Charcot neuroarthropathy triggered by osteomyelitis and/or surgery.

INTRODUCTION: Charcot neuroarthropathy (CN) is a rare but devastating complication of diabetic neuropathy. Osteomyelitis is also a complication of the diabetic foot and it may be difficult to differentiate from CN. PATIENTS AND METHODS: A patient with Type 1 diabetes and peripheral neuropathy developed a foot ulcer complicated by osteomyelitis of the first proximal phalanx. He was successfully treated with antibiotics and surgical excision of the infected bone. Six months later, he developed a hot, swollen, red foot and X-ray showed destruction of the second and third metatarsal heads. At the second presentation, it was difficult to determine whether this was a recurrence of osteomyelitis or a new onset of CN. Thus, to obtain a definitive diagnosis, recourse was made to more sophisticated imaging techniques. RESULTS: 99mTc methylenediphosphonate (MDP) bone scans and magnetic resonance imaging proved inconclusive to differentiate between osteomyelitis and CN. Subsequently, an indium-labelled white cell scan confirmed the absence of osteomyelitis and the patient was successfully treated for CN. DISCUSSION: Infection and/or surgery may be predisposing factors in the development of diabetic CN but the combination of the two could accelerate the onset of the Charcot process in people with diabetes and neuropathy.

Automated characterization of multiple alpha peaks in multi-site electroencephalograms.

The identification of alpha rhythm in the human electroencephalogram (EEG) is generally a laborious task involving visual inspection of the spectrum. Moreover the occurrence of multiple alpha rhythms is often overlooked. This paper seeks to automate the process of identifying alpha peaks and quantifying their frequency, amplitude and width as a function of position on the scalp. Experimental EEG was fitted with parameterized spectra spanning the alpha range, with results categorized by multi-site criteria into three distinct classes: no distinguishable alpha peak, a single alpha peak, and two alpha peaks. The technique avoids visual bias, integrates spatial information, and is automated. We show that multiple alpha peaks are a common feature of many spectra.

Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.

Angiogenesis is a key process in tumor growth and metastasis and is a major independent prognostic factor in breast cancer. A range of cytokines stimulate the tumor neovasculature, and tumor-associated macrophages have been shown recently to produce several important angiogenic factors. We have quantified macrophage infiltration using Chalkley count morphometry in a series of invasive breast carcinomas to investigate the relationship between tumor-associated macrophage infiltration and tumor angiogenesis, and prognosis. There was a significant positive correlation between high vascular grade and increased macrophage index (P = 0.03), and a strong relationship was observed between increased macrophage counts and reduced relapse-free survival (P = 0.006) and reduced overall survival (P = 0.004) as an independent prognostic variable. These data indicate a role for macrophages in angiogenesis and prognosis in breast cancer and that this cell type may represent an important target for immunoinhibitory therapy in breast cancer.

Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.

Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis in vivo are not well defined. Multiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the relationship of expression to estrogen receptor and vascular density was also examined. Vascular endothelial growth factor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor (TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, and thymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNase protection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidine phosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that of ER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P = 0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesis may involve a coordinate regulation of some vascular growth factors. High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normal breast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P = 0.01). Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be of value in a combined approach to therapy.

A note on the bone age at which patients with true isolated growth hormone deficiency enter puberty.

Nineteen boys with true isolated growth hormone deficiency developed the first stages of puberty at an average bone age of 12.0"years" (Tanner Whitehouse Method 2, RUS score). The average chronological age was 15.0 years. Seven similar girls entered puberty at 10.9"years" in bone age and 13.7 years in chronological age. The means and ranges of bone age at beginning of puberty of these patients are very close to those of normal children.

Dose dependence of growth response to human growth hormone in growth hormone deficiency.

