Anti-α4ß7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease.

Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of T cells to the gastrointestinal (GI) endothelium by blocking the α4ß7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.

Portable Pocket colposcopy performs comparably to standard-of-care clinical colposcopy using acetic acid and Lugol's iodine as contrast mediators: an investigational study in Peru.

OBJECTIVE: Our goal was to develop a tele-colposcopy platform for primary-care clinics to improve screening sensitivity and access. Specifically, we developed a low-cost, portable Pocket colposcope and evaluated its performance in a tertiary healthcare centre in Peru. DESIGN AND SETTING: Images of the cervix were captured with a standard-of-care and Pocket colposcope at la Liga Contra el Cáncer in Lima, Peru. POPULATION: Two hundred Peruvian women with abnormal cytology and/or human papillomavirus positivity were enrolled. METHODS: Images were collected using acetic acid and Lugol's iodine as contrast agents. Biopsies were taken as per standard-of-care procedures. MAIN OUTCOME MEASURES: After passing quality review, images from 129 women were sent to four physicians who provided a diagnosis for each image. RESULTS: Physician interpretation of images from the two colposcopes agreed 83.1% of the time. The average sensitivity and specificity of physician interpretation compared with pathology was similar for the Pocket (sensitivity = 71.2%, specificity = 57.5%) and standard-of-care (sensitivity = 79.8%, specificity = 56.6%) colposcopes. When compared with a previous study where only acetic acid was applied to the cervix, results indicated that adding Lugol's iodine as a secondary contrast agent improved the percent agreement between colposcopes for all pathological categories by up to 8.9% and the sensitivity and specificity of physician interpretation compared with pathology by over 6.0 and 9.0%, respectively. CONCLUSIONS: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when used to identify precancerous and cancerous lesions using acetic acid and Lugol's iodine during colposcopy examinations in Peru. TWEETABLE ABSTRACT: The Pocket colposcope performance was similar to that of a standard-of-care colposcope when identifying cervical lesions.

Introduction of biosimilar insulins in Europe.

Regulatory approval of the first biosimilar insulin in Europe, LY2963016 insulin glargine (Abasaglar® ), in 2014 expanded the treatment options available to people with diabetes. As biosimilar insulin products come to market, it is important to recognize that insulin products are biologicals manufactured through complex biotechnology processes, and thus biosimilar insulins cannot be considered identical to their reference products. Strict regulatory guidelines adopted by authorities in Europe, the USA and some other countries help to ensure that efficacy and safety profiles of biosimilar insulins are not meaningfully different from those of the reference products, preventing entry of biological compounds not meeting quality standards and potentially affecting people's glycaemic outcomes. This review explains the concept of biosimilar medicines and outlines regulatory requirements for registration of biosimilar insulins in Europe, which is illustrated by the successful development of LY2963016 insulin glargine and MK-1293 insulin glargine (Lusduna® ). Preclinical and clinical comparative studies of the biosimilar insulin glargine programmes include in vitro bioassays for insulin and insulin-like growth factor 1 receptor binding, assessment of in vitro biological activity, evaluation of pharmacokinetic/pharmacodynamic profiles in phase I studies and assessment of long-term safety and efficacy in phase III studies. The emergence of biosimilar insulins may help broaden access to modern insulins, increase individualized treatment options and reduce costs of insulin therapy.

Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine.

The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52-week open-label (ELEMENT-1) and 24-week double-blind (ELEMENT-2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment.

Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study.

AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus®) insulin glargine (IGlar) in patients with type 1 diabetes (T1D). METHODS: This phase III, randomized, open-label, 52-week study enrolled patients with T1D [glycated haemoglobin (HbA1c) ≤11%] being treated with basal (once-daily) and bolus insulin. Patients were randomized to receive once-daily LY IGlar (n = 268) or IGlar (n = 267) in combination with mealtime insulin lispro for 52 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met the non-inferiority criteria compared with IGlar for change in HbA1c from baseline to 24 weeks [-0.35 vs -0.46%, least-squares mean difference 0.108% (95% confidence interval -0.002 to 0.219), p > 0.05]. There were no significant (p > 0.05) treatment differences in other efficacy measures, including proportion of patients reaching HbA1c <7%, daily mean blood glucose, and insulin dose at 24 and 52 weeks. At 52 weeks, similar findings were observed between LY IGlar and IGlar for safety outcomes, including adverse events, allergic reactions, hypoglycaemia, weight change and insulin antibodies. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with mealtime insulin lispro, provided effective and similar glucose control and similar safety profiles.

