Viral colonization in intubated patients: initial pathogen pattern and follow‐up

Introduction: Colonization of the lower respiratory tract is an independent risk factor for ventilator‐associated pneumonia. Little is known about the frequency of viral colonization on intubation and during mechanical ventilation. Methods: Overall, 65 eligible intubated patients with no initial signs of pulmonary infection were studied over a period of up to 7 days. Tracheobronchial aspirates were taken: (i) within 48 h after intubation; and (ii) when clinical signs of nosocomial tracheobronchitis were present, before extubation, or after 7 days. Presence of respiratory viruses was investigated using quantitative polymerase chain reaction. Results: Patients were 67 ± 11 years old and had been in hospital for 5.1 ± 8.4 days when intubated (major cause for intubation: cardio‐pulmonary resuscitation 25/65, 38%). The average Acute Physiology and Chronic Evaluation II score was 27.3 ± 4.9. Microbiology detected Candida spp. (17/65; 26%) and Staphylococcus aureus (methicillin sensitive: 11/65; 17%; methicillin resistant: 3/65; 5%) and only few respiratory viruses (4/65, 6%). Thirty‐eight percent of the samples (25/65) were sterile. At the given endpoints, 27/65 (42%) patients were available for follow‐up and only one aspirate became positive for respiratory syncytial virus (RSV). Conclusions: After endotracheal intubation, fungi, but not viruses were most frequently isolated. Only one patient acquired RSV, therefore colonization with respiratory viruses does not seem to play a major role early after intubation. Please cite this paper as: Hauptmeier BM, Borg I, Rohde G, Anders A, Kronsbein J, Gatermann S, Bufe A, Blum T, Schultze‐Werninghaus G and Bauer TT. Viral colonization in intubated patients: initial pathogen pattern and follow‐up. The Clinical Respiratory Journal 2010; 4: 139–146.     

The entorhinal cortex of the Megachiroptera: a comparative study of Wahlberg’s epauletted fruit bat and the straw-coloured fruit bat

This study describes the organisation of the entorhinal cortex of the Megachiroptera, straw-coloured fruit bat and Wahlberg’s epauletted fruit bat. Using Nissl and Timm stains, parvalbumin and SMI-32 immunohistochemistry, we identified five fields within the medial (MEA) and lateral (LEA) entorhinal areas. MEA fields E _CL and E _C are characterised by a poor differentiation between layers II and III, a distinct layer IV and broad, stratified layers V and VI. LEA fields E _I, E _R and E _L are distinguished by cell clusters in layer II, a clear differentiation between layers II and III, a wide columnar layer III and a broad sublayer Va. Clustering in LEA layer II was more typical of the straw-coloured fruit bat. Timm-staining was most intense in layers Ib and II across all fields and layer III of field E _R. Parvalbumin-like staining varied along a medio-lateral gradient with highest immunoreactivity in layers II and III of MEA and more lateral fields of LEA. Sparse SMI-32-like immunoreactivity was seen only in Wahlberg’s epauletted fruit bat. Of the neurons in MEA layer II, ovoid stellate cells account for ~38%, polygonal stellate cells for ~8%, pyramidal cells for ~18%, oblique pyramidal cells for ~6% and other neurons of variable morphology for ~29%. Differences between bats and other species in cellular make-up and cytoarchitecture of layer II may relate to their three-dimensional habitat. Cytoarchitecture of layer V in conjunction with high encephalisation and structural changes in the hippocampus suggest similarities in efferent hippocampal → entorhinal → cortical interactions between fruit bats and primates.     

In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate

OBJECTIVE: Spinal muscular atrophy results from loss of the survival motor neuron 1 (SMN1) gene and malfunction of the remaining SMN2. We investigated whether valproic acid can elevate human SMN expression in vivo. METHODS: Blood was collected from 10 spinal muscular atrophy carriers and 20 spinal muscular atrophy patients treated with valproic acid. RESULTS: Seven of 10 carriers demonstrated increased SMN messenger RNA and protein levels. SMN2 messenger RNA levels were elevated in 7 patients and unchanged or decreased in 13 patients. INTERPRETATION: We provide first proof of the in vivo activation of a causative gene by valproic acid in an inherited disease and discuss strategies of monitoring drug response in patients.     

Dietary patterns and breast cancer risk among women in northern Tanzania: a case–control study

Background

Breast cancer is the second most common cancer among women in the Kilimanjaro Region of Tanzania. It was tested within a case–control study in this region whether a specific dietary pattern impacts on the breast cancer risk.

