Progressive plasticity during colorectal cancer metastasis.

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

Epidemiology of acute kidney injury and the role of urinary [TIMP-2]·[IGFBP7]: a prospective cohort study in critically ill obstetric patients.

BACKGROUND: There are few data regarding acute kidney injury in critically-ill obstetric patients. A combination of urinary cell cycle arrest markers, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein7 (IGFBP7), is validated for the early prediction of acute kidney injury in non-obstetric patients. METHODS: We evaluated the epidemiology of acute kidney injury in critically-ill obstetric patients and the role of the biomarker combination in predicting acute kidney injury and mortality. Acute kidney injury, its severity and risk factors, were assessed using Kidney Disease: Improving Global Outcomes (KDIGO) guidelines during the intensive care unit stay. An ELISA technique measured TIMP-2 and IGFBP7 in urine samples collected at the time of admission there. RESULTS: Results for 66 patients showed an overall incidence of acute kidney injury of 40/66 (61%), with 50%, 10% and 40% being in stage 1, 2 and 3 respectively. Patients with acute kidney injury showed significantly greater sepsis and shock; longer stay and higher mortality during intensive care (33% vs 0%) and in hospital (38% vs 0%) compared to those without (P <0.05). The area-under-the receiver operating characteristics curve was <0.5 for urinary [TIMP-2]·[IGFBP7] as a predictor of kidney injury and mortality (P >0.05). CONCLUSIONS: Acute kidney injury is common in critically-ill obstetric patients, increasing mortality and duration of hospitalization. It was significantly more common in patients with septic shock. Previously validated results of urinary [TIMP-2]·[IGFBP7] that successfully predict early acute kidney injury or mortality are not applicable to obstetric patients.

Aneurysmal hemorrhage in a pregnant patient with coarctation of aorta: An anesthetic challenge.

A 25years old female patient with pregnancy of 16weeks (G2 P1), diagnosed to have distal anterior cerebral artery aneurysm (DACA) with Hunt & Hess grade I, subarachnoid hemorrhage (SAH) and coexisting atretic type of aortic coarctation posted for aneurysmal clipping under general anesthesia is a challenge to anesthesiologists in perioperative period. Hypertensive surges in a pregnant patient may result in rupture of aneurysms. Mortality in the mothers with CoA has been reported to be in the range of 0 to 9%. Anesthetic management of a pregnancy with CoA and SAH has never been reported.

Nanodiscs in the studies of membrane-bound cytochrome P450 enzymes.

Cytochromes P450 from eukaryotes and their native redox partners cytochrome P450 reductases both belong to the class of monotopic membrane proteins containing one transmembrane anchor. Incorporation into the lipid bilayer significantly affects their equilibrium and kinetic properties and plays an important role in their interactions. We describe here the detailed protocols developed in our group for the functional self-assembly of mammalian cytochromes P450 and cytochrome P450 reductases into Nanodiscs with controlled lipid composition. The resulting preparations are fully functional, homogeneous in size, composition and oligomerization state of the heme enzyme, and show an improved stability with respect to P420 formation. We provide a brief overview of applications of Nanodisc technology to the biophysical and biochemical mechanistic studies of cytochromes P450 involved in steroidogenesis, and of the most abundant xenobiotic-metabolizing human cytochrome P450 CYP3A4.

Facial wrigglies: live extralymphatic filarial infestation in subcutaneous tissues of the head and neck.

We report a rare case of a 32-year-old male with live extralymphatic filarial infestation presenting as a facial subcutaneous soft-tissue swelling. To the best of our knowledge these imaging findings have not been previously reported in the head and neck region in the existing English language literature. Real-time high-resolution ultrasonography revealed a solitary well-defined subcutaneous cystic lesion over the right zygomatic arch. It showed multiple linear, echogenic, undulating structures exhibiting a persistent twirling motion during the examination. This typical ultrasonographic appearance was consistent with the filarial dance sign (FDS) of live adult filarial worms. Subsequent MRI confirmed the cystic and solitary nature of the lesion. Complete excision of the cyst was performed, which revealed intracystic straw-coloured fluid and multiple white-coloured adult worms within the lesion. Histopathological examination confirmed multiple adult filarial worms with surrounding reactive inflammatory changes. In an endemic region, identification of the FDS in any normal anatomical structure or abnormal swelling, however remote or unusual the location within the body, should strongly suggest the diagnosis of live active filarial infestation. In view of the increasing migratory trends in the global population, it is imperative for radiologists in all countries to be aware of the typical imaging findings of this disease to arrive at the correct diagnosis.

