Extra pulmonary tuberculosis presenting as fever with massive splenomegaly and pancytopenia.

Disseminated tuberculosis is an important differential diagnosis for fever of unknown origin (FUO) and it can present with hepatosplenomegaly and lymphadenopathy and may have meningitis and with hematological abnormalities including pancytopenia or a leukemoid reaction. We report the case of a 13-year old male who presented with fever, weight loss, pallor and massive splenomegaly with pancytopenia, in whom a bone marrow trephine biopsy showed caseating granulomata, who responded well to antituberculous treatment and has remained healthy on follow up after nine years.

Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition.

Cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) are defined by high self-renewal and drug refractory potential. Involvement of Wnt/ß-catenin signaling has been implicated in rapidly cycling cells such as CSCs, and inhibition of the Wnt/ß-catenin pathway is a novel approach to target CSCs from HNSCC. In this study, we found that an antagonist of FrzB/Wnt, the secreted frizzled-related protein 4 (sFRP4), inhibited the growth of CSCs from two HNSCC cell lines, Hep2 and KB. We enriched the CD44(+) CSC population, and grew them in spheroid cultures. sFRP4 decreased the proliferation and increased the sensitivity of spheroids to a commonly used drug in HNSCC, namely cisplatin. Self-renewal in sphere formation assays decreased upon sFRP4 treatment, and the effect was reverted by the addition of Wnt3a. sFRP4 treatment of spheroids also decreased ß-catenin, confirming its action through the Wnt/ß-catenin signaling pathway. Quantitative PCR demonstrated a clear decrease of the stemness markers CD44 and ALDH, and an increase in CD24 and drug-resistance markers ABCG2 and ABCC4. Furthermore, we found that after sFRP4 treatment, there was a reversal in the expression of epithelial to mesenchymal (EMT) markers with the restoration of the epithelial marker E-cadherin, and depletion of EMT-specific markers twist, snail and N-cadherin. This is the first report demonstrating that the naturally occurring Wnt inhibitor, sFRP4, can be a potential drug to destroy CSC-enriched spheroids from HNSCCs. The repression of EMT and the decrease in stemness profile further strengthen the use of sFRP4 as a potent therapeutic against CSCs.

MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines.

Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor-resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes.

A case series of paediatric hearing preservation cochlear implantation: a new treatment modality for children with drug-induced or congenital partial deafness.

OBJECTIVE: To investigate the use of hearing preservation cochlear implantation in children with partial deafness. PATIENTS AND METHODS: Five children with either drug-induced or congenital partial deafness were enrolled in a pilot study. The patients ranged in age from 13 months to 14 years. Implantation was performed using a hearing preservation technique. A Flex EAS electrode (MED-EL, Innsbruck, Austria) was used in all full insertions. RESULTS: Low frequency hearing was preserved in all patients with postoperative bone conduction within 10 dB of the preoperative hearing levels. These changes were preserved over the follow-up period of 12 months. There were significant improvements in speech perception. CONCLUSION: Hearing preservation cochlear implantation is a new effective modality in children with partial deafness.

Management of benign inverted sinonasal papilloma avoiding external approaches.

Even though endoscopic removal of inverted papillomas has gained popularity, many studies advocate supplementary external approaches. The impact of including the current surgical staging system into the pre-operative clinical and radiological assessment has not been systematically evaluated. We present our experience with total endoscopic management of inverted papillomas and compare the accuracy of the pre-operative predicted extent of surgery, with the actually performed surgery. From 1997 to 2005 data from 51 patients with inverted papillomas were prospectively collected and subsequently reviewed. All have been operated on endoscopically without an external approach. The overall recurrence rate was 3.9 per cent. Pre-operative prediction of extent of surgery was accurate in 26 of 51 (51 per cent). The main reasons for the inaccurate pre-operative prediction were the variable sizes and locations of the inverted papilloma bases, particularly in the maxillary sinus and the frontal recess. Our results encourage us to recommend endoscopic management as the standard treatment of benign inverted papillomas.

Patient's quality of life and hearing outcomes after stapes surgery.