Methods

A validated semi-quantitative Food Frequency Questionnaire was used to assess the dietary intake of 115 female breast cancer patients and 230 healthy age-matched women living in the same districts. A logistic regression was performed to estimate breast cancer risk. Dietary patterns were obtained using principal component analysis with Varimax rotation.

Results

The adjusted logistic regression estimated an increased risk for a “Fatty Diet”, characterized by a higher consumption of milk, vegetable oils and fats, butter, lard and red meat (OR = 1.42, 95 % CI 1.08–1.87; P = 0.01), and for a “Fruity Diet”, characterized by a higher consumption of fish, mango, papaya, avocado and watery fruits (OR = 1.61, 95 % CI 1.14–2.28; P = 0.01). Both diets showed an inverse association with the ratio between polyunsaturated and saturated fatty acids (P/S ratio).

Conclusion

A diet characterized by a low P/S ratio seems to be more important for the development of breast cancer than total fat intake.     

Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2‐like polarization of tumor associated macrophages

GTP cyclohydrolase (GCH1) is the key‐enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer‐biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29‐Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near‐infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor‐attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS‐induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1‐deficient HT29‐Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.     

Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly,Germany

We detected delayed and reduced antibody and T-cell responses after BNT162b2 vaccination in 71 elderly persons (median age 81 years) compared with 123 healthcare workers (median age 34 years) in Germany. These data emphasize that nonpharmaceutical interventions for coronavirus disease remain crucial and that additional immunizations for the elderly might become necessary.     

Breast cancer risk among women with long-standing lactation and reproductive parameters at low risk level: a case–control study in Northern Tanzania

Breast cancer is the leading cause of death among women worldwide. Studies in industrialised countries identified age at menarche, age at first full-term pregnancy, and lactation as determining factors in the aetiology of breast cancer. 115 female breast cancer patients (cases) and 230 age- and district-matched women clinically free from breast cancer (controls) were interviewed about their reproductive history and socioeconomic condition. Semi-structured interviews including anthropometric measurements were conducted by trained enumerators. The median age was 50 years (min/max 26 to 85 years). Estimated median BMI at age 20 was 21 kg/m² in both cases and controls. Median lifelong lactation of the mothers was 96 months (cases) and 108 months (controls). A high BMI at 20 years was associated with an increased breast cancer risk (OR 1.31 95% CI 1.11–1.55, P < 0.01). The odds ratio for lifelong lactation was slightly below one (OR 0.99 95% CI 0.98–1.00, P < 0.01). There was no significant association in risk for BMI at interview (median 25 kg/m² of cases and 26 kg/m² of controls), age at menarche (median 16 years), and age at first full-term pregnancy (median 20 years). The association of increased risk with higher BMI at age 20 years remained significant after stratification for menopause (premenopausal: OR 1.41 95% CI 1.10–1.81, P = 0.01; postmenopausal: OR 1.38 95% CI 1.06–1.80, P = 0.02). Late age at menarche and prolonged lifelong lactation were associated with a risk reduction among premenopausal women (OR_menarche 0.74 95% CI 0.56–1.00, P = 0.05; OR_lactation 0.98 95% CI 0.97–0.99, P < 0.01). In conclusion, long-standing lactation and reproductive behaviour are associated with a lower breast cancer risk in the region. As current changes in lifestyle affect age at menarche, reproductive behaviour, and nutritional status, an increased incidence of breast cancer is to be expected. Preventive efforts should include advice on reproductive and breastfeeding behaviour.     

Tumour-microenvironment interactions: role of tumour stroma and proteins produced by cancer-associated fibroblasts in chemotherapy response

Background

Cytotoxic chemotherapy improves survival for some, but not all, cancer patients. Non-responders may experience unnecessary toxicity and cancer progression, thus creating an urgent need for biomarkers that can predict the response to chemotherapy. So far, the search for such biomarkers has primarily been focused on the cancer cells and less on their surrounding stroma. This stroma is known to act as a key regulator of tumour progression and, in addition, has been associated with drug delivery and drug efficacy. Fibroblasts represent the major cell type in cancer-associated stroma and they secrete extracellular matrix proteins as well as growth factors. This Medline-based literature review summarises the results from studies on epithelial cancers and aimed at investigating relationships between the quantity and quality of the intra-tumoral stroma, the cancer-associated fibroblasts, the proteins they produce and the concomitant response to chemotherapy. Biomarkers were selected for review that are known to affect cancer-related characteristics and patient prognosis.

Results

The current literature supports the hypothesis that biomarkers derived from the tumour stroma may be useful to predict response to chemotherapy. This notion appears to be related to the overall quantity and cellularity of the intra-tumoural stroma and the predominant constituents of the extracellular matrix.

