Dallas VA Medical Center

Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.

OBJECTIVE: Although the systematic measurement of disease activity facilitates clinical decision making in rheumatoid arthritis (RA), no recommendations currently exist on which measures should be applied in clinical practice in the US. The American College of Rheumatology (ACR) convened a Working Group (WG) to comprehensively evaluate the validity, feasibility, and acceptability of available RA disease activity measures and derive recommendations for their use in clinical practice. METHODS: The Rheumatoid Arthritis Clinical Disease Activity Measures Working Group conducted a systematic review of the literature to identify RA disease activity measures. Using exclusion criteria, input from an Expert Advisory Panel (EAP), and psychometric analysis, a list of potential measures was created. A survey was administered to rheumatologists soliciting input. The WG used these survey results in conjunction with the psychometric analyses to derive final recommendations. RESULTS: Systematic review of the literature resulted in identification of 63 RA disease activity measures. Application of exclusion criteria and ratings by the EAP narrowed the list to 14 measures for further evaluation. Practicing rheumatologists rated 9 of these 14 measures as most useful and feasible. From these 9 measures, the WG selected 6 with the best psychometric properties for inclusion in the final set of ACR-recommended RA disease activity measures. CONCLUSION: We recommend the Clinical Disease Activity Index, Disease Activity Score with 28-joint counts (erythrocyte sedimentation rate or C-reactive protein), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with 3 measures, and Simplified Disease Activity Index because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity states; have remission criteria; and are feasible to perform in clinical settings.

Manometric examination of the oesophagus frequently reveals abnormalities whose cause is unknown and whose physiological importance is not clear. A large body of literature dealing with oesophageal motility abnormalities has evolved over the past few decades but comparisons among studies have been compromised by the lack of a widely accepted system for classifying the abnormal motility patterns, and by the lack of uniform diagnostic criteria for the putative disorders. Based on an extensive review and analysis of the literature, this report suggests an operational scheme to be used for the general classification of oesophageal motility abnormalities, and proposes standardised manometric criteria for the putative oesophageal motility disorders. By applying the guidelines proposed in this report, clinicians and researchers can determine if their patients fulfil the manometric criteria for a putative motility disorder. This should facilitate and improve comparisons among patients and studies. However, it is important to emphasise that fulfilment of the proposed criteria does not establish the clinical importance of the motility abnormalities.

A 55-year-old man has had frequent heartburn for more than 10 years. Endoscopy reveals columnar epithelium lining the distal 5 cm of the esophagus. Biopsy specimens show specialized intestinal metaplasia with inflammation and possible dysplasia. How should this patient's condition be managed?

Zygomycosis, an infection that is associated with significant morbidity and mortality, is becoming common in immunocompromised patients. Posaconazole is a new extended-spectrum azole antifungal that has demonstrated in vitro and in vivo activity against zygomycetes. This report provides the results from the first 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. Posaconazole was usually given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Eleven (46%) of the infections were rhinocerebral. Duration of posaconazole therapy ranged from 8 to 1,004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 subjects with zygomycosis refractory to standard therapy and 80% in 5 subjects with intolerance to standard therapy. Overall, 19 of 24 subjects (79%) survived infection. Survival was also associated with surgical resection of affected tissue and stabilization or improvement of the subjects' underlying illnesses. Failures either had worsening of underlying illnesses or requested all therapy withdrawn; none of the failures received more than 31 days of posaconazole. Posaconazole oral solution was well tolerated and was discontinued in only one subject due to a drug rash. Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness.

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred twenty-one patients with PsA were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint pain/ tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.13). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA.

