Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women.

BACKGROUND: Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference. PATIENTS AND METHODS: We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls. RESULTS: In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER-) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 0.98). CONCLUSION: Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Indications of that migration of stem cells is influenced by the extra cellular matrix architecture in the mammalian intervertebral disk region.

Disk-degeneration is believed a major cause for lumbar pain. Previously, potential stem cell niches in the intervertebral disk (IVD) region, located adjacent to epiphyseal plate, was reported. The aim of the study was to examine migration of mesenchymal stem cells (MSCs), extracellular matrix (ECM) architecture in a potential cellular migration route (CMR; area located between the niche and IVD) and in the IVD in non-degenerated lapine- and in human degenerated IVD tissues. Human MSCs (n=3), human degenerated IVD tissues (n=10) and lapine IVDs (n=10) were collected. The samples were examined by immunohistochemistry for stem cell markers; CD90, OCT3/4, pre-chondrocytic marker; GDF5, catabolic markers; MMP9, MMP13, inflammatory marker; IL1R, cellular migration markers; SNAI1, SNAI2, adhesion markers; ß1-INTEGRIN and DDR2. In addition, gene-expression analyses (Real time PCR) were performed on additional samples. Further, time lapse studies were performed with hMSCs cultured on aligned COLL-I-fibers-coated glass-slides in DMEM-LG, 10% human serum containing fibroblast growth factor (bFGF). Presence of stem cells (CD90+, OCT3/4+), pre-chondocytic cells (GDF5+) and cells positive for migration markers (SNAI1+, SNAI2+), catabolic markers (MMP9+, MMP13+), inflammatory marker (IL1R+), adhesion markers (DDR2+, B1-INTEGRIN+) were detected (gene- and protein level) in investigated CMR and IVD regions. In the time lapse studies, MSCs alignment and protrusions were observed orientated in the same direction as collagen fibers. Results display influence of ECM collagen architecture and collagen fiber spatial direction on migration of stem cells. The results can be useful when developing tissue-engineering strategies for disk-degeneration.

Moderate physical exercise results in increased cell activity in articular cartilage of the knee joint in rats.

BACKGROUND: Moderate exercise regimens have shown minor positive effects on matrix turnover in articular cartilage (AC), while effects at cellular level, e.g. proliferation, are scarcely described. AIM: The aim of this study was to investigate the effects of moderate exercise on cell proliferation and recruitment of cells possibly active in regeneration in different regions of cartilage in the rat knee joint. METHODS: Eighteen rats were orally given 5-bromo-2-deoxyuridine (BrdU) for 14 days for in vivo DNA labeling. Nine rats underwent treadmill training for 50 min/day, 5 days/week (exercise group), and 9 rats served as controls (no exercise). Animals were sacrificed after 14, 56 and 105 days, and knee joints were harvested. BrdU+ cells were visualized immunohistochemically (IHC) and counted in AC, posterior stem cell niche (PN), potential migration route (PMR; area between PN and the AC border), potential migration area (PMA; region between PN and AC including PN) and epiphyseal cartilage plate (EP) of the tibia and femur. RESULTS: Compared to controls, in the exercise group BrdU+ cells/mm(2) were increased on days 14 (p = 0.022) and 105 (p = 0.045) in AC of the tibia and on day 105 (p = 0.014) in AC of the femur. BrdU+ cell numbers were increased in the PMR region of the tibia on days 14 (p = 0.023) and 105 (p = 0.0018) and in the PMR region of the femur on day 105 (p = 0.0099) as well as in the PMA region of the tibia (p = 0.0008) and femur (p = 0.0080) on day 105. No significant differences in BrdU+ cells/mm(2) were seen in PN or EP between the groups at any time point. Regarding collagen 2A1 expression and proteoglycan accumulation, no significant differences between groups were detected. CONCLUSIONS: The results indicate increased cell activity in AC in response to physical exercise and may help to understand the complexity of AC regeneration in the normal mammal knee joint.

