Embolization of tumor cells is rare in patients with systemic cancer and cerebral large vessel occlusion.

BACKGROUND AND PURPOSE: Stroke is a dreaded complication in patients with cancer. Besides paraneoplastic coagulopathy, chemotherapy, radiotherapy and tumor-directed invasive procedures, circulating cancer cells may contribute to thrombus formation and embolic stroke. However, the incidence of tumor cells within the blood clots of cancer patients with stroke is unknown and the role of circulating tumor cells in the formation of cerebrovascular thrombi remains unclear. METHODS: All patients who had undergone cerebrovascular thrombectomy at the University Hospital Zurich between 2014 and 2017 were screened for history of cancer. Clinical information was retrieved from the local stroke registry and the electronic charts and thrombi underwent a thorough histopathological re-review. RESULTS: Thirty-two of 182 patients (18%) with thrombectomy had a history of cancer. The majority of patients had advanced stage cancer. However, even after extensive histopathological re-review, only one specimen revealed tumor cells in the thrombus: a 75-year-old patient with acute occlusion of the middle cerebral artery who had been diagnosed with non-small-cell lung cancer 8.1 months prior to stroke. CONCLUSIONS: The presence of cancer cells in clots from cerebrovascular thrombectomy, indicative of a direct involvement of circulating tumor cells in the causation of stroke, is rare.

HPV E6 oncoproteins and nucleic acids in neck lymph node fine needle aspirates and oral samples from patients with oropharyngeal squamous cell carcinoma.

Commercial assays measuring HPV E6 viral oncoproteins, E6/E7 mRNA or DNA were used to test neck lymph node fine needle aspirates (FNA) and oropharyngeal samples (saliva and oral swabs) from 59 Canadian patients with oropharyngeal squamous cell carcinomas (OPSCC). Overall agreements of p16 antigen staining of tumors to FNA tested for OncoE6™, Aptima HPV E6/E7 mRNA and cobas HPV DNA were 81.4% (k 0.53), 94.9% (k 0.83) and 91.1% (k 0.73) respectively. Using HPV presence in a subset of 25 tumors as the comparator, overall agreement was 64.0% (k 0.08) with OncoE6™, 88.0% (k 0.65) with Aptima HPV E6/E7 mRNA and 91.7% (k 0.70) with cobas HPV DNA. HPV testing of oropharyngeal samples yielded lower agreements with tumor markers; 23.7-24.0% (k 0.02), 55.9-68.0% (k 0.24-0.37) and 78.9-86.9% (k 0.49-0.58) in the 3 respective tests. HPV 16 was present in 93.7-100% of the samples tested and showed 100% genotype agreement between FNA and tumors. The high rates for HPV E6 oncoproteins and E6/E7 mRNA suggests most patients were experiencing transcriptionally active HPV-related OPSCC. Results from these commercial assays performed on FNA but not oropharyngeal samples showed moderate to very good agreements with p16 and HPV testing of tumors.

Recurrent abdominal pain in 200 children: somatic causes and diagnostic criteria.

AIM: To establish to what extent somatic causes can be found in children referred to secondary care with recurrent abdominal pain. METHODS: For 2 years, all consecutive patients (age 4-16 years) fulfilling Apley criteria, referred to secondary care, were included. After a diagnostic work-up, stepwise therapeutic interventions were performed. A diagnosis was considered to be the cause of the pain when the patient became pain free following therapeutic intervention and remained so for at least 6 months. RESULTS: Two hundred and twenty children (128 F, 92 M; mean age 8.8 years) were enrolled, of which 20 were lost to follow-up. Spontaneous recovery was seen in 54 patients, (occult) constipation in 92 patients (of whom 18 also had a somatic cause), gastrointestinal infections in 40, food allergy in five, miscellaneous disorders in seven and uncertain diagnosis in 13. In five patients, stress most likely caused the pain. A total of 198 patients became pain free and remained so during follow-up (mean 18, range 6-60 months). CONCLUSION: In 200 children with recurrent abdominal pain, somatic causes were found in 26%. Laxative therapy was successful in 46%, resulting in nearly all patients with functional abdominal pain to become pain free. Eventually, 99% became pain free using a therapeutic intervention protocol.

