Imaging-Based Diagnosis of Autosomal Dominant Polycystic Kidney Disease

The clinical use of conventional ultrasonography (US) in autosomal dominant polycystic kidney disease (ADPKD) is currently limited by reduced diagnostic sensitivity, especially in at-risk subjects younger than 30 years of age. In this single-center prospective study, we compared the diagnostic performance of MRI with that of high-resolution (HR) US in 126 subjects ages 16–40 years born with a 50% risk of ADPKD who underwent both these renal imaging studies and comprehensive PKD1 and PKD2 mutation screening. Concurrently, 45 healthy control subjects without a family history of ADPKD completed the same imaging protocol. We analyzed 110 at-risk subjects whose disease status was unequivocally defined by molecular testing and 45 unaffected healthy control subjects. Using a total of >10 cysts as a test criterion in subjects younger than 30 years of age, we found that MRI provided both a sensitivity and specificity of 100%. Comparison of our results from HR US with those from a previous study of conventional US using the test criterion of a total of three or more cysts found a higher diagnostic sensitivity (approximately 97% versus approximately 82%) with a slightly decreased specificity (approximately 98% versus 100%) in this study. Similar results were obtained in test subjects between the ages of 30 and 40 years old. These results suggest that MRI is highly sensitive and specific for diagnosis of ADPKD. HR US has the potential to rival the diagnostic performance of MRI but is both center- and operator-dependent.     

Use of Tunneled-Cuffed Central Catheters in Patients with Cancer: A Single-Center Experience

Background

Effective and reliable venous access is among the cornerstones of modern medical therapy in oncology.

E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress

Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen’s virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using α-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb’s KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites.The bacterium Mycobacterium tuberculosis (Mtb), which causes tuberculosis, has plagued humanity since antiquity (1), is estimated to infect one-third of the population today, and is the leading cause of death by a bacterium. This success as a pathogen reflects Mtb’s metabolic plasticity and resistance to host immunity (2, 3). Recent evidence suggests that certain enzymes of central carbon metabolism (CCM) can mediate both of these facets of Mtb’s adaptation to the host (4–8). Here, we demonstrate that Rv1248c, recently named 2-hydroxy-3-oxoadipate synthase (HOAS) (9), is one such enzyme.Rv1248c was first annotated as the thiamin diphosphate (ThDP)-dependent E1 component (SucA) of a canonical α-ketoglutarate (α-KG) dehydrogenase complex (KDHC) that produces succinyl CoA (SucCoA) via oxidative decarboxylation of α-KG with concomitant transfer of the resulting succinyl group to CoA (10). Classically, KDHC, composed of three enzymes, joins the oxidative and reductive half-cycles of the TCA cycle (SI Appendix, Fig. S1). The TCA cycle generates high-energy phosphate bonds and biosynthetic precursors of amino acids, nucleotides, and fatty acids (11). However, KDHC activity was not detected in Mtb lysates, and the gene product annotated as the lipoamide-bearing E2 component [Rv2215, dihydrolipoyl succinyl transferase (SucB)] functions as the E2 component dihydrolipoyl acetyl transferase (DlaT) of the pyruvate dehydrogenase complex (PDHC) (5, 12, 13). The Mtb genome does not encode another SucB (12), and KDHC activity could not be demonstrated with purified recombinant Rv1248c plus DlaT and E3 [lipoamide dehydrogenase (Lpd)] in a manner similar to cognate proteins from other actinomycetes (14). Rv1248c by itself produces succinate semialdehyde (SSA) from nonoxidative decarboxylation of α-KG in vitro, and Mtb’s succinate semialdehyde dehydrogenases (SSADHs) can generate succinate from SSA, completing a modified TCA cycle (13). Subsequently, activity-based metabolomic profiling revealed yet another function of Rv1248c that predominated over SSA production: decarboxylation of α-KG, followed by carboligation with glyoxylate to form 2-hydroxy-3-oxoadipate (HOA). Thus, Rv1248c was renamed HOAS (9). Decarboxylation of α-KG is the first step in all three reactions. The Mycobacterium smegmatis α-ketoglutarate decarboxylase (MsKGD) homolog was found to catalyze all three reactions in vitro, with augmentation of catalysis by acetyl CoA (AcCoA)-mediated allosteric modulation (15), whereas Mtb HOAS showed a kinetic preference for the HOAS pathway in vitro (16).HOAS activity is regulated in Mtb by glycogen accumulation regulator A (GarA), whose activity is controlled, in turn, by Ser/Thr kinases PknG and PknB (SI Appendix, Fig. S1B). GarA also regulates glutamate dehydrogenase (GDH) and glutamate synthase/glutamine oxoglutarate aminotransferase (17). Coregulation of these three enzymes by GarA calls attention to the contribution of HOAS to Mtb’s metabolism of glutamate. Glutamate serves as an anaplerotic substrate entering the TCA cycle as α-KG and is also a key intermediate in nitrogen assimilation and metabolism (18, 19).Despite extensive studies, the physiological function of HOAS in Mtb and its contribution to virulence remain unknown. Here, we brought genetics, metabolomics, enzymology, and mouse models of infection to bear on that question, using the hoas deletion mutant in Mtb and the deletion mutant complemented in three ways: with the WT allele, with an allele with a point mutation that abrogates catalysis, or with an allele with a point mutation that is insensitive to allosteric regulation by AcCoA. In standard culture conditions, Δhoas showed no defect in growth or changes in levels of CCM metabolites, arguing against Mtb’s reliance on the conventional function of KDHC. However, situational stresses revealed striking phenotypes in Δhoas, indicative of a defensive role of HOAS against products arising from metabolism of glutamate and against reactive nitrogen intermediates (RNIs). Mechanistic analysis of the latter phenotype revealed a previously undescribed route to antioxidant defense mediated by substrates and enzymes of CCM.     