Conclusion

Increasing evidence is emerging showing that tumour-stroma interactions may not only affect tumour progression and patient prognosis, but also the response to chemotherapy. The tumour stroma-derived biomarkers that appear to be most appropriate to determine the patient’s response to chemotherapy vary by tumour origin and the availability of pre-treatment tissue. For patients scheduled for adjuvant chemotherapy, the most promising biomarker appears to be the PLAU: SERPINE complex, whereas for patients scheduled for neo-adjuvant chemotherapy the tumour stroma quantity appears to be most relevant.     

Subcutaneous angiocentric T-cell lymphoma associated with fatal hemophagocytic syndrome

A 70-year-old woman was admitted in November 1991 for Internal fixation of a left pertrochanteric fracture. On admission, several indurated plaques and nodules were noted. Two days later she developed an acute and severe episode of rectal bleeding. The patient had a 7-month history of recurrent painful erythematous plaques and nodules on the lower extremities associated with fever and malaise. In September 1991, she was admitted to another institution for evaluation and treatment. At that time, a skin biopsy specimen from a nodular lesion showed a lobular panniculitis. She was diagnosed as having Weber-Christian disease and treatment with prednjsone, 1 mg/kg, was prescribed. In spite of this therapy, new skin nodules appeared. On admission to our institution, physical examination revealed a febrile (38.5 °C) woman, with six to 10 tender erythematous plaques and nodules, 1–3 cm in diameter, distributed over the legs, anterior chest, arms, and abdomen. Some of the nodules were ulcerated in the centers (Fig. 1). A nontender splenomegaly was present, but no enlarged lymph nodes were noted. Laboratory tests showed anemia (hemoglobin 7.9 g/dL), a platelet count of 105×10⁹/L, and a normal leukocyte count and differential. Subsequent laboratory studies showed progressive thrombocytopenia (platelet count, 26×10⁹/L) and leukopenia (leukocyte count, 3.5×10⁹/L), mild hepatic dysfunction (serum glutamate oxalacetic transaminase (SGOT), 68 U/L; serum glutamate pyruvate transaminase (SGPT), 68 U/L; 31 U/L), and lactic dehydrogenase (LDH) (2365 U/L). The rest of the laboratory data, including coagulation studies, urinalysis, screening for connective tissue disorders, pancreatic enzyme levels, VORL, and serologic tests for hepatitis B and C, were normal or negative/nonreactive. Blood cultures, cerebrospinal fluid examination, and chest roentgenogram were also normal. Abdominal computed tomographic (CT) scan revealed only an enlarged spleen. The patient's general condition markedly deteriorated and extensive hemorrhages from venpuncture sites, epistaxis, and rectal bleeding developed. Further treatment with 6-methyl-prednisolone, 160 mg/day, and an i.v. pulse of 1 g cyclophosphamide was initiated, but marked leucopenia ensued. The patient died 23 days after admission. Histopathologic, immunohistochemical, and genotypic studies Skin biopsy specimens from two nodules showed a dense mononuclear, mainly perivascular, infiltrate in the mid- and deep dermis extending into the subcutis (Fig. 2). No epidermotropism was seen. The infiltrate consisted of atypical, small and medium-sized lymphoid cells with irregular nuclei, prominent nucleoli, and frequent mitotic figures. Angioinvasion in the deep skin dermis and subcutaneous septa was noted (Fig. 3). In the subcutaneous tissue, large histiocyte-appearing cells with pale-staining cytoplasm filled with cellular debris (bean-bag cells) were seen admixed within the infiltrate (Fig. 4). The lymphoid cells stained strongly with T-cell markers (UCHL-1, CD3) and the larger histiocytic cells were positive with Mac-387 (++), a-antitrypsin, a-antichymotrypsin (+++), and lysozyme (+). Some of these macrophages also stained weakly positive with T-cell and B-cell markers (L26, CD45RA). Scattered CD30+ cells were also observed within the infiltrate. No frozen material was available for immunohistochemical studies. Immunohistochemical staining with monoclonal antibody anti-Epstein-Barr virus directed against latent membrane protein (LMP-1) (Dako-EVB, CS 1-4) revealed cytoplasmic staining with peripheral reinforcement of scattered atypical lymphoid cells. Studies to defect Epstein-Barr virus DNA were not performed. A postmortem skin biopsy specimen from a nodular lesion showed extensive necrosis of the subcutaneous tissue with some atypical lymphocytes still present in the septa. The bone marrow showed cellular hyperplasia with no evidence of lymphoma. Occasional phagocytic cells with hemophagocyfosis were observed. Genotypic analysis (Southern blot, C-beta probe) from a postmortem skin biopsy failed to demonstrate a clonal T-cell receptor gene rearrangement.