Assessment of the spatial heterogeneity of weathering rates in upland catchments using the sodium dominance index and its significance in integrated catchment management.

The sodium dominance index was developed to quantify weathering rates and critical loads in Scotland, where atmospheric aerosols of maritime origin dominate over biogeochemical weathering in providing base cation inputs to catchment soils and drainage waters. High sodium dominance in river or lake water indicates low weathering rate. Here, this concept is evaluated using intensive temporal and spatial sampling strategies in two substantial catchments, one in Scotland and the other in central England, with particular reference to detection of groundwater inputs, and to possible problems from road salting in the calibration. In the Dee network, the spatial distribution of sodium dominance reflects the distribution of soil parent material geology, but land use also influences the equations. It is postulated that road density, via winter road salting, influences the sodium dominance calibration in lowland agricultural areas. Although road salting can also be problematic in some upland areas, the index still can provide clear indication of the likely severity of acid flush events in remote upland streams. In the Etherow catchment, sodium dominance varies markedly, sometimes over relatively small distances, reflecting soil type distribution, the occurrence of ground-water inputs to streams, and the influence of water in tributaries above the sampling point.

Accommodative function in rhesus monkeys: effects of aging and calorie restriction.

Numerous degenerative changes in the visual system occur with age, including a loss of accommodative function possibly related to hardening of the lens or loss of ciliary muscle mobility. The rhesus monkey is a reliable animal model for studying age-related changes in ocular function, including loss of accommodation. Calorie restriction (CR) is the only consistent intervention to slow aging and extend lifespan in rodents, and more recently the beneficial effects of CR have been reported in nonhuman primates. The goal of the present study was to evaluate age-related changes in ocular accommodation and the potential effect of long-term (>8 years) CR on accommodation in male and female rhesus monkeys. Refraction, accommodation (Hartinger coincidence refractometer), and lens thickness (A-scan ultrasound) were measured in 97 male and female rhesus monkeys age 8-36 years under Telazol/acepromazine anesthesia. Refraction and accommodation measurements were taken before and after 40% carbachol corneal iontophoresis to induce maximum accommodation. Half the animals were in the control (CON) group and were fed ad libitum. The CR group received 30% fewer calories than age- and weight-matched controls. Males were on CR for 12 years and females for eight years. With increasing age, accommodative ability declined in both CON and CR monkeys by 1.03 ± 0.12 (P = 0.001) and 1.18 ± 0.12 (P = 0.001) diopters/year, respectively. The age-related decline did not differ significantly between the groups (P = 0.374). Baseline lens thickness increased with age in both groups by 0.03 ± 0.005 mm/year (P = 0.001) and 0.02 ± 0.005 mm/year (P = 0.001) for the CON and CR groups, respectively. The tendency for the for the lens to thicken with age occurred at a slower rate in the CR group vs. the CON group but the difference was not statistically significant (P = 0.086). Baseline refraction was -2.8 ± 0.55 and -3.0 ± 0.62 diopters for CON and CR, respectively. Baseline refraction tended to become slightly more negative with age (P = 0.070), but this trend did not differ significantly between the groups (P = 0.587). In summary, there was no difference in the slope of the age-related changes in accommodation, lens thickness, or refraction in the carbachol-treated eyes due to diet. These data are consistent with previous findings of decreased accommodative ability in aging rhesus monkeys, comparable to the age-dependent decrease in accommodative ability in humans. This study is the first to indicate that the accommodative system may not benefit from calorie restriction.

[Reduced insulin effect in subclinical fatty liver]. / Verminderte Insulinwirkung bei subklinischer Leberzellverfettung.