Antigen presenting cells recognize pathogens via pattern recognition receptors (PRR), which upon ligation transduce intracellular signals that can induce innate immune responses. Because some C-type lectin-like receptors (e.g. dectin-1 and DCSIGN) were shown to act as PRR for particular microbes, we considered a similar role for dectin-2. Binding assays using soluble dectin-2 receptors showed the extracellular domain to bind preferentially to hyphal (rather than yeast/conidial) components of Candida albicans, Microsporum audouinii, and Trichophyton rubrum. Selective binding for hyphae was also observed using RAW macrophages expressing dectin-2, the ligation of which by hyphae or cross-linking with dectin-2-specific antibody led to protein tyrosine phosphorylation. Because dectin-2 lacks an intracellular signaling motif, we searched for a signal adaptor that permits it to transduce intracellular signals. First, we found that the Fc receptor gamma (FcRgamma) chain can bind to dectin-2. Second, ligation of dectin-2 on RAW cells induced tyrosine phosphorylation of FcRgamma, activation of NF-kappaB, internalization of a surrogate ligand, and up-regulated secretion of tumor necrosis factor alpha and interleukin-1 receptor antagonist. Finally, these dectin-2-induced events were blocked by PP2, an inhibitor of Src kinases that are mediators for FcRgamma chain-dependent signaling. We conclude that dectin-2 is a PRR for fungi that employs signaling through FcRgamma to induce innate immune responses.

UNLABELLED: Bacterial infections are an important cause of mortality in cirrhosis, but there is a paucity of multicenter studies. The aim was to define factors predisposing to infection-related mortality in hospitalized patients with cirrhosis. A prospective, cohort study of patients with cirrhosis with infections was performed at eight North American tertiary-care hepatology centers. Data were collected on admission vitals, disease severity (model for endstage liver disease [MELD] and sequential organ failure [SOFA] scores), first infection site, type (community-acquired, healthcare-associated [HCA] or nosocomial), and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multivariate logistic regression model predicting mortality was created. 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community-acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter-related (26%), fungal (14%), and Clostridium difficile (12%) infections. Forty-nine patients (23.6%) who died within 30 days had higher admission MELD (25 versus 18, P < 0.0001), lower serum albumin (2.4 g/dL versus 2.8 g/dL, P = 0.002), and second infections (49% versus 16%, P < 0.0001) but equivalent SOFA scores (9.2 versus 9.9, P = 0.86). The case fatality rate was highest for C. difficile (40%), respiratory (37.5%), and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (odds ratio [OR]: 1.12), heart rate (OR: 1.03) albumin (OR: 0.5), and second infection (OR: 4.42) as significant variables. CONCLUSION: Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multicenter cirrhosis cohort.

To determine the safety and benefit of n-3 fatty acid therapy in the prevention of early restenosis after coronary angioplasty, we conducted a randomized, unblinded study comparing a conventional antiplatelet regimen (325 mg of aspirin and 225 mg of dipyridamole per day; control group) with a similar regimen supplemented with 3.2 g of eicosapentaenoic acid per day (treatment group). Treatment began seven days before angioplasty and continued for six months afterward. All angiographic analyses were blinded and performed by a method that was validated by comparison with quantitative coronary angiography. In 82 male patients, 103 coronary lesions were dilated. Both groups had similar base-line clinical and angiographic characteristics. The incidence of early vessel restenosis, as determined on a second angiogram three to four months after angioplasty, was 36 percent in the control group and 16 percent in the treatment group (P = 0.026). The incidence of restenosis per patient was also significantly lower in the treatment group (46 vs. 19 percent). Both multiple logistic regression and Mantel-Haenszel statistical analyses demonstrated a significant independent benefit of treatment with n-3 fatty acids. No important bleeding complications developed in the treated patients. These results, in a male population at relatively high risk for restenosis, suggest that a dietary supplement of n-3 fatty acids, administered for one week before and for six months after coronary angioplasty, is safe and reduces the occurrence of early restenosis after that procedure. Whether this beneficial effect also applies to other populations is unknown.

