Factors Influencing the Formation of Nitrous Acid from Photolysis of Particulate Nitrate.

Enhanced photolysis of particulate nitrate (pNO3) to form photolabile species, such as gas-phase nitrous acid (HONO), has been proposed as a potential mechanism to recycle nitrogen oxides (NOx) in the remote boundary layer ("renoxification"). This article presents a series of laboratory experiments aimed at investigating the parameters that control the photolysis of pNO3 and the efficiency of HONO production. Filters on which artificial or ambient particles had been sampled were exposed to the light of a solar simulator, and the formation of HONO was monitored under controlled laboratory conditions. The results indicate that the photolysis of pNO3 is enhanced, compared to the photolysis of gas-phase HNO3, at low pNO3 levels, with the enhancement factor reducing at higher pNO3 levels. The presence of cations (Na+) and halides (Cl-) and photosensitive organic compounds (imidazole) also enhance pNO3 photolysis, but other organic compounds such as oxalate and succinic acid have the opposite effect. The precise role of humidity in pNO3 photolysis remains unclear. While the efficiency of photolysis is enhanced in deliquescent particles compared to dry particles, some of the experimental results suggest that this may not be the case for supersaturated particles. These experiments suggest that both the composition and the humidity of particles control the enhancement of particulate nitrate photolysis, potentially explaining the variability in results among previous laboratory and field studies. HONO observations in the remote marine boundary layer can be explained by a simple box-model that includes the photolysis of pNO3, in line with the results presented here, although more experimental work is needed in order to derive a comprehensive parametrization of this process.

Magnetic Stent Removal in a Nurse Led Clinic; a Nine Month Experience.

Ureteric stents are frequently inserted post endourological procedures. However, subsequent endoscopic stent removal requires a second procedure for the patient and the availability of necessary resources. Longer duration of indwelling stents can lead to increased risk of symptoms and complications. The use of magnetic stents removed with a magnetic retrieval device (BlackStar©), offers an alternative which obviates the need for cystoscopy. We assessed the outcomes for this novel method of stent removal in our institution. A retrospective analysis was performed of all patients undergoing magnetic stent insertion and subsequent removal in a nurse-led clinic over a nine-month period. Patients were followed up with a prospective validated Ureteral Stent Symptoms Questionnaire (USSQ)3. A cost analysis was also performed. In total, 59 patients were treated using magnetic stents. The complication rate was low (6.7%). The median duration of indwelling stent was 5.8 days (range 1-11 days). Patients reported haematuria and lower urinary tract symptoms but >90% experienced no functional impairment with minimal days of employment lost (mean 0.75 days). All patients reported satisfaction with nurse-led stent removal and 97% were happy to have stents removed via this method in the future. The total financial savings were estimated at €47,790 over this period. Nurse-led removal of magnetic stents is safe and well tolerated by patients and enables expedient stent removal. It also provides a significant cost benefit and frees up valuable endoscopic resources.

Concordance and acceptability of electric stimulation therapy: a randomised controlled trial.

OBJECTIVE: A pilot single-blinded randomised controlled trial (RCT) was conducted to examine concordance with and acceptability of electric stimulation therapy (EST) in patients with venous leg ulcers (VLUs) who had not tolerated moderate to high compression. METHOD: Participants were randomised to the intervention group (n=15) or a placebo control group (n=8) in which EST was used four times daily for 20 minutes per session. Participants were monitored for eight weeks during which time concordance with the treatment and perceptions of the treatment were assessed. RESULTS: Concordance with the total recommended treatment time was 71.4% for the intervention group and 82.9% for the control group; a difference that was not statistically significant. Participants rated EST as acceptable (84.6% intervention; 83.3% control), only two participants, both from the placebo control group, would not be willing to use EST again. The majority considered EST easier to use than compression (68.4%). CONCLUSION: EST was a practical and acceptable treatment among people who have been unable to tolerate moderate to high compression therapy.

Venous leg ulcer healing with electric stimulation therapy: a pilot randomised controlled trial.

