UPMC Presbyterian

An unresolved question in neuroscience and psychology is how the brain monitors performance to regulate behavior. It has been proposed that the anterior cingulate cortex (ACC), on the medial surface of the frontal lobe, contributes to performance monitoring by detecting errors. In this study, event-related functional magnetic resonance imaging was used to examine ACC function. Results confirm that this region shows activity during erroneous responses. However, activity was also observed in the same region during correct responses under conditions of increased response competition. This suggests that the ACC detects conditions under which errors are likely to occur rather than errors themselves.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

BACKGROUND: Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS: We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS: Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. CONCLUSIONS: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

BACKGROUND: In patients with large dural defects of the anterior and ventral skull base after endonasal skull base surgery, there is a significant risk of a postoperative cerebrospinal fluid leak after reconstruction. Reconstruction with vascularized tissue is desirable to facilitate rapid healing, especially in irradiated patients. METHODS: We developed a neurovascular pedicled flap of the nasal septum mucoperiosteum and mucoperichondrium based on the nasoseptal artery, a branch of the posterior septal artery (Hadad-Bassagasteguy flap [HBF]). A retrospective review of patients undergoing endonasal skull base surgery at the University of Rosario, Argentina, and the University of Pittsburgh Medical Center was performed to identify patients who were reconstructed with a vascularized septal mucosal flap. RESULTS: Forty-three patients undergoing endonasal cranial base surgery were repaired with the septal mucosal flap. Two patients with postoperative cerebrospinal fluid leaks (5%) were successfully treated with focal fat grafts. We encountered no infectious or wound complications in this series of patients. One patient experienced a posterior nose bleed from the posterior nasal artery. This was controlled with electrocautery and the flap blood supply was preserved. CONCLUSION: The HBF is a versatile and reliable reconstructive technique for defects of the anterior, middle, clival, and parasellar skull base. Its use has resulted in a sharp decrease in the incidence of postoperative cerebrospinal fluid leaks after endonasal skull base surgery and is recommended for the reconstruction of large dural defects and when postoperative radiation therapy is anticipated.

BACKGROUND AND AIMS: Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. METHODS: This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients. CONCLUSIONS: The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.

OBJECTIVE: To evaluate the short-term outcomes for laparoscopic Roux-en-Y gastric bypass in 275 patients with a follow-up of 1 to 31 months. SUMMARY BACKGROUND DATA: The Roux-en-Y gastric bypass is a highly successful approach to morbid obesity but results in significant perioperative complications. A laparoscopic approach has significant potential to reduce perioperative complications and recovery time. METHODS: Consecutive patients (n = 275) who met NIH criteria for bariatric surgery were offered laparoscopic Roux-en-Y gastric bypass between July 1997 and March 2000. A 15-mL gastric pouch and a 75-cm Roux limb (150 cm for superobese) was created using five or six trocar incisions. RESULTS: The conversion rate to open gastric bypass was 1%. The start of an oral diet began a mean of 1.58 days after surgery, with a median hospital stay of 2 days and return to work at 21 days. The incidence of early major and minor complications was 3.3% and 27%, respectively. One death occurred related to a pulmonary embolus (0.4%). The hernia rate was 0.7%, and wound infections requiring outpatient drainage only were uncommon (5%). Excess weight loss at 24 and 30 months was 83% and 77%, respectively. In patients with more than 1 year of follow-up, most of the comorbidities were improved or resolved, and 95% reported significant improvement in quality of life. CONCLUSION: Laparoscopic Roux-en-Y gastric bypass is effective in achieving weight loss and in improving comorbidities and quality of life while reducing recovery time and perioperative complications.

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.

Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state coupled with a unique CT or MR imaging appearance. Recognized in the setting of a number of complex conditions (preeclampsia/eclampsia, allogeneic bone marrow transplantation, organ transplantation, autoimmune disease and high dose chemotherapy) the imaging, clinical and laboratory features of this toxic state are becoming better elucidated. This review summarizes the basic and advanced imaging features of PRES, along with pertinent features of the clinical and laboratory presentation and available histopathology. Many common imaging/clinical/laboratory observations are present among these patients, despite the perception of widely different associated clinical conditions.

Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state accompanied by a unique brain imaging pattern typically associated with a number of complex clinical conditions including: preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases and high dose cancer chemotherapy. The mechanism behind the developing vasogenic edema and CT or MR imaging appearance of PRES is not known. Two theories have historically been proposed: 1) Severe hypertension leads to failed auto-regulation, subsequent hyperperfusion, with endothelial injury/vasogenic edema and; 2) vasoconstriction and hypoperfusion leads to brain ischemia and subsequent vasogenic edema. The strengths/weaknesses of these hypotheses are reviewed in a translational fashion including supporting evidence and current available imaging/clinical data related to the conditions that develop PRES. While the hypertension/hyperperfusion theory has been most popular, the conditions associated with PRES have a similar immune challenge present and develop a similar state of T-cell/endothelial cell activation that may be the basis of leukocyte trafficking and systemic/cerebral vasoconstriction. These systemic features along with current vascular and perfusion imaging features in PRES appear to render strong support for the older theory of vasoconstriction coupled with hypoperfusion as the mechanism.

