Large Angiomatous Nasal Polyp Presents With Epistaxis Imitating Juvenile Nasopharyngeal Angiofibroma.

An angiomatous nasal polyp is a rare subtype of sinonasal polyp that is commonly found in the middle meatus and characterized by the presence of blood vessels within polyp tissue. It is a benign lesion but is prone to misdiagnosis as a malignant tumor because it typically grows larger and is more vascular than other types of polyps. In this report, a 16-year-old male with no significant past medical history presents with a six-month history of epistaxis and progressive nasal obstruction. Examination of the oral cavity showed a centrally located soft palate mass. CT maxillofacial with contrast showed a hypervascular 3.4 x 4.7 x 6.1 cm mass in the nasal cavity extending through the nasal choanae and down to the level of the tongue. MRI showed a heterogenous polypoid mass originating from the left middle meatus vs. nasal cavity, with characteristics favoring an aggressive tumor. The patient was taken for interventional radiology (IR) embolization and nasal endoscopy. Biopsy showed the left nasal mass contained granulation tissue and the palatal mass consisted of necrotic tissue. He was taken for second-stage endoscopic sinus surgery with plans for extensive reconstruction if necessary. Extensive polyposis was found without gross evidence of an aggressive tumor. The anterior polyposis was debulked and the polyp was cut at its root to allow for removal of the nasopharyngeal/oropharyngeal portion through the mouth. He was able to be discharged on the same day and his postoperative recovery was uncomplicated. Angiomatous nasal polyps are uncommon, share features of aggressive tumors on imaging, and require angiography and biopsy to safely rule out malignancy. Endoscopic surgical resection typically results in good outcomes and low recurrence rates.

Development of a benchmarking toolkit for adolescent and young adult rheumatology services (BeTAR).

BACKGROUND: Young people (YP; 12-24 years old) with rheumatic diseases face many challenges associated with chronic illness in addition to the physiological and psychosocial changes of adolescence. Timely access to developmentally appropriate multidisciplinary care is key to successfully managing rheumatic diseases, but gaps in the care of this vulnerable age group still exist. This study aimed to develop a benchmarking toolkit to enable comparative evaluation of YP rheumatology services in order to promote best practice and reduce variations in service delivery. METHODS: A staged and consultative method was used across a broad group of stakeholders in the UK (YP, parents/other carers, and healthcare professionals, HCPs) to develop this toolkit, with reference to pre-existing standards of YP-friendly healthcare. Eighty-seven YP (median age 19 years, range 12-24 years) and 26 rheumatology HCPs with 1-34 years of experience caring for YP have participated. RESULTS: Thirty quality criteria were identified, which were grouped into four main domains: assessment and treatment, information and involvement, accessibility and environment, and continuity of care. Two toolkit versions, one to be completed by HCPs and one to be completed by patients, were developed. These were further refined by relevant groups and face validity was confirmed. CONCLUSIONS: A toolkit has been developed to systematically evaluate and benchmark YP rheumatology services, which is key in setting standards of care, identifying targets for improvement and facilitating research. Engagement from YP, clinical teams, and commissioners with this tool should facilitate investigation of variability in levels of care and drive quality improvement.

Citizen science pioneers in Kenya - A crowdsourced approach for hydrological monitoring.

Although water is involved in many ecosystem services, the absence of monitoring data restricts the development of effective water management strategies especially in remote regions. Traditional monitoring networks can be expensive, with unaffordable costs in many low-income countries. Involving citizens in monitoring through crowdsourcing has the potential to reduce these costs but remains uncommon in hydrology. This study evaluates the quality and quantity of data generated by citizens in a remote Kenyan basin and assesses whether crowdsourcing is a suitable method to overcome data scarcity. We installed thirteen water level gauges equipped with signboards explaining the monitoring process to passers-by. Results were sent via a text-message-based data collection framework that included an immediate feedback to citizens. A public web interface was used to visualize the data. Within the first year, 124 citizens reported 1175 valid measurements. We identified thirteen citizens as active observers providing more than ten measurements, whereas 57% only sent one record. A comparison between the crowdsourced water level data and an automatic gauging station revealed high data quality. The results of this study indicate that citizens can provide water level data of sufficient quality and with high temporal resolution.

Developing and Evaluating JIApp: Acceptability and Usability of a Smartphone App System to Improve Self-Management in Young People With Juvenile Idiopathic Arthritis.