BACKGROUND AND PURPOSE: Carotid artery stenosis causes up to 10% of all ischemic strokes. Carotid endarterectomy (CEA) was introduced as a treatment to prevent stroke in the early 1950s. Carotid stenting (CAS) was introduced as a treatment to prevent stroke in 1994. METHODS: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a randomized trial with blinded end point adjudication. Symptomatic and asymptomatic patients were randomized to CAS or CEA. The primary end point was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke thereafter, up to 4 years. RESULTS: There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% versus 6.8%; hazard ratio, 1.11; 95% CI, 0.81 to 1.51; P=0.51). Symptomatic status and sex did not modify the treatment effect, but an interaction with age and treatment was detected (P=0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% versus 2.3%, P=0.012; and myocardial infarction 1.1% versus 2.3%, P=0.032). CONCLUSIONS: In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of myocardial infarction with CEA. Clinical Trial Registration-www.clinicaltrials.gov. Unique identifier: NCT00004732.

OBJECTIVE: To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA. METHODS: Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single-nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression. RESULTS: Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA)-positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection. CONCLUSION: Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.

Recently we purified and identified a previously uncharacterized transcription factor from rat liver binding to the carbohydrate responsive element of the L-type pyruvate kinase (L-PK) gene. This factor was named carbohydrate responsive element binding protein (ChREBP). ChREBP, essential for L-PK gene transcription, is activated by high glucose and inhibited by cAMP. Here, we demonstrated that (i) nuclear localization signal and basic helix-loop-helix/leucine-zipper domains of ChREBP were essential for the transcription, and (ii) these domains were the targets of regulation by cAMP and glucose. Among three cAMP-dependent protein kinase phosphorylation sites, Ser(196) and Thr(666) were the target sites. Phosphorylation of the former resulted in inactivation of nuclear import, and that of the latter resulted in loss of the DNA-binding activity and L-PK transcription. On the other hand, glucose activated the nuclear import by dephosphorylation of Ser(196) in the cytoplasm and also stimulated the DNA-binding activity by dephosphorylation of Thr(666) in the nucleus. These results thus reveal mechanisms for regulation of ChREBP and the L-PK transcription by excess carbohydrate and cAMP.

Gastroduodenal intolerance is one of the major factors limiting the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) in patients with arthritic conditions. We evaluated the endoscopic appearance of the gastroduodenal mucosa in 65 patients (63 men and two women) taking regular daily doses of NSAIDs over a long period for osteoarthritis or rheumatoid arthritis. Eight different drugs (indomethacin, ibuprofen, naproxen, sulindac, piroxicam, aspirin, salsalate, and tolmetin) had been taken continuously for at least 6 wk. Seven patients took two different NSAIDs. No other drug known to damage the mucosa was used. Twenty-one patients (32%) had an endoscopically completely normal stomach and duodenum, and 44 (68%) had evidence of injury (mucosal hemorrhage 44.6%, erosions 53.8%, both mucosal hemorrhage and erosions 34%). Ten patients had ulcers detected (seven gastric, two pyloric channel, one duodenal bulb) for a point prevalence of 15.4%. Ulcers were found in patients taking naproxen, indomethacin, tolmetin, sulindac, and ibuprofen, either alone, or in combination with aspirin. Dyspeptic symptoms were present in 19% of those with completely normal endoscopy and in only 9% of those with abnormal endoscopic findings. Only three of the 10 patients with ulcer had dyspeptic symptoms. There was no significant difference between drugs in tendency to cause gastroduodenal injury. We confirm that fairly severe gastroduodenal injury occurs in asymptomatic patients with rheumatoid and osteoarthritis, and that symptoms do not predict the presence of damage.