Thoraco-abdominal injuries: the general surgeon's perspective.

BACKGROUND: Thoraco-abdominal traumatic injuries affect the inferior part of the thoracic cavity and the superior part of the abdominal cavity. This study summarizes five years of our surgical department's experience in the diagnosis and management of thoracoabdominal trauma patients. METHODS: We examined records from our surgical and emergency room departments from January 1996 to December 2000, and selected patients with thoraco-abdominal injuries. RESULTS: Fifty-five patients were treated who suffered coexisting trauma of the thoracic and abdominal cavity. Males represented the majority of patients and mean age was 38.2 years. Traffic accidents were the major cause (55%) followed by criminal acts of violence (32%) and falls (13%). The most common thoracic injuries were rib fractures (40%) and simple lung contusions (35%) and the abdominal organs most commonly injured were the spleen (35%), liver (25%) and kidney (20%). Surgical interventions were performed in 68% of patients, whereas the remaining patients were treated conservatively. CONCLUSIONS: Thoraco-abdominal injuries are characterized by high heterogeneity and can provide significant decision-making challenges. The accurate diagnosis of all coexisting injuries is critically important, as the diagnosis will determine surgical or non-operative management of these injuries.

Neuroendocrine tumor of the cystic duct.

Neuroendocrine tumours of the extrahepatic bile ducts are extremely rare with less than 70 cases having been reported in the literature. Neuroendocrine tumours are neoplasms of variable malignant potential that arise from the embryonic neural crest cells. They most commonly occur in young females and usually present with painless jaundice. Preoperative diagnosis is seldom made and neuroendocrine tumours are usually incidentally found during abdominal surgical intervention for other indication. Due to their indolent biological behaviour aggressive surgical treatment is recommended. We present a case of an incidentally discovered neuroendocrine tumour of the cystic duct in a 41 year old woman following laparoscopic cholecystectomy for symptomatic gallbladder microlithiasis. The present case is the 8th case of cystic duct NET and the 63rd of extrahepatic bile duct NET. While a rare location for a NET, it is important to report cases of biliary tract neuroendocrine tumours in order for their pathogenesis and physical history to be clarified.

Duodenal gastrointestinal stromal tumor presenting with acute upper gastrointestinal bleeding treated with segmental resection.

Gastrointestinal stromal tumours (GISTs) are considered to derive from the interstitial cells of Cajal or their precursors and are defined by their expression of c-kit protein (CD117) that is positive in 95% percent of cases. These are rare mesenchymatous tumours, while they represent the most common mesenchymal tumours of the alimentary tract. The majority of GISTs develop in the stomach and small intestine and more rarely in the rectum, colon, esophagus and mesentery; only 3-5% of all GISTs are located in the duodenum. The presenting symptoms include early satiation, dysphagia, bloating, abdominal pain and gastrointestinal bleeding, either acute or chronic. Surgery remains the mainstay of treatment for localized, non-metastatic, resectable GISTs. We present a case of duodenal gastrointestinal stromal tumour of the third portion of the duodenum that presented with acute upper gastrointestinal bleeding treated with segmental duodenal resection.

Lymphoepithelioma-like gastric carcinoma presenting as giant ulcer of the lesser curvature: case report.

Lymphoepithelioma-like gastric carcinoma (LELGC) has special clinicopathologic features that differentiate it from the common gastric adenocarcinoma. LELGC is a rare neoplasm of the stomach with an incidence of 1-4% of all gastric cancers and is characterized by desmoplastic stroma uniformaly infiltrated by abundant lymphocytes and plasma cells. LELGC is closely associated with the Epstein-Barr virus (EBV), with 80-100% of LELGC being EBV-positive. LELGC has a male predominance, occurs in elderly people and is usually located in the upper and middle portion of the stomach. We report a rare case of lymphoepithelioma-like gastric carcinoma located in the lesser curvature at the border of the gastric body to the pyloric antrum.