The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). AIM: To evaluate the long-term efficacy of infliximab treatment in paediatric CD. METHODS: In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied. RESULTS: One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1-16.4)] received a median number of 10.5 infliximab infusions (IQR 6-21). Median follow-up after start of infliximab was 25 months (IQR 13-40). Kaplan-Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months. CONCLUSIONS: Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD.

[Pacemaker and implantable defibrillators with telemedical support]. / Schrittmacher und interne Defibrillatoren mit kardiotelemedizinischer Unterstützung.

Recent developments in pacemaker and ICD therapy can be characterized by a rising number of implantations (especially in the field of ICD and CRT systems) and an increasing complexity of the units involved. Problems evolving from this trend are the soaring numbers of necessary follow-up examinations, issues of patient safety and the necessity of device management by specialized physicians. Telemonitoring offers various possibilities of improvement in these areas. The manufacturers of the devices have developed applicable solutions for concepts of care including telemedical monitoring of patients with pacemakers, ICD and CRT systems. The systems commonly include an implant capable of either automatic or manual data transmission, a device for transmitting the implant's data (mobile communication or fixed line network), a server managing the information and a front-end (internet-based) platform for the physician. Multiple clinical trials have verified the stability and the security of this method of data transmission. Telemedical monitoring can be used in order to improve the monitoring of the patients' state of health (e. g., patients with CRT systems because of their CHF) and the management of arrhythmias (e. g., patients suffering from paroxysmal atrial fibrillation). Telemonitoring allows the intervals between follow-up check-ups to be individualized, thus, leading to financial savings. The telemedical monitoring of patients with ICD and CRT systems facilitates new opportunities for networked follow-up care and comprehensive medical treatment.

Direct observation of double-k lattice modulation in double-k magnetic structures. The case of CeAl(2).

Symmetry analysis is combined with x-ray scattering experiments to investigate the lattice modulation associated with the incommensurate magnetic structure in the case of a double- k structure. The expansion of the free energy shows that the components of the magnetic structure with propagation vectors k(1) and k(2) can couple via components of lattice modulations. It is shown that the classical diffraction peaks reflecting a 2k propagation vector, associated with magneto-elastic effects in single- k structures, will coexist with diffraction peaks with propagation vectors k(1)-k(2) or k(1)+k(2). The existence of these latter peaks can be considered as a signature of a double- k magnetic structure. In the case of the double- k modulated structure of CeAl(2), group theory is applied directly to the study of the charge modulation. An x-ray scattering study of the 2k satellites shows that the lattice displacements of the two Ce sites of the structure are antiparallel to each other, and perpendicular to the direction of the magnetic modulation. We also confirm experimentally the existence of k(1)+k(2) satellites.

Depression of spinal network activity by thiopental: shift from phasic to tonic GABA(A) receptor-mediated inhibition.

Interneuronal networks in the spinal ventral horn are plausible substrates for mediating anesthetic-induced immobility. Here, we investigated how their activity is affected by clinically relevant concentrations of thiopental, a barbiturate in clinical use. In cultured spinal cord slices from mice, thiopental reduced action potential activity with an EC(50) of 16.6+/-2.4microM. Recordings of GABA(A) and glycine receptor-mediated inhibitory currents indicated that the effect was largely mediated by GABA(A) receptors and that glycine receptors were not relevant targets. Specifically, 20microM thiopental prolonged the decay time of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) more than twofold. Although this prolongation of decay time increased the inhibitory charge per sIPSC the concomitant strong reduction of sIPSC frequency resulted in less inhibitory current entering the neurons via this route. However, 20microM thiopental also induced a tonic current of 30+/-10pA, mediated by GABA(A) receptors; 50microM thiopental nearly abolished sIPSC activity but augmented tonic currents to 69+/-14pA. Furthermore, at this concentration, activity-depressing mechanisms independent of GABA(A) receptors came into play. The results suggest that in the spinal ventral horn thiopental acts mostly, but not exclusively, via GABA(A) receptors. With increasing concentrations of the drug, inhibition via sIPSCs is limited by negative feedback on interneuronal firing whereas action potential-independent GABAergic inhibition due to tonic currents gains progressively in impact.

