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A xanthine derivative, named BL-191, was administered iv in 8 healthy volunteers alone and in association with glucose (0.33 g/kg body weight iv) or glybenclamide (1 mg iv). BL-191 was infused iv at a constant rate in a dose of 200 mg during 45 minutes. Blood glucose, free fatty acids and immunoreactive insulin were measured during one hour. It was impossible to demonstrate neither a direct effect nor an enhancement of insulin secretion during drug administration; in another experiment (treatment F) a higher dosage of BL-191 (100 mg as a priming dose + 200 mg as infusion dose) was likely ineffective. It appears that some difference in insulin response may be present in the single subject (not evident in the mean), indicating a difference in the β-cell cAMP-system sensitivity in individuals. These negative results allow some considerations on the importance of the β-cell cAMP-system in healthy human beings. [ABSTRACT FROM AUTHOR]

Aims: This study examined age-related differences between young and older adults' emotion regulation, hope, and optimism 1 year after the COVID-19 outbreak. Whether personality explained such outcomes was also examined., Method: A sample of 228 young adults and 161 older adults was interviewed in April-May 2021 to complete questionnaires assessing cognitive reappraisal (CR) and expressive suppression (ES) emotion regulation strategies use, optimism, hope (agency and pathways components), and personality traits., Results: Older adults reported greater CR and ES use, optimism, and hope-agency levels than young adults, whereas no age differences emerged for hope-pathway scores. Personality traits (more consistently emotional stability) contributed to explaining CR and ES use, and greater hopeful and optimistic dispositions., Conclusions: These findings confirm older adults' advantage in facing the emotional and psychological fallout of the COVID-19 pandemic in its third wave. They also underscore the importance of considering personality to depict individual profiles prone to experiencing long-term negative emotional/psychological consequences of emergencies as COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carbone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study examined the efficacy of a strategy-based memory training for older adults at short- and long-term with two (5- and 11 months) follow-ups. We also explored whether booster sessions (additional training before the first follow-up) facilitated the maintenance of benefits. Thirty-three older adults received a training based on the teaching of different effective memory strategies. One group completed three booster sessions before the 5 months follow-up. Training gains were examined using a word-list and a face-surname association recall tasks, and transfer effects with a grocery-word list (GL) recall task, a working memory (WM) measure, and a perceived memory functioning questionnaire. Training gains and transfer effects to the WM measure emerged and were maintained up to the second follow-up. No benefits for the GL and perceived memory functioning were found. The "boosted" group had only a slight advantage-in one of the transfer tasks-as shown by effect sizes. This pilot study confirms the efficacy of strategy-based memory training in supporting older adults' memory performance up to 11 months since training completion. However, booster sessions seem not to make a clear difference in prompting long-lasting benefits. Training features capable of fostering generalized, prolonged effects are worth investigating.

This study newly investigated the joint contribution of metamemory and personality (traits and facets) in explaining episodic memory (EM) performance in typically aging older adults. Forty-eight participants (age range: 64-75 years) completed a self-paced word list (SPWL) recall task, a metamemory questionnaire assessing perceived control and potential improvement (PCPI) and self-efficacy and satisfaction (SESA) regarding one's mental abilities (e.g., memory), and the Big-Five Questionnaire. Based on the SPWL encoding strategies reported, participants were then classified as effective (N = 20) or ineffective (N = 28) memory strategy users. Hierarchical regression analyses showed that a better SPWL performance was predicted by higher levels of PCPI, Scrupulousness and Dominance personality facets. Effective memory strategy users, then, showed higher SPWL performance and Dominance (Energy facet) than ineffective ones. These findings suggest that both specific metamemory processes and personality facets predict better EM performance in older adults. Moreover, personality dispositions relating to Dominance seem to characterize individuals adopting effective memory strategies to support EM performance. These results represent first evidence of the role of both metamemory and personality-facets-in explaining older adults' EM performance, which should thus be considered when assessing or training EM in old age., (© 2023. The Author(s).)