Incidentally discovered white subcupsular liver nodules during laparoscopic surgery: biliary hamartoma and peribiliary gland hamartoma.

During routine laparoscopic surgery, the surgeon may encounter the presence of small white subcapsular liver nodules, either solitary or multiple. The lesions may mimic liver metastasis and in many cases are not demonstrated in the preoperative ultrasound or computed tomography. The aim of this article is to familiarize the laparoscopic surgeon with the incidental discovery of these nodules which represent the two types of intrahepatic benign bile duct proliferations and include biliary hamartomas, which are usually multiple benign malformations of the intrahepatic bile ducts, and peribiliary gland hamartoma, which is usually solitary and consists of a benign epithelial tumor of the liver derived from bile duct cells.

Mesothelial mesenteric cyst in patient with ascending colon cancer. Case report.

Mesenteric cysts are rare cystic malformations of the mesentery. They are usually located at the iliac mesentery. Clinically most mesenteric cysts are asymptomatic, but sometimes they present with non-specific abdominal symptoms. Diagnosis can be aided using US, CT and MRI but careful interpretation of the images and high index of suspicion of this rare condition is essential for the correct diagnosis, which cannot always be preoperatively established. The therapeutic method of choice is complete surgical excision of the cyst which minimizes the possibility of recurrence. Histopathologically they are classified in six group. We present a case of a mesothelial mesenteric cyst in patient with colon cancer. The cyst was misdiagnosed as urinary bladder diverticulum in the preoperative CT scan.

Long term follow up of eosinophilic granuloma of the rib.

UNLABELLED: BACKROUNDS: Eosinophilic granuloma is one of the rarest causes of bone tumors, especially in adults. Eosinophilic granuloma is the commonest form of Langerhans cell histiocytosis and represents the unifocal osseous form of the disease which usually affects the skull and long bones. Eosinophilic granuloma, is a benign disease in which diagnosis and differential diagnosis presents more difficulties than treatment. OBSERVATION: We present a case of eosinophilic granuloma of the rib with long term follow-up of 14 years which was treated with a combination of surgery and chemotherapy. CONCLUSION: Prognosis of adult eosinophilic granuloma is excellent and the recurrence rate is limited. All available treatment options, including surgery, chemotherapy, corticosteroids, radiation, and even palliative treatment have very good results and in many cases the disease seems to heal spontaneously. However the disease, due to its rarity and unknown pathogenesis still remains an enigma for the clinical doctor.

Sister Mary Joseph's nodule as the sole presenting sign of gastric signet ring cell adenocarcinoma.

The Sister Mary Joseph's nodule is a periumbilical metastatic tumor originating from advanced metastatic intra-abdominal and intrapelvic malignancies. It is an inconspicuous and uncommon clinical sign, which not only shows the presence of visceral malignancy but also reveals the poor prognosis of these malignancies. The majority of cases originate from gastrointestinal or ovarian cancer. We present a case of an 80-year-old woman with an umbilical nodule, which was the sole presenting symptom of advanced signet ring cell carcinoma of the stomach with generalized peritoneal carcinomatosis. There are very few cases of gastric signet ring cell adenocarcinoma presenting as a SMJN, a fact rather striking as signet ring cell gastric carcinoma has an increased frequency of peritoneal dissemination and carcinomatosis of the peritoneum.

Pilomatricoma of the arm with extensive ossification.

Pilomatricoma is a benign skin tumor derived from the hair follicle, usually located in the head and neck and presenting in the first two decades of life. Clinically it most commonly presents as a hard, mobile, well circumscribed nodule. Microscopically it is characterized by the presence of shadow cells and may show calcification, while extensive ossification is rare. Surgical removal is the treatment of choice, as the recurrence rate is very low. We present a rare case of late regressive pilomatricoma of the arm in a 33 year old female which presented with extensive ossification.