A trial of the relative effect on growth of 20 IU/week and 10 IU/week of human growth hormone has been made in 38 patients with "isolated" growth hormone deficiency over 1 year of treatment, 18 patients over 2 years and 10 over 3 years, and in 17 patients with surgically treated craniopharyngiomata over 1 year. The velocity of height growth in the first year of treatment, compared with a full year of pre-treatment control, was 1.3 times as great in both groups of patients on the larger dose as it was in those on the smaller one. Second-degree equations fitted to the treatment catch-up curve gave estimates of 1.7 cm more height gained on the larger dose by the end of the first year, 2.7 cm by the end of the second, and 3.4 cm by the end of the third. Adjusting treatment increment by covariance for bone age at the beginning of treatment, pre-treatment velocity, and body surface area did not alter these mean differences. Bone age velocity during treatment was the same in both treatment groups (mean 1.09 "years"/year in the first year); thus we anticipate a gain in final adult height of the order of 10 cm from employing the larger dose. The decrease in skin folds occurring on treatment, however, was no different with the larger than with the smaller dose. This reinforces previous observations that the short-term metabolic and longer-term auxologic effects of hGH are not necessarily related.

Reduced bone mineral density in patients with adult onset growth hormone deficiency.

We have demonstrated previously that adults with isolated GH deficiency of childhood onset have a reduced bone mineral density (BMD) of vertebral trabecular bone [quantitative computed tomography (QCT): median Z score -1.3, P < 0.01, n = 12] and of cortical bone in the forearm [single photon absorptiometry (SPA): median Z score -2.9, P = 0.001, n = 7]. We have now examined BMD in 26 patients (13 men, 13 women), aged between 23.6 and 59.5 (mean 42.4) yr, with adult onset GH deficiency, defined as a GH response of less than 5 micrograms/L to provocative testing, of at least two years duration. BMD was measured using QCT for vertebral trabecular bone, dual energy x-ray absorptiometry (DXA) in the lumbar spine and femoral neck, and SPA in the forearm. There was a highly significant reduction in QCT (median Z score -1.07, P < 0.00005), in DXA of the lumbar spine (median Z score -0.76, P = 0.0001) and in SPA of the forearm (median Z score -0.86, P = 0.0001) but not in DXA of the femoral neck (median Z score -0.38, P = 0.35). There were no significant differences in Z scores between those patients with isolated GH deficiency and those with GH and gonadotrophin deficiency. There was a significant positive correlation between age at which BMD was measured and Z score (the older the patient, the higher the Z score) for QCT (r = 0.38, P < 0.05) and SPA (r = 0.48, P < 0.01) with a trend to a positive correlation for DXA of the lumbar spine and femoral neck. Patients were grouped according to estimated duration of GH deficiency (less than 5 yr, n = 7; 5-10 yr, n = 10; greater than 10 yr, n = 9). These groups did not show a significant difference in BMD at any site. We conclude that patients with adult onset GH deficiency (isolated or in conjunction with other pituitary hormone deficiencies) have a reduced BMD. Age at development of GH deficiency may be more important than duration of GH deficiency in determining the degree of reduction in bone mass. The impact of GH treatment on BMD in adults with adult onset GH deficiency requires investigation.

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency.

The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.

A novel cyclic adenosine monophosphate analog induces hypercalcemia via production of 1,25-dihydroxyvitamin D in patients with solid tumors.

The treatment of cancer patients with conventional chemotherapy is sometimes associated with severe systemic toxicity and only a minimal survival benefit. Because of this, new less toxic and more efficacious treatments have been sought. 8-Chloro-cAMP (8-Cl-cAMP) is one of a new generation of anticancer drugs that act at the level of signal transduction. In preclinical models, 8-Cl-cAMP modulates protein kinase A (PKA) leading to growth inhibition and increased differentiation of cancer cells. 8-Cl-cAMP was given to 16 patients with advanced cancer as an infusion via an indwelling subclavian venous catheter. We showed that 8-Cl-cAMP had a parathyroid hormone-like effect leading to increased synthesis of renal 1,25-dihydroxyvitamin D [up to 14 times the baseline value, median 3.6 times; P = 0.00001 (Student's paired t test)]. This produced the dose-limiting toxicity of reversible hypercalcemia that could not be controlled by the administration of either pamidronate or dexamethasone. The treatment was otherwise well tolerated, and other cAMP-dependent pathways (cortisol and TSH) were not affected, emphasizing the marked differences between organs in their sensitivity to this cAMP analog. Our results have shown that 8-Cl-cAMP is biologically active, and it is feasible that if the hypercalcemia can be controlled, then this drug may have a role as a single agent, or as a short infusion between cycles of chemotherapy.