Background: The advancement of physiopathological knowledge of tendon structures has shown that, in conditions of overload, there is the onset of both degenerative phenomena, such as the production of metalloproteases, apoptosis of tendon cells and neoangiogenesis, and regenerative and protective phenomena, such as the production of IGF-1 and nitric oxide. Tendinopathy results from the imbalance between these two groups of factors, leading to degeneration, weakening, and fissuring of the tendons, with the presence of local pain. The aim of the study was to evaluate the efficacy and tolerability of cetylated fatty acids (CFA) patch formulation in the control of acute localized shoulder pain and recovery of function in patients with tendinopathies., Methods: A prospective, single-center, no-profit observational study conducted in accordance with Good Clinical Practice. Thirty patients with recent onset shoulder pain symptoms (1-3 months) related to bursitis and tenosynovitis, with a diagnosis of shoulder tendon pathology confirmed by ultrasound examination, was evaluated for shoulder pain and function using the Constant Murley Score. Patients used 1 patch containing CFA for 8 h per day for 10 days. At 10 (V1) and 35 (V2) days after the first visit (V0), the Constant Score, treatment compliance and product tolerability were evaluated., Results: Thirty patients completed the treatment. At V0 the mean Constant Score (CS) was 32.37 ± 11.86, during V1 the mean CS was 50.68 ± 14.30, and at V3 the mean CS was 51.07 ± 15.29. The CS increased significantly between V0 and V1 (p < 0.0001) but did not vary significantly between V1 and V2 (p = 1). The tolerability of the product was excellent., Conclusions: Application of the CFA-based patch for 10 consecutive days in patients with shoulder tendinopathies was effective in reducing local pain and resulted in a good recovery of function. The results achieved at day 10 were maintained for 25 days, until the follow-up visit at day 35. CFA-based patch, thanks to their efficacy and tolerability, seems to be a promising solution to improve pain and functionality in subject with shoulder tendinopathy., Trial Registration: The study was approved by the Ethics Committee of Azienda USL Toscana Nord Ovest (protocol code 2018RIAB105) and conducted in accordance with Good Clinical Practice and the ethical principles outlined in the Declaration of Helsinki., (© 2022. The Author(s).)

Background: As telemedicine utilization increased during the COVID-19 pandemic, divergent usage patterns for video and audio-only telephone visits emerged. Older, low-income, minority, and non-English speaking Medicaid patients are at highest risk of experiencing technology access and digital literacy barriers. This raises concern for disparities in health care access and widening of the "digital divide," the separation of those with technological access and knowledge and those without. While studies demonstrate correlation between racial and socioeconomic demographics and technological access and ability, individual patients' perspectives of the divide and its impacts remain unclear., Objective: We aimed to interview patients to understand their perspectives on (1) the definition, causes, and impact of the digital divide; (2) whose responsibility it is to address this divide, and (3) potential solutions to mitigate the digital divide., Methods: Between December 2020 and March 2021, we conducted 54 semistructured telephone interviews with adult patients and parents of pediatric patients who had virtual visits (phone, video, or both) between March and September 2020 at the University of Chicago Medical Center (UCMC) primary care clinics. A grounded theory approach was used to analyze interview data., Results: Patients were keenly aware of the digital divide and described impacts beyond health care, including employment, education, community and social contexts, and personal economic stability. Patients described that individuals, government, libraries, schools, health care organizations, and even private businesses all shared the responsibility to address the divide. Proposed solutions to address the divide included conducting community technology needs assessments and improving technology access, literacy training, and resource awareness. Recognizing that some individuals will never cross the divide, patients also emphasized continued support of low-tech communication methods and health care delivery to prevent widening of the digital divide. Furthermore, patients viewed technology access and literacy as drivers of the social determinants of health (SDOH), profoundly influencing how SDOH function to worsen or improve health disparities., Conclusions: Patient perspectives provide valuable insight into the digital divide and can inform solutions to mitigate health and resulting societal inequities. Future work is needed to understand the digital needs of disconnected individuals and communities. As clinical care and delivery continue to integrate telehealth, studies are needed to explore whether having a video or audio-only phone visit results in different patient outcomes and utilization. Advocacy efforts to disseminate public and private resources can also expand device and broadband internet access, improve technology literacy, and increase funding to support both high- and low-tech forms of health care delivery for the disconnected., (©Maria Alcocer Alkureishi, Zi-Yi Choo, Ali Rahman, Kimberly Ho, Jonah Benning-Shorb, Gena Lenti, Itzel Velázquez Sánchez, Mengqi Zhu, Sachin D Shah, Wei Wei Lee. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 15.12.2021.)