OBJECTIVES: To determine the quality of life (QOL) after stapes surgery and whether audiological parameters for hearing correlate with specific QOL factors. DESIGN: A retrospective cross-sectional study. SETTING: A tertiary referral centre. PARTICIPANTS: A series of 35 patients who underwent stapes surgery of which three were excluded because they were <18 years of age, chronically or mentally ill, or in a dependant relationship. Response rate was 93% (30/32). Nine were further excluded because they had revision or bilateral surgery, or missing data. Twenty-one patients were included in this study. MAIN OUTCOME MEASURES: The Glasgow Benefit Inventory (GBI) was used to evaluate general QOL and the Hearing Disability and Handicap Scale (HDHS) was used as a disease-specific measure. The Belfast Rule of Thumb and Glasgow Benefit Plot assessed hearing outcomes. RESULTS: Operative success was 86% using the Belfast Rule of Thumb and 95% had closure of the air-bone gap to within 20 dB. 81.8% of patients reported a better overall QOL as surgery. Glasgow Benefit Inventory Social and GBI Physical scores correlated positively with the HDHS speech component (P < 0.05). The duration of hearing loss correlated inversely with the average HDHS score (P < 0.05). CONCLUSION: The majority of patients report a better QOL as undergoing stapes surgery. Speech impacts on people's physical and social QOL of patients. Quality of life tools, in addition to objective audiologic measurements can provide clinicians with patients' subjective perspective that helps guide clinical decision-making and counselling.

[Ignition and burning of biological tissue under simulated CO2-laser surgery conditions]. / Entflammungs- und Brandverhalten von biologischem Gewebe bei In-vitro-Bestrahlung mit dem CO2-Laser.

BACKGROUND: Laser surgery in endoscopy has greatly enhanced the surgical armamentarium for treating various laryngeal and hypopharyngeal disorders, but harbours a risk of tissue ignition and inflammation of surgical and anaesthetic instrumentation. However, even if non-inflammable material is used, there is still a residual fire hazard from endogenous tissue that may develop an ignitable aerosol (so-called laser smog) as an effect of laser irradiation. The aim of this study was to investigate how tissue carbonisation and vaporisation contributes to the risk of airway fire. METHODS: For the simulation of gas accumulation in the hypopharynx and larynx following the European standard ISO-11990, a cylindrical steel chamber with an open and a closed end has been used to simulate the operative setting. Pork meat chunks with a tissue composition similar to the larynx and hypopharynx such as fat, muscle, cartilage and bone were introduced into this chamber. Ventilation was achieved through jet ventilation with disposable, non-inflammable laser jet catheters. The tissue was then repeatedly exposed to a laser beam in super-pulse mode (pulse rate 250 Hz) with various intensities and exposure lengths at an impact angle of 75 degrees. The laser intensity was varied from 2 to 15 W. The type, duration, intensity and incidence of tissue ignition were recorded and analysed. RESULTS: The degree of tissue ignition correlated with laser intensity. Low laser intensity caused spark formation whereas high intensity resulted in sustained tissue fire. The type of tissue had an impact on ignition intensity thereby showing lower ignition thresholds and higher ignition susceptibility in fat-containing tissue compared to muscle. The most important factor for occurrence of tissue ignition was the chamber oxygen concentration which displayed an inverse correlation with the time until tissue ignition. Oxygen concentrations of 35% led to tissue ignition in 42 s, 40% oxygen in 20 s. Oxygen concentrations higher than 60% resulted in immediate tissue ignition. CONCLUSIONS: Despite the use of non-inflammable materials in endoscopic laser surgery of the upper airway and hypopharynx, the risk of tissue ignition remains due to the inflammable laser smog which is easily ignited in an oxygen-rich environment. Hence to minimise this risk, we recommend using oxygen concentrations lower than 40%, low laser intensities (<6 W) and limiting continuous laser activation to periods shorter than 10 s.

Utilization of fresh human tympanic membranes for structural analysis and cytokeratin immunocytochemistry implementing resin techniques.

CONCLUSIONS: The results of this study have demonstrated for the first time that tympanic membrane (TM) structure is preserved following removal of fresh, normal tissue from patients undergoing surgery. Greater clarity has been demonstrated using resin sections than in previous studies on paraffin sections. Of particular note, cytokeratin (CK) immunocytochemistry was successfully performed on resin sections, which has not been previously reported. This may have potential applications for future work involving tissues that express CKs. OBJECTIVES: To analyse the structure of normal, fresh human TM specimens after surgical removal and to evaluate their CK immunocytochemistry using resin techniques, neither of which have been demonstrated previously. MATERIAL AND METHODS: Seven TM specimens were removed during surgery and then preserved in a modified Karnovsky's fixative. Semi-thin and thin sections were examined by means of light and electron microscopy, respectively. For comparison purposes, paraffin block-embedded specimens were also sectioned. CK immunocytochemistry was performed on semi-thin sections using standard immunoperoxidase techniques, with expression being demonstrated using light microscopy. RESULTS: The three-layer architecture of the TM was preserved. The morphology of the TM was vastly superior in the semi-thin resin sections than in the thicker paraffin sections. The outer, middle and inner layers were clearly demonstrated. The integrity of the outer epithelial layer was maintained, with an outer keratinizing stratum corneum and underlying stratum granulosum, stratum spinosum and stratum basale layers resting on the basal lamina. The thin inner mucosal layer was also viable, consisting of simple squamous or cuboidal cells. Preservation of the middle lamina propria was achieved, with demonstration of the outer radial and inner circular fibres. CK immunocytochemistry utilizing resin techniques provided excellent staining of CK 7 and 8 in the inner layer, with positive staining of CK 5 and 10 in the outer layer.