Snake bite induced cellulitis leading to infected open dislocation of the first metacarpophalangeal joint – A rare complication

Non-traumatic open dislocation of the first metacarpophalangeal joint is a rare phenomenon. We present a rare such occurrence secondary to snake bite induced cellulitis. A 22-year-old girl presented with pain and instability of her right thumb two months. She had snake bite two months back following which she developed cellulitis which gradually became infected. She presented with raw area over her dorsal aspect of the thumb with active infection. Radiographs revealed metacarpophalangeal joint dislocation. She underwent debridement, stabilisation and soft tissue coverage. At final follow up, she was pain free and the wound healed completely.     

Carcinogens in Food: Evaluating the Presence of Cadmium,Lead, in Poultry Meat in South India

Objective: Local chickens were spontaneously sampled and slaughtered in the central markets of Coimbatore, Erode, and Namakkal districts, South India. Materials and Methods: Wet digestion was used to extract lead (Pb), cadmium (Cd), and zinc (Zn) in their blood and selected different organs (intestine, breast, liver, and gizzard), and their concentrations were measured using an atomic absorption spectrophotometer. Results: Apart from the blood of chickens from Coimbatore and Namakkal, where Pb was not found, the concentrations of Pb in the blood and organs of chickens from the three towns ranged from 1.8 to 8.33 mg/kg, exceeding the maximum tolerance thresholds (0.1 mg/kg) in internal organs of poultry birds. Except for the intestine of chickens from the three areas, Cd was only found in the heart, blood, and gizzard of Erode chickens, as well as the liver and gizzard of Namakkal chickens, in concentrations ranging from 0.13 to 0.58. According to threshold level, the upper limit met the maximum limits (0.5 mg/kg). Zn was found in all sections of chickens from the three selected districts, with concentrations ranging from 4.96 to 174.17 mg/kg. Conclusion: Its concentrations were within the permissible limits (10-50 mg/kg) in some areas of certain chickens, but it surpassed the permissible limit in the liver of chicken from Coimbatore. Any organs and blood from local chickens sold in Coimbatore, Erode, and Namakkal areas can be hazardous to one’s health.     

A Phase II Study of the Efficacy and Safety of Chloroquine in Combination With Taxanes in the Treatment of Patients With Advanced or Metastatic Anthracycline-refractory Breast Cancer

IntroductionChemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy.Patients and MethodsFemale patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis.ResultsThirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events.ConclusionA combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.     

Accurate measurement of brain changes in longitudinal MRI scans using tensor-based morphometry

This paper responds to Thompson and Holland (2011), who challenged our tensor-based morphometry (TBM) method for estimating rates of brain changes in serial MRI from 431 subjects scanned every 6 months, for 2 years. Thompson and Holland noted an unexplained jump in our atrophy rate estimates: an offset between 0 and 6 months that may bias clinical trial power calculations. We identified why this jump occurs and propose a solution. By enforcing inverse-consistency in our TBM method, the offset dropped from 1.4% to 0.28%, giving plausible anatomical trajectories. Transitivity error accounted for the minimal remaining offset. Drug trial sample size estimates with the revised TBM-derived metrics are highly competitive with other methods, though higher than previously reported sample size estimates by a factor of 1.6 to 2.4. Importantly, estimates are far below those given in the critique. To demonstrate a 25% slowing of atrophic rates with 80% power, 62 AD and 129 MCI subjects would be required for a 2-year trial, and 91 AD and 192 MCI subjects for a 1-year trial.     