BACKGROUND AND OBJECTIVE: Steatosis of the liver is known to be associated with impaired insulin action and is considered to be a feature of the metabolic syndrome. In the present study we addressed the question whether liver fat content, as measured by proton MR spectroscopy ( (1)H MRS), in healthy subjects without clinical signs (hepatomegaly, elevation of transaminases) of relevant liver disease correlates with whole-body insulin sensitivity. METHODS: 21 (18 males and 3 females, age 35 +/- 11 years) non-diabetic subjects underwent the euglycemic-hyperinsulinemic clamp test for determination of whole body insulin action. Liver fat content was measured by means of proton MR spectroscopy ( (1)H MRS). Lipid content was calculated as percentage share of the lipid signal in relation to the entire signal of the spectrum (water and lipid signals). Clinically relevant steatosis of the liver was ruled out by standard magnetic resonance imaging (MRI). Subjects with a history of alcohol intake of more than 40 g/d were excluded from analysis. RESULTS: In a single correlation analysis percentage liver fat strongly correlated with insulin sensitivity index (ISI) (r = 0.7, p = 0.001). After adjusting for the effects of percentage body fat (PFAT) percentage liver fat remained an independent determinant of ISI (p = 0.01). CONCLUSION: Our results suggest that liver fat content is an important predictor of whole-body insulin sensitivity in healthy subjects. The correlation of liver fat content with insulin sensitivity was found in the absence of clinical steatosis and was independent of body fat content.

Bone loss detection in rats using a mouse densitometer.

Estrogen-depletion bone-loss studies often use ovariectomized (ovx) rats and measure bone mineral density in vivo or ex vivo using DXA. Recently, a portable densitometer (PIXImus) was developed for mouse research; however, its use in rats is unclear. This study compared the ability of PIXImus and a standard densitometer (DPXL) to detect ovx-induced bone loss in rats both in vivo and ex vivo. Additionally, instrument accuracy was assessed by comparing measured bone mass with ash weight. Finally, the use of two distal femur regions of interest (ROI) to detect ovx-induced bone loss was evaluated. Twenty-three 6-month-old nulliparous female Sprague-Dawley rats were randomly assigned to sham or ovx groups. Distal femur bone mineral density was assessed at baseline and at 1 and 2 months postoperatively, using a PIXImus and DPXL densitometer. At 3 months postoperatively, all animals were killed, and ex vivo femur scans obtained. Distal femur bone loss was demonstrable by 1 month post-ovx using either densitometer. With the PIXImus, a 4-mm ROI demonstrated greater bone loss (p < 0.05) than an 8-mm ROI. Using the 4-mm ROI, similar amounts of bone loss were detected by the PIXImus and DPXL: 22.2% and 22.4%, respectively, at 2 months post-ovx. Total femur bone mineral content was overestimated by the PIXImus but highly correlated with the DPXL measurement (r = 0.988) and ash weight (r = 0.998). Given its comparability to standard DXA plus its rapid scan speed and portability, the PIXImus is useful in evaluating ovx-induced osteopenia in rats.

Relationship between serum adiponectin concentration and intramyocellular lipid stores in humans.

The recently identified adipocytokine adiponectin has been shown to improve insulin action and decrease triglyceride content in skeletal muscle (by stimulating lipid oxidation) in mice. In the present study, we tested the hypothesis that high serum concentrations of adiponectin are associated with lower intramyocellular (IMCL) fat content by promoting lipid oxidation in humans. IMCL-content in predominantly non-oxidative tibialis anterior muscle and oxidative soleus was determined by proton magnetic resonance spectroscopy in a cross- sectional study involving 63 healthy volunteers. In a second set of experiments, changes in IMCL in both muscles were measured after a three days dietary lipid challenge (n = 18) and after intravenous lipid challenge (n = 12) with suppressed lipid oxidation under hyperinsulinemia. Adiponectin serum concentrations were found to be negatively correlated with IMCL in the oxidative soleus muscle (IMCL [sol]) (r = - 0.46, p < 0.001) independent of measures of obesity, but not with IMCL in the non-oxidative tibialis anterior muscle (IMCL [tib]) (p = 0.40). Adiponectin serum concentrations were negatively correlated with the observed increase in IMCL load after dietary lipid challenge in the tibialis (r = 0.53, p = 0.03) but not in the soleus muscle. During suppression of lipid oxidation by hyperinsulinemia, no effect of adiponectin on IMCL was observed in either soleus or tibialis muscle. Overall, the presented findings are consistent with the hypothesis that adiponectin promotes lipid oxidation in humans resulting in lower intracellular lipid content in human muscle. These results are consistent with animal data, where adiponectin could be shown to enhance lipid oxidation and reduce muscle triglycerides.

Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans.

An increased intramyocellular lipid (IMCL) content, as quantified by (1)H-magnetic resonance spectroscopy ((1)H-MRS), is associated with reduced insulin sensitivity. At present, it is unclear which factors determine IMCL formation and how rapidly IMCL accumulation can be induced. We therefore studied the impact of hyperinsulinemia and elevated circulating nonesterified fatty acid (NEFA) levels on IMCL formation and insulin sensitivity. We further evaluated the influence of a high-fat diet on IMCL storage. In the infusion protocol, 12 healthy male subjects underwent a 6-h hyperinsulinemic-euglycemic glucose clamp with concomitant infusion of Intralipid plus heparin. IMCL was quantified by (1)H-MRS in soleus (SOL) and tibialis anterior (TA) muscle at baseline and then every hour. IMCL levels started to increase significantly after 2 h, reaching a maximum of 120.8 +/- 3.4% (SOL) and 164.2 +/- 13.8% (TA) of baseline after 6 h (both P < 0.05). In parallel, the glucose infusion rate (GIR) decreased progressively, reaching a minimum of 60.4 +/- 5.4% of baseline after 6 h. Over time, the GIR was strongly correlated with IMCL in TA (r = -0.98, P < or = 0.003) and SOL muscle (r = -0.97, P < or = 0.005). In the diet protocol, 12 male subjects ingested both a high-fat and low-fat diet for 3 days each. Before and after completion of each diet, IMCL levels and insulin sensitivity were assessed. After the high-fat diet, IMCL levels increased significantly in TA muscle (to 148.0 +/- 16.9% of baseline; P = 0.005), but not in SOL muscle (to 114.4 +/- 8.2% of baseline; NS). Insulin sensitivity decreased to 83.3 +/- 5.6% of baseline (P = 0.033). There were no significant changes in insulin sensitivity or IMCL levels after the low-fat diet. The effects of the high-fat diet showed greater interindividual variation than those of the infusion protocol. The data from the lipid infusion protocol suggest a functional relationship between IMCL levels and insulin sensitivity. Similar effects could be induced by a high-fat diet, thereby underlining the physiological relevance of these observations.

Hand-assisted laparoscopic donor nephrectomy minimizes warm ischemia.

OBJECTIVES: Traditional open donor nephrectomy is associated with good donor outcomes and excellent allograft function. Laparoscopic donor nephrectomy may accomplish these same goals with less morbidity. We report our initial experience with hand-assisted laparoscopic living donor nephrectomy using a commercially available hand-assist device. METHODS: Donor and allograft outcomes for the first 30 patients undergoing hand-assisted laparoscopic live donor nephrectomy in our institution were prospectively analyzed. RESULTS: Hand-assisted laparoscopic donor nephrectomy was successfully completed in 29 (97%) of 30 donors. Organ dissection was carried out purely laparoscopically. Vessel division and allograft extraction were performed using a hand-assisted technique. The average operative time was 275 minutes (range 193 to 360), with an estimated blood loss of 99 mL (range 50 to 300). Pneumoperitoneum was consistently maintained during the hand-assisted portion of the procedure. The mean warm ischemic time was 72.5 seconds (range 30 to 165). On average, the regular diet was resumed after 2.2 days (range 1 to 3), and patients were discharged home 3.4 days (range 2 to 5) after surgery. Eight minor complications occurred in the donor group. Immediate graft function occurred in all 30 cases. No ureteral complications occurred. The recipient creatinine levels ranged from 0.6 to 2.4 mg/dL at an average follow-up of 11.5 months (range 1 to 23). CONCLUSIONS: Laparoscopic donor nephrectomy is technically feasible and can be performed with minimal morbidity. Hand-assisted kidney extraction may help to facilitate immediate allograft function by minimizing the warm ischemic time.