Coronavirus disease 2019 (COVID-19) has provided unprecedented opportunity for the growth of telemedicine in pediatrics. Clinics rapidly expanded their telemedicine capabilities and converted in-person visits to virtual visits to offer patients continued care while limiting infection risks. Although the transition to video visits has several benefits-patient convenience, versatility of care, ease of follow up, and management of chronic conditions-these gains are only available to those who have the requisite technology access and literacy needed to conduct a video visit. The need for technology-dependent care stands to further widen preexisting disparities in access to care for those who cannot use or afford the necessary technology. Our article explores some of these benefits and challenges and reminds us that although telemedicine has proven to have high utility for many patients, there are improvements that must still be made to ensure equitable accessibility and durability of virtual visits. [ Pediatr Ann. 2021;50(12):e503-e508.] .

Introduction: The study examined age-related differences between young and older adults' emotional and psychological experience as well as cognitive functioning throughout different phases of the COVID-19 pandemic in Italy. Materials and Methods: Participants were interviewed by phone when confined at home during the national lockdown (T1-May 2020; N = 138 young adults; N = 119 older adults) and after the first wave of contagions, when restrictions were discarded (T2-September 2020; N = 52 young adults; N = 59 older adults). A sub-sample also participated in a third assessment (T3-December 2020). Participants completed questionnaires assessing their emotional and psychological functioning (i.e., positive and negative affect, perceived social and emotional loneliness, resilience) along with memory tasks (Backward Digit Span task and words list recall). Results: Although individuals reported less positive and more negative emotions during the lockdown than at T2, results showed that older adults displayed overall fewer negative emotions and greater resilience than young adults. The latter were those who reported feeling more emotionally lonely when compared to their older counterpart during the lockdown than afterward. Older adults' advantage in emotional and psychological functioning was also confirmed 7 months after the national lockdown. Only age-related differences in favor of young adults for the memory tasks were found. The measures of interest were also susceptible to mood and/or concerns of COVID-19 effects. Discussion: These findings further highlight the age-related advantage of older adults managing the emotional and psychological experience even when facing an unexpected, prolonged, and unpredictable, stressful life event such as the COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MF declared a shared affiliation, though no other collaboration, with several of the authors RP and ADD to the handling editor., (Copyright © 2021 Carbone, Palumbo, Sella, Lenti, Di Domenico and Borella.)

Background: Since the COVID-19 pandemic onset, telemedicine has increased exponentially across numerous outpatient departments and specialties. Qualitative studies examining clinician telemedicine perspectives during the pandemic identified challenges with physical examination, workflow concerns, burnout, and reduced personal connection with patients. However, these studies only included a relatively small number of physicians or were limited to a single specialty, and few assessed perspectives on integrating trainees into workflows, an important area to address to support the clinical learning environment. As telemedicine use continues, it is necessary to understand a range of clinician perspectives., Objective: This study aims to survey pediatric and adult medicine clinicians at the University of Chicago Medical Center to understand their telemedicine benefits and barriers, workflow impacts, and training and support needs., Methods: In July 2020, we conducted an observational cross-sectional study of University of Chicago Medical Center faculty and advanced practice providers in the Department of Medicine (DOM) and Department of Pediatrics (DOP)., Results: The overall response rate was 39% (200/517; DOM: 135/325, 42%; DOP: 65/192, 34%); most respondents were physicians (DOM: 100/135, 74%; DOP: 51/65, 79%). One-third took longer to prepare for (65/200, 33%) and conduct (62/200, 32%) video visits compared to in-person visits. Male clinicians reported conducting a higher percentage of telemedicine visits by video than their female counterparts (P=.02), with no differences in the number of half-days per week providing direct outpatient care or supervising trainees. Further, clinicians who conducted a higher percentage of their telemedicine by video were less likely to feel overwhelmed (P=.02), with no difference in reported burnout. Female clinicians were "more overwhelmed" with video visits compared to males (41/130, 32% vs 12/64, 19%; P=.05). Clinicians 50 years or older were "less overwhelmed" than those younger than 50 years (30/85, 35% vs 23/113, 20%; P=.02). Those who received more video visit training modalities (eg, a document and webinar on technical issues) were less likely to feel overwhelmed by the conversion to video visits (P=.007) or burnt out (P=.009). In addition, those reporting a higher ability to technically navigate a video visit were also less likely to feel overwhelmed by video visits (P=.02) or burnt out (P=.001). The top telemedicine barriers were patient-related: lack of technology access, lack of skill, and reluctance. Training needs to be focused on integrating learners into workflows. Open-ended responses highlighted a need for increased support staff. Overall, more than half "enjoyed conducting video visits" (119/200, 60%) and wanted to continue using video visits in the future (150/200, 75%)., Conclusions: Despite positive telemedicine experiences, more support to facilitate video visits for patients and clinicians is needed. Further, clinicians need additional training on trainee education and integration into workflows. Further work is needed to better understand why gender and age differences exist. In conclusion, interventions to address clinician and patient barriers, and enhance clinician training are needed to support telemedicine's durability., (©Maria Alcocer Alkureishi, Zi-Yi Choo, Gena Lenti, Jason Castaneda, Mengqi Zhu, Kenneth Nunes, George Weyer, Julie Oyler, Sachin Shah, Wei Wei Lee. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 09.07.2021.)