A Risk Score to Predict Arrhythmias in Patients with Unexplained Syncope

OBJECTIVES: To develop and validate a risk score predicting arrhythmias for patients with syncope remaining unexplained after emergency department (ED) noninvasive evaluation. METHODS: One cohort of 175 patients with unexplained syncope (Geneva, Switzerland) was used to develop and cross-validate the risk score; a second cohort of 269 similar patients (Pittsburgh, PA) was used to validate the system. Arrhythmias as a cause of syncope were diagnosed by cardiac monitoring or electrophysiologic testing. Data from the patient's history and 12-lead emergency electrocardiography (ECG) were used to identify predictors of arrhythmias. Logistic regression was used to identify predictors for the risk-score system. Risk-score performance was measured by comparing the proportions of patients with arrhythmias at various levels of the score and receiver operating characteristic (ROC) curves. RESULTS: The prevalence of arrhythmic syncope was 17% in the derivation cohort and 18% in the validation cohort. Predictors of arrhythmias were abnormal ECG (odds ratio [OR]: 8.1, 95% confidence interval [CI]=3.0 to 22.7), a history of congestive heart failure (OR: 5.3, 95% CI=1.9 to 15.0), and age older than 65 (OR: 5.4, 95% CI=1.1 to 26.0). In the derivation cohort, the risk of arrhythmias ranged from 0% (95% CI=0 to 6) in patients with no risk factors to 6% (95% CI=1 to 15) for patients with one risk factor, 41% (95% CI=26 to 57) for patients with two risk factors, and 60% (95% CI = 32 to 84) for those with three risk factors. In the validation cohort, these proportions varied from 2% (95% CI=0 to 7) with no risk factors to 17% (95% CI=10 to 27) with one risk factor, 35% (95% CI=24 to 46) with two risk factors, and 27% (95% CI=6 to 61) with three risk factors. Areas under the ROC curves ranged from 0.88 (95% CI=0.84 to 0.91) for the derivation cohort to 0.84 (95% CI=0.77 to 0.91) after cross-validation within the same cohort and 0.75 (95% CI=0.68 to 0.81) for the external validation cohort. CONCLUSIONS: In patients with unexplained syncope, a risk score based on clinical and ECG factors available in the ED identifies patients at risk for arrhythmias.     

Superior prognostic utility of gross and metabolic tumor volume compared to standardized uptake value using PET/CT in head and neck squamous cell carcinoma patients treated with intensity-modulated radiotherapy

Objective

To compare the prognostic utility of the 2-[¹⁸F] fluoro-2-deoxy-d-glucose (FDG) maximum standardized uptake value (SUV_max), primary gross tumor volume (GTV), and FDG metabolic tumor volume (MTV) for disease control and survival in patients with head and neck squamous cell carcinoma (HNSCC) undergoing intensity-modulated radiotherapy (IMRT).

Methods

Between 2007 and 2011, 41 HNSCC patients who underwent a staging positron emission tomography with computed tomography and definitive IMRT were identified. Local (LC), nodal (NC), distant (DC), and overall (OC) control, overall survival (OS), and disease-free survival (DFS) were assessed using the Kaplan?CMeier product-limit method.

Results

With a median follow-up of 24.2?months (range 2.7?C56.3?months) local, nodal, and distant recurrences were recorded in 10, 5, and 7 patients, respectively. The median SUV_max, GTV, and MTV were 15.8, 22.2?cc, and 7.2?cc, respectively. SUV_max did not correlate with LC (p?=?0.229) and OS (p?=?0.661) when analyzed by median threshold. Patients with smaller GTVs (<22.2?cc) demonstrated improved 2-year actuarial LC rates of 100 versus 56.4?% (p?=?0.001) and OS rates of 94.4 versus 65.9?% (p?=?0.045). Similarly, a smaller MTV (<7.2?cc) correlated with improved 2-year actuarial LC rates of 100 versus 54.2?% (p?p?=?0.04). Smaller GTV and MTV correlated with improved NC, DC, OC, and DFS, as well.

Conclusion

GTV and MTV demonstrate superior prognostic utility as compared to SUV_max, with larger tumor volumes correlating with inferior local control and overall survival in HNSCC patients treated with definitive IMRT.     

The electrodiagnostic evaluation of radiculopathy

Electrodiagnostic studies play an important role in the evaluation of radiculopathy. This article reviews the use of standard nerve conduction studies, late responses, evoked potentials, and needle electrode examination in the work-up of lumbosacral and cervical radiculopathy.