Tuberculosis in the head and neck--a forgotten differential diagnosis.

The aim of the present review is to illustrate the pathogenesis and imaging findings of tuberculosis in specific head and neck regions to avoid pitfalls in diagnosis. It is imperative to be aware of, and provide an early diagnosis for, extra-pulmonary tubercular lesions in the head and neck. A high index of suspicion combined with an appropriate clinical setting serves as an important background to diagnose tubercular lesions in the head and neck region and differentiate them from malignancy and other disease entities. Early diagnosis and treatment can prevent irreversible and debilitating complications and mortality from disseminated tuberculosis.

A case-control study on insulin resistance, metabolic co-variates & prediction score in non-alcoholic fatty liver disease.

BACKGROUND & OBJECTIVE: Asian Indians have a high prevalence of insulin resistance and the metabolic syndrome. Currently, non-alcoholic fatty liver disease (NAFLD) is considered to be an integral part of the metabolic syndrome with insulin resistance as a central pathogenic factor. We studied anthropometric parameters, insulin resistance and metabolic co-variates in subjects with NAFLD as compared to those without NAFLD, and also developed a prediction score for NAFLD. METHODS: Thirty nine subjects with NAFLD and 82 controls were selected for the study after ultrasonography of 121 consecutive apparently healthy subjects. Anthropometric profile [body mass index (BMI), waist circumference (WC) etc,], lipid profile, hepatic aminotransferases, fasting blood glucose (FBG), insulin were recorded and value of homeostasis model assessment of insulin resistance (HOMA-IR) was analysed. Step-wise logistic regression analysis and area under the receiver operator curve (aROC) were analysed to arrive at a prediction score. RESULTS: Overall, prevalence of NAFLD was 32.2 per cent and prevalence of metabolic syndrome was seen in 41 per cent among cases and 19.5 per cent in controls (P<0.01). Subjects with NAFLD had significantly higher values of BMI, WC, hip circumference, FBG, fasting insulin, total cholesterol and serum triglycerides. Step-wise logistic regression analysis showed odds ratio (OR) and 95 per cent confidence interval (CI) for BMI [ 4.3 (1.6, 11.3)], FBG [5.5 (1.5, 19.8)] and fasting insulin [ 2.4 (1.0, 5.8)] as independent predictors of NAFLD. The prediction score for NAFLD was; 1 (fasting insulin) +1.6 (BMI) + 1.9 (FBG) (sensitivity of 84.6%, specificity of 51.2% and aROC 76%). INTERPRETATION & CONCLUSION: In this study, presence of NAFLD indicated close relationship with multiple features of metabolic syndrome. The prediction score developed could be used as a screening tool to predict NAFLD among Asian Indians in north India.

Unloading the trunk: neurasthenia, CFS and race.

The aetiologies of both chronic fatigue syndrome (CFS) and its predecessor neurasthenia, have been linked to technological advances in 'developed' countries. This paper discusses how this has led to a form of race thinking within discussions about fatigue which has persisted for more than a century. We review the historical development of this race thinking from neurasthenia to CFS and describe how it is manifested in both the lay- and medical literature. We also review the epidemiological literature on CFS and ethnicity to better understand the relatively low percentage of non-white patients seen in tertiary referral clinics for CFS. The aim of this paper is to act as a starting point for a debate on race and CFS.

Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix.

BACKGROUND AND PURPOSE: The Eppendorf pO(2) histograph is the 'gold standard' method for measuring tumour oxygenation. The method is not suitable for widespread application because its use is limited to accessible tumours. A non-invasive imaging technique would be an attractive alternative. Therefore, the relationships between tumour oxygenation and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters were investigated. MATERIALS AND METHODS: The study comprised 30 patients with carcinoma of the cervix. Tumour oxygenation was measured pre-treatment as median pO(2) and the proportion of values less than 5 mmHg (HP5) using a pO(2) histograph. Repeat measurements were obtained for nine patients following 40-45 Gy external beam radiotherapy giving a total of 39 measurements. Dynamic contrast-enhanced MRI using gadolinium was performed prior to obtaining the oxygenation data. Time/signal intensity curves were generated to obtain two standard parameters: maximum enhancement over baseline (SI-I) and the rate of enhancement (SI-I/s). RESULTS: Using the 39 measurements, there was a significant correlation between SI-I and both median pO(2) (r=0.59; P<0.001) and HP5 (r=-0. 49; P=0.002). There was a weak, borderline significant correlation between SI-I/s and both median pO(2) (r=0.29; P=0.071) and HP5 (r=-0. 34; P=0.037). There was a significant relationship between tumour size and SI-I (r=0.54; P<0.001), but not SI-I/s. In 29 tumours, where data were available, there was no relationship between histological assessment of tumour angiogenesis (intra-tumour microvessel density; IMD) and either MRI parameter. CONCLUSIONS: Tumour oxygenation levels measured using a pO(2) histograph correlate with dynamic contrast-enhanced MRI parameters. Therefore, non-invasive dynamic MRI may be a method for measuring hypoxia in human tumours.