The COVID-19 pandemic has pushed telemedicine to the forefront of health care delivery, and for many clinicians, virtual visits are the new normal. Although telemedicine has allowed clinicians to safely care for patients from a distance during the current pandemic, its rapid adoption has outpaced clinician training and development of best practices. Additionally, telemedicine has pulled trainees into a new virtual education environment that finds them oftentimes physically separated from their preceptors. Medical educators are challenged with figuring out how to integrate learners into virtual workflows while teaching and providing patient-centered virtual care. In this viewpoint, we review principles of patient-centered care in the in-person setting, explore the concept of patient-centered virtual care, and advocate for the development and implementation of patient-centered telemedicine competencies. We also recommend strategies for teaching patient-centered virtual care, integrating trainees into virtual workflows, and developing telemedicine curricula for graduate medical education trainees by using our TELEMEDS framework as a model., (©Maria Alcocer Alkureishi, Gena Lenti, Zi-Yi Choo, Jason Castaneda, George Weyer, Julie Oyler, Wei Wei Lee. Originally published in JMIR Medical Education (https://mededu.jmir.org), 29.04.2021.)

Although generic oral contraceptives (OCPs) can improve adherence and reduce health care expenditures, use of generic OCPs remains low, and the factors that affect generic prescribing are not well understood. We aimed to understand the barriers and facilitators of generic OCP prescribing and potential solutions to increase generic OCP prescribing, as well as pilot an educational module to address clinician misconceptions about generic OCPs. We developed focus group scripts using the 4D model of appreciative inquiry. A total of four focus groups occurred, two at the American Association of Nurse Practitioners (AANP) national conference and two at the American College of Physicians (ACP) Internal Medicine meeting. Focus group transcripts were analyzed using a constant comparative method with no a priori hypothesis to generate emerging and reoccurring themes. Findings from these focus groups were used to develop an educational module promoting generic OCP prescribing. Participants were recruited from the AANP Network for Research and the ACP Research Panel. This study demonstrates that health system factors, workflow factors, clinician factors, and patient factors were the main barriers to and facilitators of generic OCP prescribing. Nurse practitioners were responsive to an educational module and reported increased willingness to discuss and prescribe generic OCPs after completing the module. Interventions to increase generic OCP prescribing must address clinician and patient factors within the context of workflow and larger health system factors.