OBJECTIVE: Compression therapy is a gold standard treatment to promote venous leg ulcer (VLU) healing. Concordance with compression therapy is, however, often sub-optimal. The aim of this study was to evaluate the effectiveness of electric stimulation therapy (EST) to facilitate healing of VLUs among people who do not use moderate-to-high levels of compression (>25 mmHg). METHOD: A pilot multicentre, single-blinded randomised controlled trial was conducted. Participants were randomised (2:1) to the intervention group or a control group where EST or a sham device was used 4 times daily for 20 minutes per session. Participants were monitored fortnightly for eight weeks. The primary outcome measure was percentage of area (wound size) change. RESULTS: In the 23 patients recruited, an average redution in wound size of 23.15% (standard deviation [SD]: 61.23) was observed for the control group compared with 32.67 % (SD: 42.54) for the intervention. A moderate effect size favouring the intervention group was detected from univariate [F(1,18)=1.588, p=0.224, partial eta squared=0.081] and multivariate repeated measures [F(1,18)=2.053, p=0.169, partial eta squared=0.102] analyses. CONCLUSION: The pilot study was not powered to detect statistical significance, however, the difference in healing outcomes are encouraging. EST may be an effective adjunct treatment among patients who have experienced difficulty adhering to moderate-to-high levels of compression therapy.

A low temperature, isothermal gas-phase system for conversion of methane to methanol over Cu-ZSM-5.

A low temperature, isothermal, gas-phase, recyclable process is described for the partial oxidation of methane to methanol over Cu-ZSM-5. Activation in NO at 150 °C followed by methane reaction and steam extraction (both at 150 °C) allowed direct observation of methanol at the reactor outlet.

Slow delivery of a nitrification inhibitor (dicyandiamide) to soil using a biodegradable hydrogel of chitosan.

Using chemical inhibitors to reduce soil nitrification decreases emissions of environmental damaging nitrate and nitrous oxide and improves nitrogen use efficiency in agricultural systems. The efficacy of nitrification inhibitors such as dicyandiamide (DCD) is limited in soil due to biodegradation. This study investigated if the persistence of DCD could be sustained in soil by slow release from a chitosan hydrogel. DCD was encapsulated in glyoxal-crosslinked chitosan beads where excess glyoxal was (i) partly removed (C beads) or (ii) allowed to dry (CG beads). The beads were tested in water and in soil. The beads contained two fractions of DCD: one which was quickly released in water, and one which was not. A large DCD fraction within C beads was readily available: 84% of total DCD bead content was released after 9h immersion in water, while between 74% and 98% was released after 7d in soil under low to high moisture conditions. A lower percentage of encapsulated DCD was readily released from CG beads: 19% after 9h in water, and 33% after 7d in soil under high rainfall conditions. Kinetic analysis indicated that the release in water occurred by quasi-Fickian diffusion. The results also suggest that DCD release was controlled by bead erosion and the leaching of glyoxal derivatives, predominantly a glyoxal-DCD adduct whose release was positively correlated with that of DCD (R(2)=0.99, p⩽0.0001). Therefore, novel chitosan/glyoxal composite beads show a promising slow-release potential in soil for agrochemicals like DCD.

Topical Yunnan Baiyao administration as an adjunctive therapy for bleeding complications in adolescents with advanced cancer.