Specific impairment of smiling increases the severity of depressive symptoms in patients with facial neuromuscular disorders.

Depressive symptoms and related emotional distress are prevalent among patients with facial neuromuscular disorders, and the psychological distress impacts the functional disabilities associated with the facial impairment. A specific impairment in the ability to smile may elevate the risk for depression, with patients experiencing a reduced physiological feedback associated with smiling as well as the social consequences of the inability to communicate positive emotion. We tested the hypothesis that specific impairments in the ability to smile increase the severity of depressive symptoms in patients with facial neuromuscular disorders. Twenty-nine consecutive patients (mean age, 50.2 years; SD, 17.0 years; range, 18-81 years) with a facial neuromuscular disorder, who volunteered and completed all of the assessment measures participated. Facial neuromuscular impairments were assessed using multiple measures of facial motility and dysfunction, and emotional functioning was assessed using self-report measures of depression, anxiety, and positive and negative affect. Severity of global facial impairment was statistically controlled in evaluating the association between specific impairment in smiling and the degree of depressive symptoms. Separate hierarchical linear regression analyses indicated the specific impairment of smiling contributed to the prediction of depression (R(2) =.41, df = 3,25, p =.00) and anxiety (R(2) =.35, df = 3,25, p =.00), controlling first for the contribution of global impairment and facial physical disability. The specific impairment of smiling did not contribute to the prediction of positive emotional experience. Specific impairment of smiling and physical disability, but not global impairment of facial motion, were key predictors of depression in patients with facial neuromuscular disorders. The results emphasize the need to assess and treat depression and anxiety in patients with a facial neuromuscular disorder.

Quantitation of patterns of facial movement in patients with ocular to oral synkinesis.

As patients with facial paralysis regain facial nerve function, they must endure and adapt to complications associated with recovery, such as synkinesis. Synkinesis is the presence of unintentional movement in one area of the face when intentionally performing movement in another area of the face. We used the Maximal Static Response Assay of facial motion to better define the differences between eye closure-associated perioral motion in normal individuals, motion of the affected side in patients with synkinesis, and motion of the unaffected side in patients with synkinesis, thereby characterizing the syndrome of ocular to oral synkinesis. The study population consisted of 78 patients with clinically defined ocular to oral synkinesis of the left or right hemiface and 27 individuals without facial impairment (control subjects). We used the Maximal Static Response Assay to quantify facial motion on the affected and unaffected sides during the motions of eye closure and smile in both groups. Patients with ocular to oral synkinesis had decreased supraorbital and infraorbital motion of the orbicularis oculi during eye closure on both the affected and unaffected sides relative to control subjects. They also had increased modiolar motion during eye closure on both sides relative to control subjects. On the affected side, the modiolus tended to move laterally; on the unaffected side, the modiolus tended to move medially (i.e., toward the side affected by the synkinesis). Modiolar motion present during eye closure in patients with ocular to oral synkinesis was not statistically different from modiolar motion present during smile on the affected side (eye closure, 0.39 cm +/- 0.25; smile, 0.47 cm +/- 0.30, p > 0.05). Using the Maximal Static Response Assay, we have quantitatively defined synkinesis of the affected hemiface and have shown that movement of the unaffected hemiface is influenced by the synkinetic movements of the affected hemiface. These data may provide the basis for a rational system of facial neuromuscular rehabilitation in this patient group.

Quantitative facial motion analysis after functional free muscle reanimation procedures.