Gas content of binary clathrate hydrates with promoters.

We develop a methodology to calculate the gas storage capacity of binary hydrates stabilized by promoters. This model utilizes equilibrium experimental data of both hydrates (i.e., the hydrate of pure promoter and the binary hydrate of gas and promoter) in order to calculate the gas occupancy in the small cavities that are not occupied by the promoter. The new approach, although based on the traditional van der Waals-Platteeuw theory, has two significant advantages. The hypothetical state of an empty hydrate for the calculation of the chemical potential of water is replaced by the hydrate of the pure promoter whose properties can be determined through simple thermodynamic calculations. In addition, the computational difficulties related to the complete occupancy of the large cavities by the promoter are removed. The proposed methodology is applied to calculate the gas storage capacity of hydrates of two energy-carrier gases (methane and hydrogen) stabilized by tetrahydrofuran. Excellent agreement is observed between the proposed-model predictions and published experimental values for the gas content of hydrates.

Hydrogen storage in sH hydrates: a Monte Carlo study.

Grand canonical Monte Carlo simulations are performed to evaluate the hydrogen-storage capacity of the recently discovered hydrogen hydrates of the sH type, at 274 K and up to 500 MPa. First, the pure H2 hydrate is investigated in order to determine the upper limit of H 2 content in sH hydrates. It is found that the storage capacity of the hypothetical pure H2 hydrate could reach 3.6 wt % at 500 MPa. Depending on pressure, the large cavity of this hydrate can accommodate up to eight H2 molecules, while the small and medium ones are singly occupied even at pressures as high as 500 MPa. Next, the binary H2-methylcyclohexane sH hydrate is examined. In this case, the small and medium cavities are again singly occupied, resulting in a maximum H2 uptake of 1.4 wt %. Finally, the results from simulations on pure H2 and binary hydrates are utilized to investigate the potential of H2 storage in sH hydrates where the promoter molecules occupy the medium instead of the large cavities.

Evidence-based review of aetiopathogenic theories of congenital and acquired cholesteatoma.

Cholesteatoma is a non-neoplastic, keratinising lesion which has two forms: congenital and acquired. Congenital cholesteatoma develops behind a normal, intact tympanic membrane, whilst acquired cholesteatoma is associated with a defect in the tympanic membrane. The pathological substrate of cholesteatoma is keratinising stratified squamous epithelium, but the origin of this epidermal tissue in the middle ear is controversial. Here, we review the most relevant and recent evidence for the principal aetiopathogenic theories of both forms of cholesteatoma, in the light of recent otopathological findings. Congenital cholesteatoma is most plausibly explained by the persistence of fetal epidermoid formation. Conclusive 'proof' awaits the unambiguous demonstration of the metamorphosis of an epidermoid nidus into a lesion in vivo. Acquired cholesteatoma may develop by various mechanisms: immigration, basal hyperplasia, retraction pocket and/or trauma (iatrogenic or non-iatrogenic). However, squamous metaplasia of the normal cuboidal epithelium of the middle ear is a highly unlikely explanation. Chronic inflammation seems to play a fundamental role in multiple aetiopathogenic mechanisms of acquired cholesteatoma. Therefore early treatment of inflammatory conditions might reduce their sequelae, perhaps by preventing the development of hyperplastic papillary protrusions. Continued otopathological, cellular and molecular research would enhance our limited understanding of cholesteatoma and may lead to new therapeutic strategies for this erosive disease, which often defies surgical treatment.

How we do it: A novel approach to the skin--abutment interface of the bone-anchored hearing aid: use of local skin flaps.