New concepts on the histogenesis of eccrine neoplasia from keratin expression in the normal eccrine gland, syringoma and poroma.

BACKGROUND: Peripheral and luminal layers of eccrine sweat gland ducts are self-renewing structures. Proliferation is restricted to the lowermost luminal layer, but randomly scattered in the peripheral layer. Each layer exhibits differential expression of keratins K5/K14 and K6/K16. Keratin K1 occurs only in peripheral cells and the novel keratin K77 is specific for luminal cells. OBJECTIVES: To investigate the expression of luminal (K77), peripheral (K1) and further discriminatory keratins in two eccrine sweat gland tumours: syringoma, thought to show differentiation towards luminal cells of intraepidermal sweat ducts and eccrine poroma, considered to arise from poroid cells, i.e. peripheral duct cells; and keratinocytes of the lower acrosyringium/sweat duct ridge differentiating towards cells of intradermal/intraepidermal duct segments. METHODS: Paraffin-embedded sections were examined by immunohistochemistry using several keratin, smooth muscle actin and Ki-67 antibodies. RESULTS: We confirmed the ductal nature of syringomas. Despite drastic morphological alterations in both layers, their keratin patterns remained almost undisturbed compared with normal ducts. In eccrine poroma epidermal keratins K5/K14 were ubiquitously expressed in all poroid cells. Cell islands deviating morphologically from poroid cells contained epidermal keratins K1/K10. K77 expression was limited to luminal cells of intact duct structures within the tumours. CONCLUSIONS: Syringomas are benign tumours of luminal cells of the lowermost intraglandular sweat duct. Poroid precursor cells of poromas do not comprise peripheral duct cells nor do poromas differentiate towards peripheral or luminal duct cells. Instead, poroid cells consist only of keratinocytes of the lowermost acrosyringium and the sweat duct ridge and poromas tend to differentiate towards the cells of the upper acrosyringium.

Abnormal liver enzymes two years after haematopoietic stem cell transplantation in children: prevalence and risk factors.

To establish the prevalence of elevated liver enzymes in children transplanted in a Dutch haematopoietic stem cell transplantation (HSCT) centre, we retrospectively assessed AST and ALT values at 2 years after HSCT. Age, sex, diagnosis, type of transplant, conditioning regimen and early post-transplant complications involving the liver (veno-occlusive disease, acute GVHD, viral reactivation) were analysed as risk factors. AST and ALT values were available at 2 years after HSCT in 216 of 290 patients (75%) alive at that time and were above normal in 53 (25%) and at least twice normal in 17 (8%) patients. Older age at HSCT and a diagnosis of benign haematological disease are risk factors for abnormal liver enzymes late after HSCT. In half of the patients with benign haematological disease, iron overload is the most likely aetiological factor. Chronic hepatitis B or C is uncommon in our centre. In conclusion, the prevalence of abnormal liver enzymes late after HSCT in our centre is lower than reported in previous studies. Abnormal liver enzymes occur more often in children who are older at HSCT and transplanted for benign haematological disease. Long-term follow-up is crucial to establish if elevated liver enzymes precede clinical liver disease.

Efficacy and safety of valsartan 160/HCTZ 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 mg in free combination.