Neurophysical modeling of brain dynamics.

A recent neurophysical model of brain electrical activity is outlined and applied to EEG phenomena. It incorporates single-neuron physiology and the large-scale anatomy of corticocortical and corticothalamic pathways, including synaptic strengths, dendritic propagation, nonlinear firing responses, and axonal conduction. Small perturbations from steady states account for observed EEGs as functions of arousal. Evoked response potentials (ERPs), correlation, and coherence functions are also reproduced. Feedback via thalamic nuclei is critical in determining the forms of these quantities, the transition between sleep and waking, and stability against seizures. Many disorders correspond to significant changes in EEGs, which can potentially be quantified in terms of the underlying physiology using this theory. In the nonlinear regime, limit cycles are often seen, including a regime in which they have the characteristic petit mal 3 Hz spike-and-wave form.

Enlargement of the tensor intermuscularis muscle in Graves' ophthalmopathy. A computed tomographic and magnetic resonance imaging study.

OBJECTIVE: To determine whether the tensor intermuscularis muscle (TIM), which consists of muscle fibers in the superolateral intermuscular orbital septum, is involved in Graves' ophthalmopathy (GO). DESIGN: The computed tomographic (n = 24) and magnetic resonance imaging (n = 10) appearances of the TIM were retrospectively examined in 34 patients with known GO. The severity of GO was assessed by applying a scoring system from 0 to 3 (ie, normal [0], mild [1], moderate [2], and severe [3]) to each of the rectus muscles and superior oblique muscle. The severity of exophthalmos, enlargement of the superior ophthalmic vein, and displacement of the lacrimal gland were also recorded. RESULTS: The TIM appeared as thickening of the septum immediately behind the globe, and it was best seen on coronal magnetic resonance images. There was enlargement of the TIM in 19 of the 34 patients, and it was bilateral in 17. Enlargement was present only in patients with moderate or severe involvement of other muscles (muscle index, > 7/15), and it was significantly correlated with the muscle index (P < .05), exophthalmos (P < .05), enlargement of the superior ophthalmic vein (P < .005), and anterior displacement of the lacrimal gland (P < .01). Severe enlargement of the TIM was seen in only five of the 34 patients, and it showed a close correlation with the muscle index (P < .005), exophthalmos (P < .001), enlargement of the superior ophthalmic vein (P < .001), and anterior displacement of the lacrimal gland (P < .001). CONCLUSIONS: Enlargement of the TIM in GO can be identified on computed tomographic and magnetic resonance imaging scans. It is invariably associated with moderate or severe involvement of other extraocular muscles, and it correlates closely with other well-recognized imaging features of severe GO.

Tumor angiogenesis in stage II colorectal carcinoma: association with survival.

We studied the frequency of microvessels in T3 N0 M0 colorectal carcinomas from patients with widely different survival times. Microvessels (<50 microm diameter) were enhanced by immunostaining with antibody to factor VIII-related antigen and counted in 40x high-power fields in sections of resected carcinomas from 9 patients who died of disease in 24 months or less (short-term survivors) and 13 who had no evidence of disease at 109 months or longer (long-term survivors). The means of the 10 highest counts for each case were compared between the long- and short-term survivor groups. The mean +/- SD microvessel count was 25.4 +/- 6.5 for the short-term survivors and 30.3 +/- 6.4 for the long-term survivors. Median counts were 27.2 and 29.4, respectively. The distribution of microvessel counts was skewed toward higher counts in the long-term survivors. There was no correlation between microvessel counts and tumor site, size, or grade; lymphovascular invasion; or the presence of a mucinous component. Although there was a trend toward a higher frequency of microvessels in patients with longer survival, it is unlikely that microvessel count is an independent prognostic indicator for patients with T3 N0 M0 colorectal carcinoma because there is only a small difference in microvessel frequency between patients with widely different survival times.

Prediction of enophthalmos by computed tomography after 'blow out' orbital fracture.

