth-year high school students in Northern Switzerland. We examined the importance of criteria when choosing a university major: personality traits, career motivation, life goals, and other considerations influencing the choice of human medicine versus other fields of study. Results Of 1790 high school students, 456 (25.5%) participated in the survey (72.6% women, mean age 18.4 years); 32.7% of the respondents aspired to major in medicine at university. For all respondents, the foremost criterion for selecting a field of study was ‘interest in the field,’ followed by ‘income’ and ‘job security.’ High school students aiming to study human medicine attached high importance to ‘meaningful work’ as a criterion; supported by 36.2% of those students answering that helping and healing people was a core motivation to them. They also scored high on altruism (p < 0.001 against all groups compared) and intrinsic motivation (p < 0.001) and were highly performance- (p < 0.001) and career-minded (p < 0.001). In contrast, all the other groups except the law/economics group had higher scores on extraprofessional concerns. Conclusions: Swiss Gen Z students aspiring to study human medicine show high intrinsic motivation, altruism, and willingness to perform, sharing many values with previous generations. Adequate work-life balance and job security are important issues for Gen Z. Regarding the current working conditions, the ongoing shortage of physicians, and recent findings on physicians’ well-being, the potential for improvement and optimization is high

The worse we feel, the more intensively we need to stick together: a qualitative study of couples’ emotional co-regulation of the challenge of multimorbidity

IntroductionBeing faced with multimorbidity (i.e., being diagnosed with at least two chronic conditions), is not only demanding in terms of following complicated medical regimes and changing health behaviors. The changes and threats involved also provoke emotional responses in the patients but also in their romantic partners. This study aims at exploring the ways of emotional co-regulation that couples facing multimorbidity express when interviewed together.MethodN = 15 opposite sex couples with one multimorbid patient after an acute health crisis that led to hospitalization were asked in a semi-structured interview about how they found ways to deal with the health situation, what they would recommend to other couples in a similar situation, and how they regulated their emotional responses. Interviews were analyzed qualitatively following open, axial, and selective coding, as in the grounded theory framework.ResultsEmerging categories from the romantic partners’ and the patients’ utterances revealed three main categories: First, overlapping cognitive appraisals about the situation (from fighting spirit to fatalism) and we-ness (construing the couple self as a unit) emerged as higher order factor from the utterances. Second, relationship-related strategies including strategies aimed at maintaining high relationship quality in spite of the asymmetric situation like strengthening the common ground and balancing autonomy and equity in the couple were often mentioned. Third, some couples mentioned how they benefit from individual strategies that involve fostering individual resources of the partners outside the couple relationship (such as cultivating relationships with grandchildren or going outdoors to nature).DiscussionResults underline the importance of a dyadic perspective not only on coping with disease but also on regulating the emotional responses to this shared challenging situation. The utterances of the couples were in line with earlier conceptualizations of interpersonal emotion regulation and dyadic perspectives on we-disease. They broaden the view by integrating the interplay between individual and interpersonal regulation strategies and underline the importance of balancing individual and relational resources when supporting couples faced with chronic diseases

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

Eosinophilia in patients infected with the human immunodeficiency virus

The prevalence and significance of peripheral blood eosinophilia in patients infected with the human immunodeficiency virus (HIV) were evaluated. Fifteen of 119 consecutive patients had absolute eosinophil counts of > 450/mm3. During a mean follow-up period of 419 days eosinophilia could be identified as secondary to a parasitic infection in only one patient. Correlation with disease stage showed a higher rate of advanced disease in patients with absolute eosinophilia. In a multivariate regression analysis, only low CD4+ cell counts, not the CDC disease stage or the use of antiretroviral therapy or primary prophylaxis, contributed significantly to the prevalence of eosinophilia. It is concluded that expen-sive laboratory investigations in asymptomatic patients with advanced-stage HIV disease are neither necessary nor cost effectiv

Pulmonary Histoplasmosis Mimicking Metastatic Lung Cancer: A Case Report.

Histoplasmosis is a well-known endemic fungal infection but experience in non-endemic regions is often limited, which may lead to delayed diagnosis and extensive testing. The diagnosis can be especially challenging, typically when the disease first presents with pulmonary nodules accompanied by hilar and mediastinal lymphadenopathy, suggesting a much more common malignant disease. In this situation, a greater FDG uptake in draining lymph nodes in comparison with the associated lung nodule seen in [ &lt;sup&gt;18&lt;/sup&gt; F]FDG-PET/CT, the so-called "flip-flop fungus" sign, can help to orientate further diagnostic measures. We report a case of a 56-year-old woman living in Switzerland, a non-endemic region, whose diagnosis of imported histoplasmosis was delayed since the findings had been initially misinterpreted as pulmonary malignancy. Further, histological workup was inconclusive due to lack of specific fungal staining, leading to ineffective treatment and non-resolving disease. This paper intends to highlight the pitfalls in diagnosing Histoplasma capsulatum and presents images of particularities of fungal infections in [ &lt;sup&gt;18&lt;/sup&gt; F]FDG-PET/CT, which in our case showed a "flip-flop fungus" sign