OBJECTIVE: Free combination hypertension medication is associated with a lower compliance and less persistence compared to fixed combination therapy and can, therefore, be associated with insufficient blood pressure reductions. This non-randomized study investigated whether valsartan 160 mg/hydrochlorothiazide 25 mg (Val 160/HCTZ 25) in fixed dose combination could provide additional blood pressure control in hypertensive patients not adequately controlled by the free combination of candesartan 32 mg plus HCTZ 25 mg. RESEARCH DESIGN AND METHODS: One hundred and ninety-seven patients with a mean sitting diastolic blood pressure (MSDBP) between 100 and 110 mmHg entered a 4-week treatment phase with 32 mg of candesartan in free combination with 25 mg of HCTZ once daily. One hundred and thirty-eight patients with uncontrolled BP at Week 4, entered a second 4-week treatment phase with Val160/HCTZ 25 once daily. MAIN OUTCOME MEASURES: The primary efficacy parameter was the reduction in MSDBP at trough between Week 4 and Week 8 in the intent-to-treat population. RESULTS: At baseline, MSDBP was 103.0 +/- 2.8 mmHg. After Week 4, MSDBP had decreased to 93.8 +/- 4.5 mmHg. Subsequent treatment with Val 160/HCTZ 25 for 4 weeks reduced MSDBP to 88.7 +/- 8.6 mmHg. This represented an additional decrease in MSDBP of 5.1 +/- 7.9 mmHg (p < 0.0001). Val 160/HCTZ 25 reduced mean sitting systolic BP by 3.4 +/- 13.0 mmHg (p = 0.0029). CONCLUSIONS: The fixed dose combination of valsartan 160/HCTZ 25 mg provided a statistically and clinically significant additional BP reduction in patients not controlled by the free combination of candesartan 32 mg and HCTZ 25 mg.

Candesartan treatment for peripheral occlusive arterial disease after stent angioplasty : a randomised, placebo-controlled trial.

OBJECTIVES: In this prospective, double-blind, placebo-controlled study we observed the influence of treatment with candesartan 8mg on restenosis rates after stent implantation into the femoral artery 6 months after percutaneous transluminal angioplasty (PTA). We hypothesised that angiotensin II type 1 (AT1)-receptor blockade with candesartan would reduce restenosis rates by reducing angiotensin II-mediated intima hyperproliferation within the stented vessel segment in patients with peripheral occlusive disease. PATIENTS AND METHODS: Eighty-seven patients with peripheral occlusive arterial disease stage IIb who had been successfully treated with PTA and stent implantation were randomised to receive orally either candesartan 8mg (n = 44) or placebo (n = 43). Follow-up included evaluation of the degree of stenosis and thickness of the intima-media complex (primary endpoint). In addition, thickness of the interventricular septum, crurobrachial pressure ratios, and pain-free walking distance were determined (secondary endpoints). RESULTS: The degree of stenosis after 6 months was not significantly different between the groups studied (35.9 +/- 39.6% for candesartan vs 36.0 +/- 38.4% for placebo). Relevant restenosis including stent occlusions was found in nine patients (20.5%) in the candesartan group and in ten patients (23.3%) in the placebo group. The thickness of the intima-media complex 6 months after stent implantation was 1.60 +/- 0.32mm in the candesartan group and 1.64 +/- 0.32mm in the placebo group (not significant). There were no differences in secondary endpoints between the treatment groups. Controls after 3 months (20.9 +/- 33.6% for candesartan vs 27.6 +/- 38.3% for placebo; p = 0.39) and 9 months (44.1 +/- 40.8% for candesartan vs 47.7 +/- 37.2% for placebo; p = 0.67) of therapy revealed a lower degree of stenosis in patients treated with candesartan. CONCLUSIONS: Although not significant, candesartan treatment tended to improve the prognostic benefits after stent implantation, suggesting that an antiproliferative effect after stenting may need higher doses than an antihypertensive effect of the drug. This hypothesis requires confirmation in further prospective studies with higher daily doses of candesartan, which are already in progress.

Expression of hair keratins in the adult nail unit: an immunohistochemical analysis of the onychogenesis in the proximal nail fold, matrix and nail bed.