In Brief Study Design. A prospective nonrandomized, longitudinal cohort study. Objective. To evaluate the clinical outcomes of single-fraction radiosurgery as part of the management of metastatic spine tumors. Summary of Background Data. The role of stereotactic radiosurgery for the treatment of spinal lesions has previously been limited by the availability of effective target immobilization and target tracking devices. Large clinical experience with spinal radiosurgery to properly assess clinical experience has previously been limited. Methods. A cohort of 500 cases of spinal metastases underwent radiosurgery. Ages ranged from 18 to 85 years (mean 56). Lesion location included 73 cervical, 212 thoracic, 112 lumbar, and 103 sacral. Results. The maximum intratumoral dose ranged from 12.5 to 25 Gy (mean 20). Tumor volume ranged from 0.20 to 264 mL (mean 46). Long-term pain improvement occurred in 290 of 336 cases (86%). Long-term tumor control was demonstrated in 90% of lesions treated with radiosurgery as a primary treatment modality and in 88% of lesions treated for radiographic tumor progression. Twenty-seven of 32 cases (84%) with a progressive neurologic deficit before treatment experienced at least some clinical improvement. Conclusions. The results indicate the potential of radiosurgery in the treatment of patients with spinal metastases, especially those with solitary sites of spine involvement, to improve long-term palliation. Five hundred spinal metastases were treated with single-fraction radiosurgery. Long-term pain improvement occurred in 86% of cases, long-term tumor control was demonstrated in 90%, radiographic tumor control was demonstrated in 88%, and 84% of patients with a progressive neurologic deficit before treatment experienced at least some clinical improvement.

BACKGROUND AND PURPOSE: Although the term posterior reversible encephalopathy syndrome (PRES) was popularized because of the typical presence of vasogenic edema in the parietal and occipital lobes, other regions of the brain are also frequently affected. We evaluated lesion distribution with CT and MR in a large cohort of patients who experienced PRES to comprehensively assess the imaging patterns identified. MATERIALS AND METHODS: The locations of the PRES lesion at toxicity were comprehensively identified and tabulated in 136 patients by CT (22 patients) and MR (114 patients) imaging including the hemispheric, basal ganglial, and infratentorial locations. Clinical associations along with presentation at toxicity including blood pressure were assessed. RESULTS: Vasogenic edema was consistently present in the parietal or occipital regions (98%), but other locations were common including the frontal lobes (68%), inferior temporal lobes (40%), and cerebellar hemispheres (30%). Involvement of the basal ganglia (14%), brain stem (13%), and deep white matter (18%) including the splenium (10%) was not rare. Three major patterns of PRES were noted: the holohemispheric watershed (23%), superior frontal sulcal (27%), and dominant parietal-occipital (22%), with additional common partial or asymmetric expression of these primary PRES patterns (28%). CONCLUSION: Involvement of the frontal lobe, temporal lobe, and cerebellar hemispheres is common in PRES, along with the occasional presence of lesions in the brain stem, basal ganglia, deep white matter, and splenium. Three primary PRES patterns are noted in the cerebral hemispheres, along with frequent partial or asymmetric expression of these PRES patterns. Awareness of these patterns and variations is important to recognize PRES neurotoxicity more accurately when present.

The blood coagulation system of 66 consecutive patients undergoing consecutive liver transplantations was monitored by thrombelastograph and analytic coagulation profile. A poor preoperative coagulation state, decrease in levels of coagulation factors, progressive fibrinolysis, and whole blood clot lysis were observed during the preanhepatic and anhepatic stages of surgery. A further general decrease in coagulation factors and platelets, activation of fibrinolysis, and abrupt decrease in levels of factors V and VIII occurred before and with reperfusion of the homograft. Recovery of blood coagulability began 30-60 min after reperfusion of the graft liver, and coagulability had returned toward baseline values 2 hr after reperfusion. A positive correlation was shown between the variables of thrombelastography and those of the coagulation profile. Thrombelastography was shown to be a reliable and rapid monitoring system. Its use was associated with a 33% reduction of blood and fluid infusion volume, whereas blood coagulability was maintained without an increase in the number of blood product donors.