PURPOSE: Yunnan Baiyao (White Medicine from Yunnan, YNB) is a Chinese herbal medicinal powder used to stop bleeding and improve circulation in traumatic injuries. We describe the use of YNB in adolescents with cancer as an adjunct to uncontrolled bleeding in the palliative care setting. METHODS: Through a retrospective chart review of all patients receiving integrative medicine consultations at the Integrative Therapies Program at Columbia University from January 1, 2007 to January 31, 2012, we describe the outcome of patients treated with YNB for management of uncontrolled bleeding. RESULTS: Four patients were identified who received topical YNB for uncontrolled bleeding; patients included two males and two females with diagnoses of solid tumors (n = 3) and Burkitt's lymphoma (n = 1). Mean age was 15.5 years (range 15-17). Fifty percent had life-threatening bleeding from the tumor site and 50 % experienced uncontrollable epistaxis. All patients received preceding therapy with packed red blood cells and platelet transfusions, topical thrombin, and oral aminocaproic acid. Two patients used YNB in the inpatient setting, and all four patients used YNB as outpatients. In all patients, bleeding control improved with the addition of YNB to conventional hemostatic interventions. Two patients using YNB in their home reported control of bleeding episodes. There were no adverse events reported. CONCLUSIONS: YNB may be an efficacious agent for uncontrolled bleeding in conjunction with conventional hemostatic agents in adolescents with advanced cancer. It is well accepted by patients. YNB may be especially valuable in the outpatient setting to prevent the recurrence of hemorrhage.

The energetics of tetrahydrocarbazole aromatization over Pd(111): a computational analysis.

The carbazole moiety is a component of many important pharmaceuticals including anticancer and anti-HIV agents and is commonly utilized in the production of modern polymeric materials with novel photophysical and electronic properties. Simple carbazoles are generally produced via the aromatization of the respective tetrahydrocarbazole (THCZ). In this work, density functional theory calculations are used to model the reaction pathway of tetrahydrocarbazole aromatization over Pd(111). The geometry of each of the intermediate surface species has been determined and how each structure interacts with the metal surface addressed. The reaction energies and barriers of each of the elementary surface reactions have also been calculated, and a detailed analysis of the energetic trends performed. Our calculations have shown that the surface intermediates remain fixed to the surface via the aromatic ring in a manner similar to that of THCZ. Moreover, the aliphatic ring becomes progressively more planer with the dissociation of each subsequent hydrogen atom. Analysis of the reaction energy profile has revealed that the trend in reaction barriers is determined by the two factors: (i) the strength of the dissociating ring-H bond and (ii) the subsequent gain in energy due to the geometric relaxation of the aliphatic ring.

Randomized phase II trial of gemcitabine plus weekly versus three-weekly paclitaxel in previously untreated advanced non-small-cell lung cancer.

INTRODUCTION: Gemcitabine and paclitaxel (Taxol) each provides an efficacious non-platinum option for the treatment of advanced non-small-cell lung cancer (NSCLC), but the optimal dosage and schedule of the two agents used in combination are not well defined. METHODS: Previously untreated patients with advanced NSCLC were randomized to receive gemcitabine-paclitaxel on a traditional three-weekly schedule (Arm A) or a novel weekly schedule (Arm B) as follows-Arm A (three-weekly): gemcitabine 1000 mg/m2 infused>30 min on days 1 and 8 and paclitaxel 200 mg/m2 infused>3 h on day 1 of a 21-day cycle or Arm B (weekly): gemcitabine 1000 mg/m2 infused>30 min and paclitaxel 100 mg/m2 infused>1 h, both administered on days 1 and 8 of a 21-day cycle. RESULTS: One hundred patients received at least one dose of treatment. The weekly schedule, Arm B, was more efficacious and less hematologically toxic than Arm A. Confirmed complete and partial response rates were 28.2% and 26.8%, respectively. Median survival was 10.3 months on Arm B and 7.9 months on Arm A (log-rank P=0.10); 1- and 2-year survival rates also favor Arm B: 42.0% versus 34.0% and 18.0% versus 6.0%. Progression-free survival was 5.8 versus 4.8 months, again favoring Arm B (log-rank P=0.06). There was a two-fold lower frequency of grade 3/4 hematologic events with Arm B as follows: neutropenia (16% versus 30%), thrombocytopenia (4% versus 8%), and anemia (2% versus 6%). One patient (2%) in each treatment group developed febrile neutropenia. CONCLUSION: In this trial, both schedules were efficacious and tolerable, although the weekly schedule resulted in improved survival and lower hematologic toxicity compared with a three-weekly schedule. The weekly schedule of gemcitabine-paclitaxel indicates an improved therapeutic index.