BACKGROUND: Recently, the expression profiles of the members of the complex hair keratin family have been determined in the human anagen hair follicle. In contrast, the details of hair keratin expression in the human nail unit are poorly known. OBJECTIVES: In order to fill this gap, we have performed an immunohistochemical study of the adult human nail unit by means of specific antibodies against nine hair keratins of both types (hHa2, hHb2, hHa5, hHb5, hHa1, hHb1, hHb6, hHa4 and hHa8) as well as three epithelial keratins (K5, K17 and K10). METHODS: Formalin-fixed paraffin sections of adult nails were examined using monoclonal and polyclonal keratin antibodies, respectively. Longitudinal as well as transverse sections were investigated. RESULTS: Our study revealed two types of epithelial tissue compartments in the nail unit. The first comprised the eponychium and hyponychium and the nail bed, which expressed only epithelial keratins. While keratins K5, K17 (basal) and K10 (suprabasal) were found in the orthokeratinizing eponychium and hyponychium, throughout, the nail bed epithelium expressed only K5 and K17. The second type comprised the apical and ventral matrix which exhibited a mixed pattern of epithelial and hair keratin expression. Thus, K5 and K17 were expressed in the entire multilayered basal cell compartment of the apical and ventral matrix; however, in the latter, K5 and K17 also occurred in the lowermost layers of the overlying keratogenous zone. The hair matrix keratin hHb5, but not its type II partner hHa5, was seen in the entire keratogenous zone of the apical and ventral matrix, but was also located in the uppermost cell layers of the basal compartment of the ventral matrix, where it overlapped with K5 and K17. Similar to their sequential expression in the hair follicle cortex, hair keratins hHa1, hHb1, hHb6 and hHa4 were consecutively expressed in the keratogenous zone of both the ventral and, albeit less distinctly, apical matrix, with hHa1 initiating in the lowermost cell layers. The expression of hHa8 in only single cortex cells of the hair follicle was also preserved in cells of the keratogenous zone. In the region of the so-called dorsal matrix, we observed two histologically and histochemically distinct types of epithelia: (i) a dominant type, histologically similar to the eponychium and an associated K5, K17 and K10 keratin pattern which clearly extended into the apical matrix, and (ii) a minor type, histologically resembling the postulated dorsal matrix without a granular layer and a cuticle, and exhibiting extended K5 expression as well as hair keratin expression in superficial cells. CONCLUSIONS: The coexpression of hHb5 with K5 and K17 in the uppermost cell layers of the basal compartment and the lowermost layers of the keratogenous zone of the ventral matrix prompts us to designate this region the prekeratogenous zone of the ventral matrix. The two alternating types of histology and keratin expression in the dorsal matrix identify this region as a transitional zone between the eponychium and the apical matrix. Finally, our data clearly show that the ventral matrix is the main source of the nail plate. In addition, the mixed scenario of hair and epithelial keratins, including demonstrable amounts of K10, in superficial cells of the apical matrix, lends support to the notion that the dorsal portion of the nail is generated by the apical matrix.

Coeliac disease in The Netherlands.

BACKGROUND: The prevalence of adult coeliac disease in The Netherlands was studied in the Dutch Coeliac Disease Society and in blood donors but not in the general population. We therefore studied the prevalence of recognized and unrecognized coeliac disease in a large cohort, representative of the adult Dutch general population. Blood samples were available for anonymous research, as well as data on dietary habits, self-reported physical characteristics, health problems, quality of life and socio-economic circumstances. METHODS: Subjects included 50,760 individuals who had previously participated in two large population-based studies on health status in relation to lifestyle factors. Recognized coeliac disease was studied in all subjects by identification of self-reported adherence to a gluten-free diet and subsequent confirmation of the diagnosis of coeliac disease. Unrecognized coeliac disease was studied in a random sample of 1440 out of the 50,760 subjects through serologic screening and human lymphocyte antigen (HLA) typing. RESULTS: The prevalence of recognized coeliac disease was 0.016% (95% confidence interval 0.008-0.031) and of unrecognized coeliac disease 0.35% (95% confidence interval 0.15-0.81). Menarcheal age was higher in women with recognized coeliac disease than in women without coeliac disease. CONCLUSIONS: The prevalence of adult recognized coeliac disease in The Netherlands is one of the lowest in Europe, while the prevalence of unrecognized coeliac disease is comparable with that in other European countries. Adult coeliac disease is strongly under diagnosed in The Netherlands. The higher menarcheal age in women with recognized coeliac disease may be explained by diagnostic delay.