Adenocarcinoma in Barrett's esophagus has been increasing in incidence at a rapid rate for more than two decades. Cyclooxygenase (COX)-2 appears to play an important role in gastrointestinal carcinogenesis, and COX-2 overexpression has been demonstrated both in esophageal adenocarcinomas and in the metaplastic epithelium of Barrett's esophagus. The aim of our study was to determine whether selective inhibition of COX-2 by NS-398 would alter the rates of cell growth and apoptosis in human Barrett's-associated esophageal adenocarcinoma cell lines. COX-1 and COX-2 expression in adenocarcinoma cell lines was determined using reverse transcription-PCR and Western blotting for mRNA and protein, respectively. Esophageal adenocarcinoma cell lines were treated with various concentrations of NS-398 (selective for COX-2 inhibition) and flurbiprofen (selective for COX-1 inhibition). Cell growth was compared in flurbiprofen-treated and untreated tumor cell lines; cell growth and apoptosis were compared in NS-398-treated and untreated tumor cell lines. COX-2 mRNA and protein were detected in two of three cell lines (SEG-1 and FLO); the third cell line, BIC-1, did not express COX-2 mRNA or protein under basal conditions or after stimulation with phorbol 12-myristate 13-acetate. Treatment with COX-1-selective concentrations of flurbiprofen did not affect cell growth in any of the three tumor cell lines. In contrast, treatment with COX-2-selective concentrations of NS-398 significantly suppressed cell growth and increased apoptosis in the cell lines that expressed COX-2 (SEG-1 and FLO), but not in the cell line that did not express COX-2 (BIC-1). We conclude that the administration of a selective inhibitor of COX-2 significantly decreases cell growth and increases apoptosis in Barrett's-associated adenocarcinoma tumor cells that express COX-2. These observations suggest a potential role for selective COX-2 inhibitors in the prevention and treatment of esophageal adenocarcinoma for patients with Barrett's esophagus.

THIS article reviews the clinical pharmacology of histamine2-receptor antagonist drugs (H2 blockers) and their usefulness in the treatment and prevention of acid-peptic disorders — namely, peptic ulcer disease, Zollinger—Ellison syndrome, gastroesophageal reflux disease, and acute stress ulcers and erosions. Erosive gastritis and erosive duodenitis are often considered acid-peptic diseases, but because they overlap with peptic ulcer disease they are not considered as separate entities in this review. Non-ulcer dyspepsia is not included as an acid-peptic disorder since it does not appear to respond to therapy with H2 blockers or antacids.1 H2 blockers are quite effective . . .

The North American Consortium for the Study of End-Stage Liver Disease's definition of acute-on-chronic liver failure (NACSELD-ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD-ACLF's ability to predict 30-day survival (defined as in-hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol-induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End-Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD-ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End-Stage Liver Disease score, and presence of infection. The c-statistics were 0.8073 for the training set and 0.8532 for the validation set. CONCLUSION: Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30-day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (Hepatology 2018;67:2367-2374).

OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: /kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172).

The application of immunofluorescence technique with anti-insulin, anti-glucagon, anti-somatostatin, and anti-pancreatic polypeptide (PP) antisera to sections of precisely sampled regions of the human pancreas allowed the quantitative evaluation of the total content of these four endocrine cell populations in 13 nondiabetics, in 2 insulin-dependent diabetics (IDDM), and in 2 non-insulin-dependent diabetic subjects (NIDDM) of various age and sex. In nondiabetic subjects, PP-cells appear sex-related. Male individuals have a significantly greater volume of PP-cells than female. In diabetic subjects, the only marked difference as compared with nondiabetics is the reduction of insulin cell volume in IDDM. Other small differences between individual endocrine cell volumes are detectable in both IDDM and NIDDM as compared with nondiabetics, but their significance is at present unclear. The qualitative changes of islet structure accompanying insulin cell reduction in IDDM were not considered in the present study.

Insulin-, glucagon-, and somatostatin-contianing cells, identified by immunofluorescent staining, were quantitated morphometrically in sections of pancreas obtained from diabetic and nondiabetic humans and rats. Both the volume density and number of somatostatin- and glucagon-containing cells were significantly increased in the islets of juvenile-type human diabetics and of streptozotocin diabetic rats.