The purpose of this study was to evaluate the success of functional free muscle transfer in patients with chronic facial paralysis using a recently developed quantitative method known as the maximum static response assay of facial motion. A retrospective review of a single surgeon series of six patients with longstanding facial paralysis was performed. The maximum static response assay was performed on all patients preoperatively and serially during the postoperative period. Twenty-seven patients (54 sides) with normal facial function were also evaluated and served as controls. The contralateral normal side in those patients with unilateral facial paralysis (n = 4) also served as a control. Movement of the modiolus during smile was recorded in the x axis and y axis. To determine net smile movement, the vector of movement was calculated by means of the Pythagorean theorem. Vectors were then defined mathematically by calculating direction and magnitude. The average direction of the vector during smile for the normal control population was 58.3 degrees (range 32.5 to 83.1 degrees) from the horizontal through the modioli, and the average magnitude was 10.6 mm (range 4.2 to 20.1 mm). The average preoperative direction for the reanimated sides was 176.8 degrees with a range of 83.3 to 225 degrees. Patients with bilateral paralysis (n = 2) were excluded for calculation of the vectors on the normal contralateral side. The average preoperative direction for the normal contralateral side in patients with facial paralysis was 58.3 degrees with a range of 48.2 to 68.4 degrees. Postoperatively, the average direction of the vector during smile for the reanimated sides improved to a value of 77.6 degrees with a range of 45.7 to 113.8 degrees. The average change in direction of the preoperative reanimated side compared with the postoperative reanimated side was significant (p = 0.01). Postoperatively, the average direction of the vector for the contralateral normal sides was 43 degrees with a range of 11 to 57.2 degrees. The change in direction for the contralateral normal side was not significant (p = 0.18). The average magnitude of the reanimated side improved from a non-anatomic 2.8 mm preoperatively (range 0.8 to 6.8 mm) to an anatomic 4.9 mm postoperatively (p = 0.02). The contralateral normal side magnitude decreased from 9.4 mm (range 7.3 to 11.6 mm) preoperatively to 5.7 mm (range 3.8 to 7.7 mm) postoperatively (p = 0.006). More specifically, the absolute change in movement on the reanimated side during smile for the x axis and y axis was 2.3 mm (p = 0.05) and 4.0 mm (p = 0.002), respectively. This corresponded to an absolute change in the magnitude of the vector of 4.6 mm in an anatomic direction. On the contralateral side the absolute change in magnitude during smile from preoperative to postoperative for the x axis and y axis decreased by 1.5 mm (p = 0.13) and 5.3 mm (p = 0.05), respectively. This reflected an absolute change in the magnitude of the vector of 5.5 mm. Functional free muscle transfer in patients with chronic facial paralysis resulted in anatomic recovery of motion in the majority of patients in this series. The maximum static response assay can be used to objectively assess the results of facial reanimation.

Quantitative analysis of facial motion components: anatomic and nonanatomic motion in normal persons and in patients with complete facial paralysis.

The maximal static response assay of facial motion, described in 1994, enables the simultaneous measurement of multiple facial motions by tracking the positions of specific facial points. While the maximal static response assay provides accurate measurement of facial motion, the analysis of these data lacks the simplicity of a single-number scale such as the House-Brackmann system, a subjective scale traditionally used to classify facial function. The purpose of this study was to develop a simplified numerical index capable of summarizing the data generated by the maximal static response assay in a clinically meaningful way. We also wanted to develop a method whereby only anatomic motion or nonanatomic motion in the paralyzed face could be quantitated. Anatomic motion is the motion of the specific facial points studied by the maximal static response assay that can be attributed solely to the pull of the regional facial muscles that govern the movement of those points. Nonanatomic motion is motion that is secondary to the pull of the unaffected contralateral muscles that is transmitted to the paralyzed hemiface. Thirty-four patients with complete facial paralysis were studied. The maximal static response assay was performed on all patients on presentation to the Facial Nerve Center at the University of Pittsburgh Medical Center or after development of complete facial palsy postoperatively. The data from these patients were compared with maximal static response assay data from 26 unaffected controls. The anatomic index of facial motion and the nonanatomic index of facial motion were calculated for all study participants. The anatomic index of facial motion measures anatomic facial motion, and the nonanatomic index of facial motion measures nonanatomic facial motion. To calculate the anatomic index of facial motion, the vector magnitudes of the supraorbital, infraorbital, and modiolar motions during brow lift, eye closure, and smile are summed. The anatomic index of facial motion represents a ratio of this sum on the affected side to the corresponding sum on the unaffected side using only anatomic motions. The nonanatomic index of facial motion is a similar ratio using nonanatomic motion only (i.e., motions in directions that cannot be produced by the ipsilateral muscles). The anatomic index of facial motion represents a single number that can be used to assess facial motion. The value of the anatomic index of facial motion for patients with complete facial paralysis is 0.07 +/- 0.08. The anatomic index of facial motion for normal individuals is 1.05 +/- 0.13 (p < 0.0001, Mann-Whitney rank-sum test). The nonanatomic index of facial motion in normal individuals is 0.05 +/- 0.08; in patients with complete facial paralysis, it is 0.34 +/- 0.32 (p < 0.0001, Mann-Whitney rank-sum test). During recovery from complete facial paralysis, the anatomic index of facial motion and the nonanatomic index of facial motion each revert steadily toward normal values. The anatomic index of facial motion and the nonanatomic index of facial motion are single numbers based on the maximal static response assay, which quantitatively describes anatomic motion and nonanatomic motion in patients with complete facial paralysis. Although patients with complete facial paralysis have motion on the paralyzed hemiface, the motion is primarily nonanatomic. Both indices can be used to track recovery from complete facial paralysis.