[Laser-resistance of a new jet ventilation catheter (LaserJet) under simulated clinical conditions]. / Verhalten des neuen LaserJet((R))-Katheters bei CO(2)-Laser-Anwendung unter simulierten klinischen Bedingungen.

BACKGROUND: Laser surgery within the airway is often performed with the patient under general anaesthesia and with infraglottic jet ventilation via a specially designed catheter which should not be inflammable. We investigated the laser-resistance of a recently introduced jet ventilation catheter (LaserJet) made of polytetrafluoroethylene. METHODS: For the simulation of gas accumulation in the hypopharynx a cylindric steel chamber with an open and a closed end was used to simulate the operative setting according to the European standard ISO-11990. In a series of 12 tests the disposable laser jet catheter was attached to the proximal end of the oxygen supply tubing, and the distal end was introduced 10 cm into the steel chamber. The catheter was repeatedly exposed to the beam of a CO(2)-laser device with energies varying from 2-15 W and with an impact angle of 75 degrees. The changes in the catheter were assessed with and without an oxygen flow of 6 l/min. Time of exposure varied from 1 to 10 s. Size and nature of the changes in the catheter were documented. RESULTS: We found damage to the catheter that occurred in the following order: simple (front wall) and double perforation (front and back wall), smoke emission as evidence for pyrolysis, discolouration, deformation and rupture. The extent of damage to the catheter shaft under direct laser beam exposition was dependent on the laser intensity. When there was no oxygen flow, a beam of 2 W needed 40 s to perforate the catheter shaft, while with an oxygen flow of 6 l/min, a laser intensity of 4 W needed 20 s to cause perforation. Rupture of the catheter occurred in less than 10 s with a laser intensity of 8 W or more. CONCLUSIONS: We could demonstrate that the LaserJet catheter is not inflammable and also does not sustain fire. However, it is not laser-resistant as to maintaining its texture and shape while under direct exposure to a continuous laser beam, as applied under clinical conditions. Polytetrafluoroethylene deforms and melts at temperatures above 327 degrees C which is usually exceeded by the CO(2)-laser.

A soccer player with a sore toe: recognizing subungual osteochondromas.

In contrast to usual osteochondromas, subungual osteochondromas may arise following trauma rather than from aberrations in bone development. The rarity of subungual osteochondromas frequently leads to misdiagnosis and undertreatment, especially as a sports injury. When patients have nail-bed bruising, x-rays can rule out or confirm bone involvement, as in our case of a 20-year-old soccer player who had increasing pain in his left great toe. Treatment consists of radical, anatomic resection of symptomatic osteochondromas with periosteal realignment to prevent recurrence. Functional outcome after resection is excellent.

Differences in the abundance of nuclear proteins in the bovine mammary gland throughout the lactation and gestation cycles.

The mechanisms that control the synthesis of milk protein are not fully understood and could well involve undiscovered proteins within the mammary gland. A search for such proteins in high salt extracts of nuclei that had been isolated from bovine mammary tissues was undertaken using two-dimensional electrophoresis on large format gels. The sensitivity of the procedure was sufficient to detect the transcription factors Sp1 and NF-1 by Coomassie blue stain; over 300 proteins were routinely detected. Analysis of mammary tissue taken from 5 nonlactating cows in midpregnancy, 5 cows in late lactation, and 4 cows in early involution revealed five proteins where relative abundance was altered with stage of lactation or reproductive cycle. Four of these proteins were identified by Western blotting or amino acid sequencing as lactoferrin, annexin II, vimentin, and heavy-chain immunoglobulin. Analysis of proteins after further enrichment of the extracts by heparin-Sepharose affinity chromatography revealed an additional protein that was substantially more abundant in samples from lactating cows. This 90-kDa protein did not react with anti-Stat5 antibodies. Conceivably, one or more of these six proteins could play a role in the lactational function of the bovine mammary gland.

Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA.

Interferon-alpha combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-alpha antibodies (IFN ab) occur regularly during IFN-alpha treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subcutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg bodyweight) daily or with 5-methoxypsoralen (1.2 mg/kg bodyweight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of beta 2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

Waldenstrom's macroglobulinaemia.

Waldenstrom's macroglobulinaemia is a rare form of monoclonal plasma cell dyscrasia in which there is excess production of immunoglobulin M. Clinically the patient has features of hyperviscosity syndrome and the effects of bone marrow replacement by lympho-plasmacytoid cells. We report here two such cases seen within a period of two months.