In 11 patients with blow out fracture of the orbit, measurement of orbital volume using computed tomography (CT) more than 20 days after injury correlated well with enophthalmos measured from the same scans (r = 0.87, p < 0.001, SEE 0.63 mm), with a 1 cm3 increase in orbital volume causing 0.8 mm of enophthalmos. This confirms the cause of enophthalmos after blow out fracture to be increase in orbital volume rather than fat atrophy or fibrosis. In a further 25 patients scanned within 20 days of injury the degree of enophthalmos was less marked than would be predicted from the orbital volume measurement. This was probably because of the presence of oedema, haemorrhage, or both behind the globe which would prevent immediate development of enophthalmos. CT measurement of orbital volume within 20 days of injury may predict the final degree of enophthalmos and identify those patients at risk of late enophthalmos, allowing appropriate early surgical intervention.

Orbital volume measurement in the management of pure blowout fractures of the orbital floor.

With the recent advent of accurate orbital volume assessment by computed tomography, a retrospective analysis was made of 31 patients with 'pure' blowout fracture of the orbital floor, managed either surgically or conservatively, to determine whether orbital volume measurement could provide an additional parameter of use in the management of such fractures. There was a significant difference in orbital volume discrepancy between patients managed surgically or conservatively suggesting that this investigation may be of use in decision making on surgical intervention in patients with orbital blowout fractures.

C-erbB-2 oncoprotein expression in operable non-small cell lung cancer.

Although c-erbB-2 oncoprotein immunohistochemical expression has been thoroughly studied in a variety of human tumors, its prognostic significance remains unclear. Moreover, differences in assessment criteria further complicate the evaluation of c-erbB-2 as a prognostic marker. In the present study we examined the expression of c-erbB-2 protein in 107 patients suffering from operable (T 1,2-N0, 1 staged) non-small cell lung cancer (30 adenocarcinomas and 69 squamous cell carcinomas) treated with surgery alone. A 3-7 year of follow up (median 45 months) was available for all patients. Paraffin embedded sections were stained with the NCL-CB11 monoclonal antibody using the immunoperoxidase technique. Analysis was based on cytoplasmic reactivity as membrane staining was impossible to assess against this background. Strong positive cytoplasmic staining was identified in 20/107 (19%) of cases, weak in 30/107 (20%) and negative in 57/107 (53%). Results were correlated with patient variables (age,sex) and tumor parameters (T,N-stage, grade, histology, Ki67 proliferation index, p53 and EGFR expression). C-erbB-2 expression was not related to any of these factors. Although c-erbB-2 defined a worse prognosis, univariate analysis of survival did not confirm any statistically significant difference between the c-erbB-2 staining groups (p=0.5). T,N-stage were the only statistically significant prognostic variables. Any contribution of c-erbB-2 to the development of tumour aggressive behaviour in non-small cell lung cancer requires assessment in the specific subgroups of patients.

Non-small cell lung cancer: c-erbB-2 overexpression correlates with low angiogenesis and poor prognosis.

Tumour angiogenesis is an important prognostic factor in non-small cell lung cancer. Recently, EGFR and c-erbB-2 protein was found to regulate cell adhesion and the invasive growth of cancer through its association with the cadherin-catenin complex. The role of c-erbB-2 protein in cell migration has been also reported. In this study we investigate the combined role of tumoral neoangiogenesis and c-erbB-2/EGFR expression in the metastatic behaviour and prognosis of operable non-small cell lung cancer. 107 tumour samples from patients suffering from operable non small cell lung cancer were examined. EGFR and c-erbB-2 were not correlated with each other. C-erbB-2 expression was associated with low angiogenesis, approaching statistical significance in adenocarcinomas (p = 0.08). The absence of expression of both c-erbB-2 and EGFR oncogenes in tumours with high angiogenesis, was most frequently observed in node negative cases (p = 0.04). C-erbB-2 overexpression defined a subgroup of node negative patients with low angiogenesis and prognosis similar to patients with tumours bearing high angiogenesis. These findings support the hypothesis that expression of the erb genes is a mechanism activated in non-small cell lung cancer to enable cancer cell migration. This pathway seems to be activated mainly in tumours with poor vasculature presumably lading to an unfavourable intratumoral nutritional and oxygen ambience.

Predicting distant failure in nasopharyngeal cancer.