Gastric regurgitation during general anaesthesia in different positions with the laryngeal mask airway.

Ninety patients, divided into three groups of 30, were investigated to determine the incidence of gastric regurgitation during general anaesthesia administered via the laryngeal mask airway in the supine, Trendelenburg and lithotomy positions. Fifteen minutes before induction of anaesthesia each patient swallowed a 75 mg methylene blue capsule. At the end of surgery, the LMA and the oropharynx were inspected for bluish discoloration which was considered to be a sign of gastric regurgitation. No blue dye was detected in the supine group but it was observed in one patient in each of the other two groups.

The evaluation of a new intravascular blood gas monitoring system in the pig.

OBJECTIVE: Our objective was to investigate the accuracy of a new intravascular blood gas sensor, the Paratrend 7 (P7) (Biomedical Sensors Ltd, Pfizer Hospital Products Group, High Wycombe, England) in a porcine model. METHODS: A total of 12 sensors were inserted into 10 animals under total intravenous anesthesia. Changes in blood gas chemistry were produced over a wide range by manipulating the inspired oxygen and carbon dioxide concentrations and by adjustments in minute ventilation. Blood gas samples (BGA) were taken and analyzed during periods of stability; the results obtained were compared with the readings from the intravascular sensor. RESULTS: A total of 292 blood gas samples were taken and analyzed for pHa, PaCO2, and Po2; the results were compared with the readings from the intravascular sensor. Correlation coefficients of r = 0.98 for PCO2 and r = 0.99 for PO2 were obtained. Analysis of bias and precision as mean +/- SD of the difference (P7 - BGA) gave the following results: pH bias = -0.03, precision = +/- 0.04; PCO2 bias = 0.65 mm Hg, precision = +/- 3.1 mm Hg; and PO2 bias = -6.50 mm Hg, precision = +/- 0.6 mm Hg. No problems with clot formation on the sensor were seen, and the sensors did not appear to show the "wall effect" seen with other systems. CONCLUSIONS: The results obtained were well within the requirements for a clinically useful blood gas monitoring system.

Genetic aspects of variability in superficial vein responsiveness to norepinephrine.

Venoconstriction of the dorsal hand vein by local norepinephrine infusion was measured by the linear variable differential transformer method in 15 healthy unrelated subjects and eight pairs of monozygotic and six pairs of dizygotic twins. Incremental norepinephrine infusion produced dose-related venoconstriction. In unrelated subjects the doses of norepinephrine constricting basal vein diameter by 50% (ED50) ranged from 3.9 to 120.5 ng/min. There was a positive linear relationship between doses of norepinephrine infused and local steady-state plasma concentrations of norepinephrine achieved in each subject. The reciprocals of the slopes of these dose-concentration relationships, which reflect local norepinephrine clearance (disposition) in the vein, ranged from 0.47 to 1.86 ml/min. Plasma concentrations of norepinephrine associated with reduction of basal vein diameter by 50% (EC50) ranged from 1.4 to 110.2 ng/ml, with variability similar to that of ED50. There was a very high level of concordance in ED50, EC50, and clearance of norepinephrine within pairs of monozygotic twins but not within dizygotic twins. Differences in pharmacokinetics of infused norepinephrine exert a minor impact on overall intersubject variability. Genetic aspects of "tissue responsiveness" (i.e., vascular alpha-adrenoceptor response, smooth muscle contractility, and endothelial function) appear to be largely responsible for the wide intersubject variability in venoconstrictor responsiveness to norepinephrine.