Active surveillance using electronic triggers to detect adverse events in hospitalized patients.

BACKGROUND: Adverse events (AEs) occur with alarming frequency in health care and can have a significant impact on both patients and caregivers. There is a pressing need to understand better the frequency, nature, and etiology of AEs, but currently available methodologies to identify AEs have significant limitations. We hypothesized that it would be possible to design a method to conduct real time active surveillance and conducted a pilot study to identify adverse events and medical errors. METHODS: Records were selected based on 21 electronically obtained triggers, including abnormal laboratory values and high risk and antidote medications. Triggers were chosen based on their expected potential to signal AEs occurring during hospital admissions. Each AE was rated for preventability and severity and categorized by type of event. Reviews were performed by an interdisciplinary patient safety team. RESULTS: Over a 3 month period 327 medical records were reviewed; at least one AE or medical error was identified in 243 (74%). There were 163 preventable AEs (events in which there was a medical error that resulted in patient harm) and 138 medical errors that did not lead to patient harm. Interventions to prevent or ameliorate harm were made following review of the medical records of 47 patients. CONCLUSIONS: This methodology of active surveillance allows for the identification and assessment of adverse events among hospitalized patients. It provides a unique opportunity to review events at or near the time of their occurrence and to intervene and prevent harm.

Diabetes with partial lipodystrophy following sclerodermatous chronic graft vs. host disease.

BACKGROUND: The importance of adipose tissue in metabolism, as a target for insulin action and a secretor of metabolic regulatory proteins, is increasingly recognized. Lipodystrophic conditions are often associated with significant insulin resistance. The commonest acquired form occurs with highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection. Other medical conditions and drugs also have the potential to cause chronic subcutaneous fat damage. CASE REPORT: We describe an unfamiliar partial lipodystrophy in a young woman, associated with markedly insulin-resistant diabetes, acquired following allogeneic bone marrow transplantation for childhood leukaemia complicated by late sclerodermatous chronic graft vs. host disease (GVHD). Clinical examination revealed scarring and lipodystrophy affecting mainly legs, thighs, buttocks and forearms but sparing her face, neck and thorax. Her serum adiponectin level was markedly reduced. CONCLUSIONS: However, although thiazolidinediones lower insulin resistance and increase subcutaneous peripheral fat in Type 2 diabetes, pioglitazone treatment had little effect on either serum adiponectin, glycaemic control or the lipoatrophy. In this case, effective glycaemic control was best achieved using a combination of metformin and highly concentrated soluble insulin injections.

Insights from the sharp end of intravenous medication errors: implications for infusion pump technology.

BACKGROUND: Intravenous (IV) medication errors are a common type of error identified in hospitals and can lead to considerable harm. Over the past 20 years there have been several hundred FDA reported incidents involving IV pumps, many of which have led to patient deaths. OBJECTIVE: To determine the actual types, frequency, and severity of medication errors associated with IV pumps. To evaluate the likelihood that smart pump technology without an interface to other systems could have prevented errors. METHODS: Using a point prevalence approach, investigators prospectively compared the medication, dose, and infusion rate on the IV pump with the prescribed medication, doses, and rate in the medical record. Preventability with smart pump technology was retrospectively determined based on a rigorous definition of currently available technology. RESULTS: A total of 426 medications were observed infusing through an IV pump. Of these, 285 (66.9%) had one or more errors associated with their administration. There were 389 documented errors overall; 37 were "rate deviation" errors and three of these were judged to be due to a programming mistake. Most of the documented events would not have caused patient harm (NCC MERP category C). Only one error would have been prevented by smart pump technology without additional interface and software capabilities. CONCLUSION: Medication errors associated with IV pumps occur frequently, have the potential to cause harm, and are epidemiologically diverse. Smart pumps are a necessary component of a comprehensive safe medication system. However, currently available smart pumps will fail to generate meaningful improvements in patient safety until they can be interfaced with other systems such as the electronic medical record, computerized prescriber order entry, bar coded medication administration systems, and pharmacy information systems. Future research should focus on the effectiveness of new technology in preventing latent and active errors, and on new types of error that any technology can introduce.