What Is Known and Objective: The use of generic oral contraceptives (OCPs) can improve adherence and reduce healthcare costs, yet scepticism of generic drugs remains a barrier to generic OCP discussion and prescription. An educational web module was developed to reduce generic scepticism related to OCPs, improve knowledge of generic drugs and increase physician willingness to discuss and prescribe generic OCPs., Methods: A needs assessment was completed using in-person focus groups at American College of Physicians (ACP) Annual Meeting and a survey targeting baseline generic scepticism. Insights gained were used to build an educational web module detailing barriers and benefits of generic OCP prescription. The module was disseminated via email to an ACP research panel who completed our baseline survey. Post-module evaluation measured learner reaction, knowledge and intention to change behaviour along with generic scepticism., Results and Discussion: The module had a response rate of 56% (n = 208/369). Individuals defined as generic sceptics at baseline were significantly less likely to complete our module compared to non-sceptics (responders 9.6% vs non-responders 16.8%, P = 0.04). The majority (85%, n = 17/20) of baseline sceptics were converted to non-sceptics (P < 0.01) following completion of the module. Compared to non-sceptics, post-module generic sceptics reported less willingness to discuss (sceptic 33.3% vs non-sceptic 71.5%, P < 0.01), but not less willingness to prescribe generic OCPs (sceptic 53.3% vs non-sceptic 67.9%, P = 0.25). Non-white physicians and international medical graduates (IMG) were more likely to be generic sceptics at baseline (non-white 86.9% vs white 69.9%, P = 0.01, IMG 13.0% vs USMG 5.0% vs unknown 18.2%, P = 0.03) but were also more likely to report intention to prescribe generic OCPs as a result of the module (non-white 78.7% vs white 57.3%, P < 0.01, IMG 76.1% vs USMG 50.3% vs unknown 77.3%, P = 0.03)., What Is New and Conclusion: A brief educational web module can be used to promote prescribing of generic OCPs and reduce generic scepticism., (© 2019 John Wiley & Sons Ltd.)

Various fluorogenic assays exist for monitoring the activity of inflammatory caspases. However, there are no continuous assays that provide C-terminal substrate sequence specificity for inflammatory caspases. As a first step towards this, we have developed a continuous in vitro assay that relies on monitoring emission from tryptophan after cleavage of a quenching coumarin chromophore. The coumarin can be attached as an amino acid side chain or capping the C-terminus of the peptide. When the coumarin is a side chain, it allows for C-terminal and N-terminal sequence specificities to be explored. Using this assay, we obtained Michaelis-Menten kinetic data for four proof-of-principle peptides: WEHD-AMC (K M  = 15 ± 2 μM), WEHD-MCA (K M  = 93 ± 19 μM), WEHDG-MCA (K M  = 21 ± 6 μM) and WEHDA-MCA (K M  = 151 ± 37 μM), where AMC is 7-amino-4-methylcoumarin and MCA is β-(7-methoxy-coumarin-4-yl)-Ala. The results indicate the viability of this new assay approach in the design of effective fluorogenic substrates for inflammatory caspases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar K i values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: The complex nature of stroke sequelae requires several assessment instruments to quantify correctly every residual symptom. As there was no general consensus on stroke evaluation among Italian Physiatrists, in 2004 the Italian Society of Physical Medicine and Rehabilitation and S. Lucia Foundation (a Scientific Institute for hospitalization and treatment) established a Project Group to propose a standardized assessment tool (''Protocollo di Minima per l'Ictus PMIC'') for acute, post-acute and community-living stroke patients. This tool aimed to be easy to use and comprehensive of all the elements necessary for accurately address the great range of different rehabilitation needs. The objective was to provide physiatrists with a standard assessment battery and to make prognostic factors available on large community samples., Methods: From end 2004 to early 2006, the Project Group examined literature data on stroke assessment, prognostic factors and outcome and selected the specific data elements to be included in a data collection tool., Results: A consensus was reached on a ''minimum'' core set of data. This protocol was peer submitted in early 2006, to test the burden of data collection, and to allow modifications and adjustments. Specific forms (file to download) for data collection and database to be shared (a dedicated ''Client'' software) are now freely offered by the Project Group for data collection., Conclusion: PMIC is an evaluation procedure manageable in every-day practice and in every setting, a quick screening instrument that, given its large diffusion, can be expanded from a National Database into a National Rehabilitation Stroke Registry.

Background and Purpose: Physical deconditioning is involved in the impaired exercise tolerance of patients with multiple sclerosis (MS), but data on the effects of aerobic training (AT) in this population are scanty. The purpose of this study was to compare the effects of an 8-week AT program on exercise capacity-in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of life-as compared with neurological rehabilitation (NR) in subjects with MS., Subjects and Methods: Nineteen subjects (14 female, 5 male; mean age [X+/-SD]=41+/-8 years) with mild to moderate disability secondary to MS participated in a randomized crossover controlled study. Eleven subjects (8 female, 3 male; mean age [X+/-SD]=44+/-6 years) completed the study., Results: After AT, but not NR, the subjects' walking distances and speeds during a self-paced walk were significantly improved, as were their maximum work rate, peak oxygen uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in peak oxygen uptake and maximum work rate, but not in walking capacity, were significantly higher after AT, as compared with after NR. Additionally, the subjects who were most disabled tended to benefit more from AT. There were no differences between AT and NR in effects on fatigue, and the results showed that AT may have partially affected health-related quality of life., Discussion and Conclusion: The results suggest that AT is more effective than NR in improving maximum exercise tolerance and walking capacity in people with mild to moderate disability secondary to MS.