In a prospective study of 78 patients with nasopharyngeal cancer, we examined the prognostic significance of T stage, histology, parapharyngeal involvement, and lymph node dimensions, size, and level concerning distant metastasis. AU patients were treated with radical radiotherapy alone and completed 3 to 7 years of follow-up. In univariate analysis of time to metastasis, there was a significant difference stratifying for T stage (T1 and 2 versus T3 and 4), node dimensions (less than 6 versus more than or equal to 6 cm), neck level (above versus below the thyroid notch), and parapharyngeal involvement, but not for bilaterality of lymphadenopathy. Histology was an important prognostic factor related to distant metastasis since none of the 24 World Health Organization class I cases showed distant metastasis versus 14 (26%) of 54 patients with World Health Organization class II/III carcinoma. A multivariate duration model of time to metastasis within the later histologic group suggested that lymph node dimensions, node level, and T stage were the most important factors related to distant metastases, with the hazard ratios being 3.98, 3.23, and 1.76, respectively. Multivariate analysis within the T3- to T4-stage group showed that node dimension was the only significant variable, with an associated hazard ratio of 4.09. Cases with upper-neck lymphadenopathy and node dimensions of less than 6 cm had a distant metastasis rate of <5%. We conclude that adjuvant chemotherapy for nasopharyngeal cancer is justified in T3- and T4-staged cases with nonkeratinizing or undifferentiated histology and with lymph nodes larger than 6 cm and/or located below the thyroid notch.

Computed tomography attenuation measurements for the characterization of hepatic haemangiomas.

The attenuation values of 21 hepatic haemangiomas in 19 patients were measured on non-enhanced computed tomographic (CT) scans and compared with the attenuation of adjacent liver and the inferior vena cava (IVC). The attenuation of hepatic haemangiomas was lower than that of the surrounding liver, but there was no correlation between these two measurements. There was a highly significant correlation between the attenuation of haemangiomas and blood in the vena cava (r = 0.905, p less than 0.001). All the haemangiomas had attenuations within 7 HU of caval blood. By comparison, in 34 hypodense hepatic lesions that did not show contrast-enhanced appearances characteristic of haemangioma, there was no significant correlation between the attenuation of the lesions and the IVC. Nineteen (56%) of these lesions had attenuations differing more than 7 HU from that of caval blood. The influence of this observation on the requirement for dynamic contrast-medium-enhanced and delayed post-contrast CT in the assessment of hepatic lesions is discussed.

Low-dose computed tomographic imaging in orbital trauma.

We review the findings in 75 computed tomographic (CT) examinations of 66 patients with orbital trauma who were imaged using a low-radiation-dose CT technique. Imaging was performed using a dynamic scan mode and exposure factors of 120 kVp and 80 mAs resulting in a skin dose of 11 mGy with an effective dose-equivalent of 0.22 mSv. Image quality was diagnostic in all cases and excellent in 73 examinations. Soft-tissue abnormalities within the orbit including muscle adhesions were well demonstrated both on primary axial and reconstructed multiplanar images. The benefits of multiplanar reconstructions are stressed and the contribution of soft-tissue injuries to symptomatic diplopia is examined.

Contrast-enhanced computed tomography of the normal and abnormal gallbladder.

One hundred and fourteen upper abdominal computed tomography examinations performed before and after intravenous contrast were reviewed. In 48 patients who had no evidence of biliary or pancreatic disease, the mean gallbladder wall attenuation before contrast was 25 +/- 13 HU and after contrast 42 +/- 18 HU, with a wall thickness of 1.9 +/- 0.43 mm. In 14 patients with chronic pancreatitis these values were 24 +/- 10.5 HU, 44 +/- 25 HU and 2.0 +/- 0.54 mm, respectively. In a further group of 15 patients with chronic biliary disease, the values were 34 +/- 15 HU, 53 +/- 18 HU and 2.3 +/- 0.9 mm. The degree of wall enhancement was statistically significant in each group. There was no statistical difference in the attenuation characteristics or wall enhancement between normal patients and those with chronic pancreatitis. Patients with chronic biliary disease had a thicker gallbladder wall with higher attenuation before contrast but a similar degree of enhancement.