Case of partial trisomy 2q3 with clinical manifestations of Marshall-Smith syndrome.

We describe a girl with physical anomalies, accelerated skeletal maturation, failure to thrive, and respiratory difficulties consistent with a diagnosis of Marshall-Smith syndrome (MSS). Chromosome analysis showed an inverted duplication of chromosome 2 [46,XX,inv dup(2)(q37q32) de novo] identified by G banding and confirmed by FISH. Several cases of trisomy 2q3 have been reported and established a syndrome, but the present case is the first to be associated with accelerated skeletal maturation and a clinical picture resembling MSS. This raises the possibility that the cause of MSS involves the q3 region of chromosome 2. Few reports of MSS include study of the karyotype, although the chromosomes were apparently normal in those cases where they have been examined. We suggest that karyotyping be undertaken with particular attention to the 2q3 region in patients with suspected MSS. It also would be prudent to assess bone age in all children with trisomy 2q.

Cure of hyperparathyroidism in pregnancy by sternotomy and removal of a mediastinal parathyroid adenoma.

Primary hyperparathyroidism is rarely reported during pregnancy but can cause significant maternal and neonatal morbidity. We report a case of hyperparathyroidism during pregnancy requiring a median sternotomy for resection of a mediastinal parathyroid adenoma. Surgery resulted in normalisation of serum calcium, resolution of symptoms, and prevented neonatal hypocalcaemia.

Tonic regulation of excitation-contraction coupling by basal protein kinase C activity in isolated cardiac myocytes.

A high-speed imaging technique was used to investigate the effects of inhibitors and activators of protein kinase C (PKC) on the [Ca2+]i transients and contraction of fura-2 loaded rat ventricular cardiac myocytes. The amplitude of the [Ca2+]i transient was reduced following treatment with 100 nM phorbol 12,13-dibutyrate (PDBu), whereas the PKC inhibitors staurosporine (0.5 microM) and calphostin C (10 microM) increased [Ca2+]i transient amplitude, elevated basal [Ca2+]i and slowed the decay of the [Ca2+]i transient. These changes were paralleled by similar alterations in the rate and extent of cell shortening. The activity of nitrendipine-sensitive Ca2+ channels was monitored indirectly as the rate of Mn2+ quench of cytosolic fura-2 in electrically-paced cells. PDBu reduced Mn2+ influx by six-fold, whereas staurosporine and calphostin C increased the influx rate by eight-fold and seven-fold over basal quench, respectively. The caffeine releasable Ca2+ pool was reduced in the presence of PDBu and increased transiently in presence of staurosporine. The effects of PKC activation and inhibition on sarcoplasmic reticulum Ca2+ content may be secondary to alterations of sarcolemmal Ca2+ influx. However, the PKC inhibitors also decreased the rate of sarcoplasmic reticulum Ca2+ uptake in permeabilized myocytes, suggesting that a direct effect of PKC on the sarcoplasmic reticulum may contribute to the prolongation of the [Ca2+]i transient under these conditions. The present work demonstrates that basal PKC activity has a potent depressant effect, mediated primarily through inhibition of sarcolemmal Ca2+ influx, which may play a key role in setting the basal tone of cardiac muscle.

Insulin action and hepatic glucose cycling in Cushing's syndrome.