To compare the chronic hyperlactatemic effect of phenformin and metformin, we performed a double-blind study in 10 non insulin-dependent diabetics without any other known hyperlactatemic condition. After a pre-study period, each patient was allocated to a 6-month treatment with phenformin (50 mg bid) or metformin (850 mg bid) in random sequence. Body weight values were not significantly different between phenformin and metformin. Diabetic control was significantly (p less than 0.001) improved by both biguanides versus pre-study, but was the same during metformin and phenformin: HbAI = 13.8 +/- 0.3 SEM% during pre-study 9.7 +/- 0.2% during phenformin, 10.2 +/- 0.2% during metformin. Mean values of plasma lactate during metformin were significantly lower versus phenformin (1.30 +/- 0.05 vs 1.64 +/- 0.05 mmol/l, p less than 0.001). Mean values of plasma lactate/pyruvate ratio during metformin were significantly lower versus phenformin (16.92 +/- 0.59 vs 22.65 +/- 0.87, p less than 0.001), but not versus pre-study (16.19 +/- 0.51). These results indicate that: 1) during a 6-month treatment with a diabetic control of similar degree phenformin produces a significantly higher hyperlactatemic effect vs metformin; 2) metformin treatment is associated with less impairment of intracellular redox state versus phenformin, and therefore should be considered advantageous in the long-term treatment of non insulin-dependent diabetics.

The metabolic and hormonal changes during a standard physical exercise were studied in healthy subjects and in insulin-dependent diabetics well matched for body weight, and therefore submitted to a similar work load in a physiologic range, and in obese subjects that, owing to their weight, faced a significant heavier work in the same environmental conditions. Moderate work load did not lead to significant changes in metabolic and hormonal blood parameters (blood glucose, FFA and glycerol; insulin, glucagon, growth hormone and cortisol) in healthy subjects. A similar substrate homeostatis was seen in insulin-dependent diabetics, that however showed marked hormonal alterations. In these subjects, indeed, higher levels of plasma glucagon and GH were reached during work and in the recovery phase. Obese subjects, submitted to a heavier work load, presented a marked increase in blood glucose and glycerol which agrees with high GH and cortisol levels, and a subsequent increment of IRI which corresponds to a normalization of blood glucose and glycerol. Obese subjects, therefore, show a normal sensitivity to work load. Considerations about the work load in everyday life are discussed.

Hyperinsulinemia in human cirrhosis is generally considered an expression of reduced hepatic insulin degradation. To determine whether hyperinsulinemia may also depend on an altered feedback inhibition of insulin secretion, we performed euglycemic hyperinsulinemic clamp studies, infusing 40, 372, or 1280 mU/m2 X min biosynthetic human insulin in 30 compensated cirrhotic patients with portal hypertension and impaired glucose tolerance and 25 normal subjects, matched for age, sex, and weight. Mean fasting plasma insulin was significantly higher in cirrhotic patients [26.1 +/- 2.3 vs. 12.4 +/- 0.6 (+/- SE) microU/ml; P less than 0.001], while fasting plasma glucose levels were similar in the 2 groups. The mean plasma C-peptide level was significantly higher in cirrhotic patients, both basally (2.7 +/- 0.1 vs. 1.7 +/- 0.1 ng/ml; P less than 0.001) and during the clamp studies. Suppression of C-peptide at 120 min of the clamp was significantly less in cirrhotic patients (37 +/- 7% vs. 79 +/- 4%, 52 +/- 9% vs. approximately 100%, and 54 +/- 4% vs. approximately 100% during the 40, 372, and 1280 mU/m2 X min insulin infusions, respectively). The fasting C-peptide to insulin molar ratio was significantly lower in cirrhotic patients (5.4 +/- 0.3 vs. 6.4 +/- 0.3; P less than 0.005). The MCR of insulin at the three steady states was not significantly different between the 2 groups, whereas the basal systemic delivery rate of insulin was significantly higher in cirrhotic patients (14.7 +/- 1.7 vs. 6.5 +/- 0.4 mU/m2 X min; P less than 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.