OBJECTIVE: Reconstruction of the cranial base using vascularized tissue promotes rapid and complete healing, thus avoiding complications caused by persistent communication between the cranial cavity and the sinonasal tract. The Hadad-Bassagasteguy flap (HBF), a neurovascular pedicled flap of the nasal septum mucoperiosteum and mucoperichondrium based on the nasoseptal artery, seems to be advantageous for the reconstruction of the cranial base after endonasal cranial base surgery. METHODS: We performed a retrospective review of patients who underwent endonasal cranial base surgery at the University of Pittsburgh Medical Center from January 30, 2006 to January 30, 2007, identifying patients who experienced reconstruction with a vascularized septal mucosal flap (HBF). We analyzed the demographic data, pathological characteristics, site and extent of resection, use of cerebrospinal fluid (CSF) diversion techniques, and outcome. RESULTS: Seventy-five patients who underwent endonasal cranial base endoscopic surgery received repair with the HBF. In this population, we encountered eight postoperative CSF leaks (10.66%), all in patients who required intra-arachnoidal dissection. When we correct the statistical analysis to include only patients with intra- arachnoidal lesions, the postoperative CSF leak rate is 14.5% (eight of 55 patients). It is notable that six CSF (33%) leaks occurred in our first 25 repairs, whereas we encountered only two postoperative leaks (4%) in the last 50 patients. The corrected CSF leak rate, considering only intra-arachnoidal lesions, was two (5.4%) of 37 patients. This improvement in the CSF leak rate reflects our growing experience and comfort with this reconstructive technique. All of our failures could be matched to a specific technical mistake. In addition, we modified the flap-harvesting technique to allow for staged procedures and the removal of caudal lesions. These special circumstances require storage of the flap in the antrum during the removal of caudal lesions, and suturing of the flap in its original position for staged procedures. One patient experienced a posterior nose bleed from the posterior nasal artery. This was controlled with bipolar electrocautery, thereby preserving the flap blood supply. We encountered no infectious or wound complications in this series of patients. The donor site accumulates crusting, which requires debridement until mucosalization is complete; this usually occurs 6 to 12 weeks after surgery. CONCLUSION: The HBF is a versatile and reliable reconstructive technique for repairing defects of the anterior, middle, clival, and parasellar cranial base. Its use has resulted in a significant decrease in our incidence of CSF leaks after endonasal cranial base surgery. Attention to technical details is of paramount importance to achieve the best outcomes.

To determine the natural history of brain cavernous malformations, the authors entered patients referred to their center into a prospective registry between 1987 and 1993. All patients underwent magnetic resonance imaging, which showed the typical appearance of this lesion, and conservative management was recommended in all. Patients or their referring physicians were contacted for follow-up data. The purpose of the study was to define the rate of symptomatic hemorrhage and to determine the outcome in those patients who had suffered seizures. Follow-up data were available for 122 patients with a mean age at entry of 37 years (range 4-82 years). The malformation was located in the brainstem in 43 cases (35%), the basal ganglia/thalamus in 20 (17%), and a hemispheric area in 59 (48%). Fifty percent of patients had never had a symptomatic hemorrhage, 41% had one bleed, 7% had two, and 2% had three. Seizures were reported in 23% of patients and headaches in 15%. Lesions were solitary in 80% of patients and multiple in 20%. The retrospective annual hemorrhage rate (61 bleeds/4550.6 patient-years of life) was 1.3%. The mean prospective follow-up period was 34 months. There were nine bleeds during this time, six with new neurological deficits. In patients without a prior bleed, the prospective annual rate of hemorrhage was 0.6%. In contrast, patients with prior hemorrhage had an annual bleed rate of 4.5% (p = 0.028). Patient sex (p = 0.97) or the presence of seizures (p = 0.11), headaches (p = 0.06), or solitary versus multiple lesions (p = 0.15) were not significant predictors of later hemorrhage. There was no difference in the rate of bleeds between brain locations. Four patients with seizures became seizure-free and four patients without seizures later developed seizures; only one patient developed intractable seizures. Fourteen had radiosurgery. No patient died in the follow-up period. This study indicates that conservative versus operative management strategies may need to be redefined, especially in patients who present with hemorrhage and who appear to have a significantly increased risk of subsequent rehemorrhage.

BACKGROUND: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based. METHODS: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations. RESULTS: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. CONCLUSIONS: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.