OBJECTIVE: Although it is well established that hypercortisolism causes insulin resistance, the mechanisms responsible for impaired insulin action in Cushing's syndrome are unclear. This study investigated the contribution of the glucose/glucose-6-phosphate substrate cycle (G/G6P). PATIENTS: Eight patients with Cushing's syndrome and seven control subjects were studied. All had normal fasting plasma glucose. DESIGN: Insulin action was assessed using the euglycaemic glucose clamp at insulin infusion rates of 0.4 and 2.0 mU/kg/min combined with a simultaneous infusion of [2(3)H]- and [6(3)-H]-glucose. Glucose/ glucose-6-phosphate cycle activity was calculated as the difference in glucose turnover rates determined separately for [2(3)H]- and [6(3)H]-glucose by selective enzymatic detritiation. MEASUREMENTS AND RESULTS: Exogenous glucose infusion rates required to maintain euglycaemia were significantly lower in Cushing's patients compared to controls, during the 0.4 mU/kg/min (7.8 +/- 1.2 vs 15.7 +/- 0.5 mumol/kg/min, P < 0.001) and the 2.0 mU/ kg/min insulin infusions (26.2 +/- 2.8 vs 51.5 +/- 3.5 mumol/ kg/min, P < 0.001). Endogenous glucose production was similar in both groups in the postabsorptive state (10.2 +/- 0.3 vs 10.8 +/- 0.4 mumol/kg/min, P = 0.50) and suppressed to a similar degree during hyperinsulinaemia. G/G6P cycle activity was markedly increased in the Cushing's group in the postabsorptive state (5.4 +/- 1.1 vs 2.0 +/- 0.5 mumol/kg/min, P = 0.028) and during the 0.4 mU/kg/min (3.2 +/- 0.6 vs 1.2 +/- 0.4 mumol/kg/min, P = 0.014) and 2.0 mU/kg/min insulin infusions (3.3 +/- 0.8 vs 1.1 +/- 0.5 mumol/kg/min, P = 0.049). CONCLUSIONS: Patients with Cushing's syndrome show marked peripheral insulin resistance and enhanced hepatic G/G6P cycle activity. In the fasting state increased glucose/glucose-6-phosphate cycle activity may be a protective mechanism limiting hyperglycaemia. During hyperinsulinaemia G/G6P cycle activity was increased but insulin resistance was predominantly due to reduced peripheral glucose uptake.

Inhibition of hepatic inositol 1,4,5-trisphosphate receptor function by ethanol and other short chain alcohols.

The ability of alcohols to regulate InsP3-receptor activity was examined in permeabilized hepatocytes. Incubation with 30-300 mM ethanol decreased the sensitivity to InsP3 for Ca2+ release, with little effect on the size of the Ca2+ store that could be released with maximal concentrations of InsP3. Ethanol (300 mM) increased the EC50 for InsP3 from a control value of 134.0 +/- 13.5 nM to 220.0 +/- 25.9 nM. Although ethanol also caused a partial depletion of the total pool of stored Ca2+, the ethanol-induced shift in InsP3 sensitivity was not secondary to this alteration in Ca2+ loading. Partial depletion of the Ca2+ stores with low doses of ionomycin and thapsigargin did not cause a shift in InsP3 sensitivity. Furthermore, measurements of InsP3 receptor channel activity using retrograde flux of Mn2+ to quench the fluorescence of Fura-2 within the Ca2+ stores demonstrated that ethanol inhibited InsP3-activated channel activity in the absence of stored Ca2+. Other short chain alcohols (methanol, 1-propanol and 1-butanol) also decreased the efficacy of InsP3 to release Ca2+. Measurements of [3H]-InsP3 binding demonstrated that ethanol decreased the total number of InsP3 binding sites without changing the KD. The effect of ethanol on InsP3 binding was apparent in the presence or absence of Ca2+ and was observed when the cells were pre-incubated with ethanol at either 37 degrees C or 4 degrees C. The initial rate of InsP3-induced Mn2+ quenching of compartmentalized Fura-2 was reduced by ethanol at all doses of InsP3. These data suggest that ethanol decreases the sensitivity of the intracellular Ca2+ store to release by InsP3, by reducing the number of channels that can be activated by InsP3.

Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy.