Ganglioside treatment was evaluated with a multicenter, randomized, double-blind, controlled, cross-over vs placebo trial in 140 insulin-treated diabetic subjects with peripheral neuropathy. The patients entered the study when they showed an impairment in at least two of the electroneurographic parameters, and were assigned to two protocols according to the presence and severity of their neurological symptoms. Ninety-seven diabetic subjects with no or mild symptoms were assigned to protocol I, whereas 43 symptomatic patients were assigned to protocol II. the treatment periods lasted 6 weeks with an intermediate washout period of 4 weeks. The treatment consisted in the daily i.m. administration of 20 mg gangliosides or of placebo. Electroneurographic parameters were recorded at the beginning and at the end of each treatment period, whereas clinical and metabolic data (mean daily plasma glucose, glycosuria and glycosylated hemoglobin) were evaluated every three weeks in protocol I and every two weeks in protocol II. No change in the metabolic parameters was observed throughout the trial period. However, the treatment induced a statistically significant improvement of paresthesias (protocol II) and of some electrophysiological parameters; in particular, ganglioside treatment improved MCV of peroneal nerve (p less than 0.03) in patients of protocol I, MCV o ulnar nerve (p less than 0.002) and SCV of median nerve (p less than 0.06) in patients of protocol II. Furthermore, 22 subjects of protocol II showed a 'drug preference' while 10 preferred placebo and 9 had no preference. In conclusion, ganglioside treatment seems to have a positive effect on diabetic peripheral neuropathy, improving both some symptoms and some electrophysiological parameters.

The present study was performed to see whether insulin receptor evaluation is useful as a diagnostic tool in the differential diagnosis of hypoglycemia. The receptor numbers and affinity constants of insulin binding to adipocytes isolated from subcutaneous tissue were determined in 5 metabolically healthy subjects, undergoing laparatomy for cholecystectomy, and in 4 patients undergoing surgery for insulinoma removal. The specific insulin binding to monocytes at physiological concentrations (1 ng/ml) was also determined in all these subjects, and in 6 patients with functional hypoglycemia. The study was repeated in insulinoma patients 7 days after surgery. Results show that insulinoma patients before tumor removal have greater than 50% fall in binding capacity on both monocytes and fat cells, in keeping with the down-regulation mechanism, whereas the values for patients with functional hypoglycemia are in the normal range. After surgery, the insulin binding to monocytes sharply increased, nearly to the lower level of the normal range when the insulinoma was removed; no change was observed when the tumor was not resected (case 3). Insulin receptor study may therefore be of diagnostic and prognostic assistance in the investigation of hypoglycemic syndromes.

Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivity in vivo (hyperglycemic clamp) and in vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8 +/- 1.0 vs 4.8 +/- 0.8 microU/ml in controls, p less than 0.0005), with a significant reduction in early and late insulin secretion (14.0 +/- 1.5 vs 20.8 +/- 2.0 microU/ml, p less than 0.01 and 24.8 +/- 3.3 vs 34.7 +/- 2.14 microU/ml, p less than 0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30 +/- 0.32 vs 4.14 +/- 0.40, p less than 0.005). Endogenous glucose production was significantly increased (107 +/- 10.2 vs 84 +/- 3.7 mg/m2 per min, p less than 0.025) and displayed a positive correlation with fasting glycemia (r = 0.51, p less than 0.05). Insulin binding to monocytes was significantly lower than in controls (2.36 +/- 0.22% vs 4.06 +/- 0.32%, p less than 0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1 +/- 2.8 microU/ml, p less than 0.0005 vs controls) but, typically, lacked the early secretory phase (20.6 +/- 3.6 microU/ml vs baseline, n.s.). A similar increase of hepatic glucose production (107 +/- 11.2 mg/m2 per min, p less than 0.025 vs controls, n.s. vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I = 1.78 +/- 0.31, p less than 0.0005 vs controls, n.s. vs non-obese diabetics) was found in moderately obese diabetics, as well as a significant reduction of insulin binding to insulated monocytes (2.62 +/- 0.4% p less than 0.01 vs controls, n.s. vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.