Amebas belonging to the genera Naegleria, Acanthamoeba and Balamuthia are free-living, amphizoic and opportunistic protozoa that are ubiquitous in nature. These amebas are found in soil, water and air samples from all over the world. Human infection due to these amebas involving brain, skin, lung and eyes has increased significantly during the last 10 years. The epidemiology, immunology, protozoology, pathology, and clinical features of the infections produced by these protozoa differ strikingly. Infection by the pathogenic Naegleria fowleri is acquired by exposure to polluted water in ponds, swimming pools and man-made lakes. Raised temperatures during the hot summer months or warm water from power plants facilitate the growth of N. fowleri. N. fowleri is a thermophilic ameba that grows well in tropical and subtropical climates. The CNS infection, called Primary Amebic Meningoencephalitis (PAM), produced by N. fowleri is characterized by an acute fulminant meningoencephalitis leading to death 3-7 days after exposure. Victims are healthy, young individuals with a history of recent water-related sport activities. The portal of entry is the olfactory neuroepithelium. The pathologic changes are an acute hemorrhagic necrotizing meningoencephalitis with modest purulent exudate, mainly at the base of the brain, brain-stem and cerebellum. Trophozoites can be seen within the CNS lesions located mainly around blood vessels. Thus far 179 cases have been reported; 81 in the USA alone. Balamuthia mandrillaris and several species of Acanthamoeba are pathogenic "opportunistic" free-living amebas which cause Granulomatous Amebic Encephalitis (GAE) in humans and animals. GAE is an infection, usually seen in debilitated, malnourished individuals, in patients undergoing immunosuppressive therapy for organ transplants and in Acquired Immunodeficiency Syndrome (AIDS). The granulomatous component is negligible, particularly in immunocompromised individuals. Pathologically these amebas produce a patchy, chronic or subacute granulomatous encephalitis with the presence of trophozoites and cysts. The portal of entry is probably through the respiratory tract or an ulceration of the skin reaching the CNS by hematogenous spread. As of October 1, 1996, 166 cases (103 due to Acanthamoeba and 63 due to Balamuthia) of GAE have been reported from around the world. Of these 103 cases due to Acanthamoeba (72 have been reported in the USA alone, > 50 in AIDS). It is well known that several species of Acanthamoeba can also produce, chronic sight threatening ulceration of the cornea called Acanthamoeba keratitis (AK), mostly in contact lens wearers or in individuals with minor corneal abrasions. Hundreds of cases of AK have been documented world wide.

BACKGROUND AND OBJECTIVE: Fluoroquinolones have not been frequently implicated as a cause of Clostridium difficile outbreaks. Nosocomial C. difficile infections increased from 2.7 to 6.8 cases per 1000 discharges (P < .001). During the first 2 years of the outbreak, there were 253 nosocomial C. difficile infections; of these, 26 resulted in colectomy and 18 resulted in death. We conducted an investigation of a large C. difficile outbreak in our hospital to identify risk factors and characterize the outbreak. METHODS: A retrospective case-control study of case-patients with C. difficile infection from January 2000 through April 2001 and control-patients matched by date of hospital admission, type of medical service, and length of stay; an analysis of inpatient antibiotic use; and antibiotic susceptibility testing and molecular subtyping of isolates were performed. RESULTS: On logistic regression analysis, clindamycin (odds ratio [OR], 4.8; 95% confidence interval [CI95], 1.9-12.0), ceftriaxone (OR, 5.4; CI95, 1.8-15.8), and levofloxacin (OR, 2.0; CI95, 1.2-3.3) were independently associated with infection. The etiologic fractions for these three agents were 10.0%, 6.7%, and 30.8%, respectively. Fluoroquinolone use increased before the onset of the outbreak (P < .001); 59% of case-patients and 41% of control-patients had received this antibiotic class. The outbreak was polyclonal, although 52% of isolates belonged to two highly related molecular subtypes. CONCLUSIONS: Exposure to levofloxacin was an independent risk factor for C. difficile-associated diarrhea and appeared to contribute substantially to the outbreak. Restricted use of levofloxacin and the other implicated antibiotics may be required to control the outbreak

Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI), presumably through disruption of indigenous intestinal microflora, thereby allowing C. difficile to grow and produce toxin. Investigations involving animal models and studies performed in vitro suggest that inhibitory activity against C. difficile and differences in the propensity to stimulate toxin production may also influence the likelihood that particular drugs may cause CDI. Although nearly all antimicrobial classes have been associated with CDI, clindamycin, third-generation cephalosporins, and penicillins have traditionally been considered to harbor the greatest risk. Recent studies have also implicated fluoroquinolones as high-risk agents, a finding that is most likely to be related in part to increasing fluoroquinolone resistance among epidemic strains (i.e., restriction-endonuclease analysis group BI/North American PFGE type 1 strains) and some nonepidemic strains of C. difficile. Restrictions in the use of clindamycin and third-generation cephalosporins have been associated with reductions in CDI. Because use of any antimicrobial has the potential to induce the onset of CDI and disease caused by other health care-associated pathogens, antimicrobial stewardship programs that promote judicious use of antimicrobials are encouraged in concert with environmental and infection control-related efforts.

BACKGROUND: Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS: We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS: After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS: Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.