A survey of mental health care provider's and managed care organization attitudes toward, familiarity with, and use of group interventions.

Managed Care has had a significant impact on delivery systems for mental health services. Direct and indirect persuasion to provide more cost-effective treatments has been one consequence. The cost-saving qualities and the effectiveness of group interventions have produced clear expectations for an increased use of therapy groups. This study compared perceptions and uses of group treatments on a national sample of managed care organizations and mental health providers. Because group psychotherapy encompasses such a broad definition, five specific types of group interventions were defined: problem-focused homogenous, process-oriented heterogeneous, psycho-educational, self-help, and short-term groups. Implications of differences and similarities between directors of managed care organizations and treatment providers are examined and discussed across five response categories (familiarity/training, perceived effectiveness, likelihood of reimbursement/referral, daily use, and expectation for future use).

Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study.

The influence of a short-term elevation of free fatty acids (FFAs) on intramyocellular lipids (IMCL) under hyperinsulinemic conditions was monitored in five healthy male subjects in the course of a 5-hr hyperinsulinemic glucose clamp. During the glucose clamp a lipid emulsion (Intralipid 20(R)) and heparin were administered intravenously. IMCL was quantified in the tibialis anterior (TA) and the soleus (SOL) muscle by (1)H-MRS. A rapid elevation of the IMCL pool was found in both muscles (61% in TA and 22% in SOL) in the 5-hr time period. A control hyperinsulinemic glucose clamp in the same study group, repeated without elevation of circulating FFAs, did not lead to significant changes in IMCL for both muscles. The present study shows for the first time that only the combination of high concentrations of FFAs and insulin lead to marked storage of lipids in skeletal muscle cells in humans. Magn Reson Med 45:179-183, 2001.

Heterosynaptic transformation of GABAergic gating in the hippocampus and effects of carbonic anhydrase inhibition.

Recordings from CA1 pyramidal cells were made in rat hippocampal slices (in vitro). Activation of cholinergic receptors associated with tetanization of GABAergic inputs from stratum pyramidale transformed the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials into depolarizing responses of rat hippocampal CA1 pyramidal neurons. The synaptic transformation was characterized by a significant shift of reversal potential of postsynaptic responses toward positive membrane potentials. This effect lasted more than 1 h and changed the function of the GABAergic synapses from excitation filter to amplifier. This long-term synaptic transformation was prevented by carbonic anhydrase inhibitors or the presence of HEPES buffer, indicating a dependence on HCO(3-). The presence or absence of an associated activation of cholinergic with GABAergic inputs thus gates the information processing through the pyramidal cells and network, forming an amplified "center" of attention and a filtered "surround". Information flow through the neural circuit is thereby directed according to temporal association of the relevant signals.

Optic disc topography in pseudopapilledema: a comparison to pseudotumor cerebri.

OBJECTIVES: To determine if confocal scanning laser (CSL) tomography can quantify optic disc topography in patients with pseudopapilledema (PP) and to contrast the regional topography of the optic disc in PP and pseudotumor cerebri (PTC). MATERIALS AND METHODS: Three-dimensional optic disc images from 10 PP patients PP and 17 PTC patients were obtained using the Heidelberg Retinal Tomograph (HRT). Two conventional HRT parameters, volume above the reference plane and volume above the surface, were used to quantify global disc elevation. In addition, local topography was determined at 100 microm intervals along eight meridians at 100 to 1700 microm from the disc center. The global and local measures of disc topography in the two groups were compared statistically. RESULTS: Significant between group differences were detected for both global measures. Regional analysis revealed vertical symmetry and horizontal asymmetry in PP and PTC as well as significant between group differences in peripapillary height. CONCLUSIONS: CSL tomography can quantify disc elevation in both PP and PTC and may be useful for differentiating disc morphology in PP and PTC. The volume of the disc above the retinal surface is greater in PTC than in PP. However, most of the difference in elevation between the two groups occurs over the disc rim and peripapillary retina.