Impaired epinephrine secretion and symptom unawareness are characteristic of severe hypoglycemia in individuals with long-standing type I diabetes. Recently, the avoidance of clinical hypoglycemia has been reported to improve epinephrine and symptom responses to hypoglycemia in type I patients. However, the extent to which these defects can be restored in individuals with long-standing type I diabetes and autonomic neuropathy has not been assessed, nor has it been determined whether pancreas transplantation, which not only obviates hypoglycemia but also prevents hyperglycemia, results in the complete recovery of either epinephrine response or symptom awareness during insulin-induced hypoglycemia. We performed stepped hypoglycemic clamp studies in successful pancreas transplantation recipients to assess epinephrine and other counterregulatory hormone responses during hypoglycemia and to determine the degree to which hypoglycemic symptom recognition could be restored. Thirteen pancreas transplant recipients and matched control subjects were studied utilizing stepped hypoglycemic clamp protocol to achieve target glucose levels of 3.9, 3.3, 2.8, and 2.2 mmol/l (70, 60, 50, and 40 mg/dl, respectively). Plasma epinephrine response was significantly greater in healthy control subjects and pancreas transplant patients compared with type I subjects at the glucose plateaus of 3.9, 3.3, and 2.8 mmol/l. However, epinephrine response in pancreas transplant recipients was significantly less than that seen in either healthy control subjects or nondiabetic kidney transplant recipients at each of these glucose plateaus. The magnitude of the epinephrine response in pancreas transplant type I patients did not correlate with either the duration of diabetes, the duration of transplantation, or the measures of autonomic nerve function. Hypoglycemic symptom recognition was significantly greater in pancreas transplant subjects than type I patients and did not differ between pancreas transplant and control groups. No improvement in norepinephrine response was observed after pancreas transplantation, while glucagon responses to hypoglycemia were normalized in pancreas transplant patients. In conclusion, these studies uniquely demonstrate that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long-standing diabetes and established autonomic neuropathy. No correlation was observed between the severity of autonomic neuropathy or the duration of diabetes and the recovery of either the epinephrine or symptom responses to hypoglycemia.

The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined.

The optimal site for pancreatic islet cell transplantation is presently unclear, although the liver has been the most commonly used. However, glucagon secretion from islets that have been autotransplanted in liver has been reported to be unresponsive to hypoglycemia yet responsive to arginine. To determine whether this selective glucagon secretory defect is related to the intrahepatic site of islet implantation or to the process of transplantation per se, we studied counterregulatory responses to hypoglycemia in dogs with pancreatic islet autotransplantation in the hepatic parenchyma (the intrahepatic [IH] group, n = 9) or the peritoneal cavity (the intraperitoneal [IP] group, n = 9), following total pancreatectomy, and compared them with the responses in normal controls (n = 10). Dogs were subjected to a hypoglycemic hyperinsulinemic (5 mU x kg-1 x min-1) clamp for 90 min under general anesthesia. Arterial glucose concentrations were clamped at 2.7 mmol/l for the final 45 min of the clamp. Immediately following the clamp, glucagon responses to IV arginine (5 g) were also assessed. During hypoglycemia, glucagon responses in the IH group (maximal incremental glucagon = 33 +/- 21 ng/l; glucagon area under curve [AUC] = 713 +/- 1,022 ng x l-1 x min-1) were significantly lower than either the IP (maximal incremental glucagon = 92 +/- 32 ng/l; glucagon AUC = 4,090 +/- 1,600 ng x l-1 x min-1) or control (maximal incremental glucagon = 154 +/- 71 ng/l; glucagon AUC = 6,943 +/- 2,842 ng x l-1 x min-1) group (IH vs. IP group, P < 0.05; control vs. IH group, P < 0.01). Glucagon responses in the IP group did not differ significantly from the control group. Epinephrine responses to hypoglycemia were similar in all groups, whereas neither of the transplanted groups (IH and IP) had pancreatic polypeptide responses. There was a prompt rise in plasma glucagon after intravenous arginine in all groups. These data indicate that glucagon unresponsiveness to hypoglycemia is specific to intrahepatically transplanted islets, rendering the liver a disadvantageous site for optimal alpha-cell function.