Coeliac disease and (extra)intestinal T-cell lymphomas: definition, diagnosis and treatment.

Intestinal lymphomas encompass those lymphomas with a dominant or only localized occurrence in the intestinal tract. Coeliac disease is highly associated with enteropathy-associated T-cell lymphomas (EATLs). Coeliac disease-related lymphomas can appear at nodal or extranodal sites. EATL is often multifocal with ulcerative lesions, which explains the high perforation rate at presentation or during chemotherapy. Staging includes ear-nose-throat examination and CT scan of the chest and abdomen. Positron emission tomography (PET) scanning may be valuable. Accurate diagnosis based on endoscopic biopsies is preferable; if necessary, full thickness laparoscopic small-bowel biopsies are mandatory. Refractory coeliac disease (RCD) with aberrant T cells carries a high risk of development of EATLs. There is no satisfactory treatment for EATL, the only possibility of preventing EATL development in RCD being autologous bone marrow transplantation. EATLs can present in 20% of patients as extra-small-bowel T-cell lymphomas; such as subcutaneous panniculitis-like lymphoma, hepatosplenic gamma/delta lymphoma, nodal as well as sinus, gastric or colon disease and extraintestinal T-cell lymphomas. The majority of EATLs present as large cell lymphoma CD3+, CD8-, CD30+; however, they also present as small cell lymphoma CD3+, CD8+, CD30-. Sometimes gamma/delta lymphomas in CD are recognized. Work-up of EATL must include immunohistology, T-cell flow cytometry, T-cell rearrangement and adequate imaging with CT and PET scanning.

[Two children with severe recurrent infections and the X-linked hyper-IgM syndrome]. / Twee kinderen met ernstige, recidiverende infecties en het X-gebonden hyper-IgM-syndroom.

A boy suffered from severe recurrent intestinal infections from the age of 8 months onwards; investigation into an immune disorder ultimately resulted in the diagnosis of 'hyper-IgM syndrome'. He was treated successfully with bone marrow transplantation, using an HLA-matched donor. Another boy had severe recurrent respiratory tract infections from the age of 3 months onwards. At the age of 6.5 years, 'hyper-IgM syndrome' was diagnosed. No suitable donor was available. In addition, he developed sclerosing cholangitis and end-stage liver disease, making a combined bone marrow and liver transplantation too risky. He died at 10.5 years of age. X-linked hyper-IgM syndrome is a rare congenital immunodeficiency disorder, characterised by a defect in both humoral and cellular immune responses. Deficiency in the membrane glycoprotein CD40 ligand (expressed on activated T-cells) compromises T-cell interactions with antigen-presenting cells. In a child with severe recurrent infections, and with dysgammaglobulinaemia with a normal or increased IgM level, the diagnosis of 'X-linked hyper-IgM syndrome' should be considered.

Hair keratin pattern in human hair follicles grown in vitro.

The keratin family includes epithelial (soft) keratins and hair (hard) keratins, and can be divided into acidic type I and basic to neutral type II subfamilies. Recently, nine type I and six type II hair keratin genes have been characterized through the screening of a human PAC library. The expression of these genes in the hair follicle was determined in vivo and a combined catalog of acidic and basic hair keratins was established. In this study, we investigated the expression and localization of most of the human hair keratin members of both types in human hair grown in vitro. We show that in vitro growth of hair follicles for 10 days in complete William's E culture medium did not alter the expression pattern of hair keratins. Similarly to the in vivo situation, each hair keratin was localized in precise and discrete compartments of the follicle, ranging from the matrix to the upper cortex and/or the hair cuticle. This study shows that the increase in length of in vitro grown follicles was accompanied by the proper hair shaft keratinization process. It also shows that hair follicle integrity was maintained in vitro, both in terms of gross morphology and molecular organization despite the complexity of the keratin expression pattern.