Various techniques involving skin grafts have been described to obtain thin hairless immobile skin at the abutment interface of the bone-anchored hearing aid (BAHA), but none are without significant complications such as necrosis and/or infection leading to total graft failure. A novel technique involving four local thin skin flaps was developed to prevent serious complications. The procedure essentially involves raising skin flaps at the intradermal level leaving the hair follicles in the subcutaneous tissue, which is subsequently excised. We have used the skin-flap approach around 21 BAHAs on 19 patients (two patients had bilateral devices) and the only complications were minor skin loss immediately adjacent to the implants in two patients and mild skin infections, which settled with topical antibiotics, in three patients. The innovative technique described is simple and straightforward, and does not require any special instrumentation. Furthermore, it may have specific advantages, in terms of morbidity, over contemporary skin grafting methods primarily because of the retained intrinsic blood supply of the skin flaps.

Schwannoma of tongue base treated with transoral carbon dioxide laser.

Schwannomas are benign slow growing solitary tumours of nerve sheath origin and can arise from any myelinated nerve. They have been reported to occur in most parts of the body with the highest incidence (25%) in the head and neck region, although tongue base lesions are rare. The tumour is resistant to radiotherapy, and therefore, the treatment of choice is surgery. We present a case of a tongue base schwannoma which was completely extirpated with a carbon dioxide laser via the transoral approach. The patient experienced virtually no morbidity from the use of the laser. Whilst tongue base schwannoma has been documented, we could not find an earlier report in the English literature describing our method of treatment. We conclude that transoral carbon dioxide laser can be added to the surgical armamentarium for the management of other similar cases in the future.

Idiopathic sudden sensorineural hearing loss: prognostic factors.

OBJECTIVES: Sudden sensorineural hearing loss (SSHL) remains a challenge for the clinician. In the majority of cases, no definite cause can be found and the prognosis is variable. METHODS: The present study assessed 114 patients suffering from idiopathic SSHL, with regard to the prognostic value of demographic, epidemiologic, neurotologic and audiometric factors. In addition, the relationship between the identification of wave V in auditory brainstem responses and the final hearing outcome was investigated. All patients received 75 mg/day intravenous prednisolone, divided into three daily doses, for 10 days, with gradual tapering of the dose over the next 10 days. RESULTS: The results (after one year follow up) revealed the following factors to be related to a better hearing outcome: younger age; male sex; less time elapsed between the onset of hearing loss and the beginning of treatment; and an upward-sloping or cupeloid audiogram contour. The detection of wave V early in recovery and within the first month of medical treatment might also constitute a significant favourable factor in respect to hearing recovery. CONCLUSIONS: The present study revealed that there are certain factors that affect prognosis in idiopathic SSHL. This is very important in counselling patients and may affect current clinical practice.

Bleeding from the upper gastrointestinal tract after Mason's vertical banded gastroplasty.

BACKGROUND: Gastric bleeding is a rare complication after a vertical banded gastroplasty (VBG). Only a few cases of gastric bleeding after a VBG have been reported, and there is discussion about its etiology. We present two cases of gastric bleeding after a VBG, and discuss the etiology, diagnostic approach and management. METHODS: During the period 1989-98, we treated two cases of gastric bleeding out of 328 morbidly obese patients that underwent a VBG. The first patient was a 36-year-old woman with body mass index (BMI) 61.5. Gastric bleeding occurred on the 7th postoperative day, due possibly to the increased dose of Low Weight Molecular Heparin (LWMH) which was administrated as prophylactic anticoagulation. The second case concerns a 27-year-old man with 54.0 BMI. Gastric bleeding occurred on the 16th postoperative day and was attributed to a stress ulcer. RESULTS: Both patients were treated conservatively successfully. In the first patient, bleeding was stopped when LWMH was discontinued. In the second patient, bleeding was stopped by gastroscopic epinephrine injection in the bleeding spot. CONCLUSIONS: From our cases and review of the literature, gastric bleeding after a VBG is rare, may be treated easily with conservative measures. Tension of the mesh that surrounds the canal between the two compartments, gastric mucosal irritation from the nasogastric tube and postoperative stress ulcer formation are the most frequent causes of this complication.