A view of prescriptive practice collaboration: perspectives of psychiatric-mental health clinical nurse specialists and psychiatrists.

A majority of states require collaborative prescribing agreements between advanced practice nurses and physicians. Unfortunately, there is limited research describing the collaboration that occurs between the clinicians who have such prescribing agreements. This exploratory study identifies the characteristics, activities, and outcomes of collaboration between psychiatric-mental health clinical nurse specialists (CNSs) with prescribing agreements and their collaborating psychiatrists. Surveys were sent to all the 73 prescribing psychiatric-mental health CNSs identified by the Minnesota Board of Nursing in 1998 and their primary collaborating psychiatrists. Forty-nine CNSs and 32 psychiatrists returned the surveys with 31 matched collaborating dyads identified. Overall satisfaction with the collaborative relationship was high, CNSs (chi = 4.34/5) and psychiatrists (chi = 4.46/5). Good communication, trust, shared goals for patient outcomes, shared professional values, and respect for clinical competency were identified as important characteristics for effective collaboration. CNSs identified increased professional growth and job satisfaction as professional benefits, while psychiatrists reported shared workload responsibilities. Fewer than half of the CNSs and psychiatrists perceived professional liability as a professional constraint. Psychiatric-mental health CNSs and psychiatrists agreed that the continuity of patient care and efficient access to mental health care were patient benefits. The statistically significant differences between the CNSs' and psychiatrists' responses were related to the number of years they had been in practice, the number of years the CNS had been a prescriber, and the length of time the CNS and psychiatrist had worked together within a collaborative prescribing agreement.

Cellular phenotypes of age-associated skeletal muscle mitochondrial abnormalities in rhesus monkeys.

Rhesus monkey vastus lateralis muscle was examined histologically for age-associated electron transport system (ETS) abnormalities: fibers lacking cytochrome c oxidase activity (COX(-)) and/or exhibiting succinate dehydrogenase hyperreactivity (SDH(++)). Two hundred serial cross-sections (spanning 1600 microm) were obtained and analyzed for ETS abnormalities at regular intervals. The abundance and length of ETS abnormal regions increased with age. Extrapolating the data to the entire length of the fiber, up to 60% of the fibers were estimated to display ETS abnormalities in the oldest animal studied (34 years) compared to 4% in a young adult animal (11 years). ETS abnormal phenotypes varied with age and fiber type. Middle-aged animals primarily exhibited the COX(-) phenotype, while COX(-)/SDH(++) abnormalities were more common in old animals. Transition region phenotype was affected by fiber type with type 2 fibers first displaying COX(-) and then COX(-)/SDH(++) while type 1 fibers progressed from normal to SDH(++) and then to COX(-)/SDH(++). In situ hybridizations studies revealed an association of ETS abnormalities with deletions of the mitochondrial genome. By measuring cross-sectional area along the length of ETS abnormal fibers, we demonstrated that some of these fibers exhibit atrophy. Our data suggest mitochondrial (mtDNA) deletions and associated ETS abnormalities are contributors to age-associated fiber atrophy.

Human granulocytic ehrlichiosis presenting with acute renal failure and mimicking thrombotic thrombocytopenic purpura. A case report and review.

We present the case of an elderly female patient presenting with recurrent acute renal failure, fever, altered mental status, abdominal pain, thrombocytopenia and a small number of fragmented red cells on peripheral smear mimicking recurrent thrombotic thrombocytopenic purpura (TTP). Eventually, however, she was diagnosed to have human granulocytic ehrlichiosis (HGE), and after treatment for HGE her clinical and laboratory abnormalities resolved. Ehrlichiosis mimicking TTP, diagnosed at postmortem examination, has been described in a single prior case. As illustrated in this case, there are potential difficulties in diagnosing HGE after plasma exchange, blood transfusion and immunosuppressive therapy. Ehrlichiosis, a potentially curable disease, should be considered in the differential diagnosis of thrombotic microangiopathic disorders.