BACKGROUND: Flare-ups in juvenile idiopathic arthritis (JIA) are characterized by joint pain and swelling and often accompanied with fatigue, negative emotions, and reduced participation in activities. To minimize the impact of JIA on the physical and psychosocial development and well-being of young people (YP), it is essential to regularly monitor disease activity and side effects, as well as to support self-management such as adherence to treatment plans and engagement in general health-promoting behaviors. Smartphone technology has the potential to engage YP with their health care through convenient self-monitoring and easy access to information. In addition, having a more accurate summary of self-reported fluctuations in symptoms, behaviors, and psychosocial problems can help both YP and health care professionals (HCPs) better understand the patient's condition, identify barriers to self-management, and assess treatment effectiveness and additional health care needs. No comprehensive smartphone app has yet been developed in collaboration with YP with JIA, their parents, and HCPs involved in their care. OBJECTIVES: The objective of this study was to design, develop, and evaluate the acceptability and usability of JIApp, a self-management smartphone app system for YP with JIA and HCPs. METHODS: We used a qualitative, user-centered design approach involving YP, parents, and HCPs from the rheumatology team. The study was conducted in three phases: (1) phase I focused on developing consensus on the features, content, and design of the app; (2) phase II was used for further refining and evaluating the app prototype; and (3) phase III focused on usability testing of the app. The interview transcripts were analyzed using qualitative content analysis. RESULTS: A total of 29 YP (aged 10-23, median age 17) with JIA, 7 parents, and 21 HCPs were interviewed. Major themes identified as the ones that helped inform app development in phase I were: (1) remote monitoring of symptoms, well-being, and activities; (2) treatment adherence; and (3) education and support. During phase II, three more themes emerged that informed further refinement of the app prototype. These included (4) adapting a reward system to motivate end users for using the app; (5) design of the app interface; and (6) clinical practice integration. The usability testing during phase III demonstrated high rates of overall satisfaction and further affirmed the content validity of the app. CONCLUSIONS: We present the development and evaluation of a smartphone app to encourage self-management and engagement with health care for YP with JIA. The app was found to have high levels of acceptability and usability among YP and HCPs and has the potential to improve health care and outcomes for this age group. Future feasibility testing in a prospective study will firmly establish the reliability, efficacy, and cost-effectiveness of such an app intervention for patients with arthritis.

[The questionnaire survey on glaucoma diagnosis and treatment in China (2016)].

Objective: To investigate the present situation of diagnosis and treatment for primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) and awareness of the relevant progress among Chinese ophthalmologists. Methods: This study was a cross-sectional, non-randomized sampling survey. Participants were ophthalmologists who attended the 11st Chinese Glaucoma Society Congress during November 11 to 12, 2016. They were invited to fill out a questionnaire. The questionnaire included participants' basic information and their knowledge about glaucoma diagnosis and treatment. The data collected through questionnaire were analyzed with SAS9.4. Results: A total of 450 questionnaires were distributed and 372 valid questionnaires were retrieved, with a response rate of 82. 7%(372/450). ISGEO classification system was adopted by 58.9% (219/372) of the participants as the diagnostic criteria for PACG. Of the respondents, 48.1% (179/372) of the participants believed that "anterior chamber angle closure mechanism-based PACG classification system" was more instructive for treatment, the percentage was higher than ISGEO classification system (42.2%, 157/372). Most (72.3%, 269/372) of the participants knew the 3-minute dark room prone test, but only 27.7%(103/372) of them applied it in clinical practice. A total of 83.4%(310/372) of the participants believed that low cerebrospinal fluid pressure is a risk factor for POAG. In all, 71.8% (267/372) of the participants reported that their institutes had applied compound trabeculectomy with adjustable suture, with 76.9%(286/372) of the participants agreeing that the adjustable suture reduced the rate of complications after trabeculectomy. Conclusions: Currently, both ISGEO classification system and anterior chamber angle closure mechanism-based PACG classification system were adopted in the diagnosis and treatment of glaucoma. Low cerebrospinal fluid pressure as new risk factors for POAG has been widely acknowledged and given attentions by Chinese ophthalmologists. The 3-minute darkroom prone test and compound trabeculectomy with adjustable suture still need to be promoted. (Chin J Ophthalmol, 2017, 53: 115-120).

Analysis of the Relationship between the Location of the Anterior Ethmoid Artery and Keros Classification.

Objective We sought to identify a relationship between skull base height and anterior ethmoid artery (AEA) anatomy. Study Design Retrospective radiologic chart review. Setting University of Arkansas for Medical Sciences. Subjects Patients seen in a tertiary rhinology clinic between September 2014 and October 2015. Methods Review of 101 maxillofacial computed tomography scans with institutional review board approval. Skull base height and AEA locations were measured on each side. Prevalence of the AEA outside of the skull base and distance of the AEA from skull base were calculated and compared with Keros classification using χ2 testing. Comparisons of skull base height between sexes and age and distance between skull base and the AEA among Keros 2 and Keros 3 patients were made using an unpaired, 2-tailed t test. Results The AEA was located below the skull base in 25.7% of cases and more often in Keros type 3 (55%) than in Keros type 2 (29.5%) or Keros type 1 (0%) ( P < .05). Male patients were significantly more likely to have a greater average skull base height (5.25 vs 4.28 mm) and to have AEAs below the skull base (38.4% vs 14.8%). In addition, the distance of the AEA from the skull base was significantly higher in Keros type 3 patients compared with Keros type 2 patients (4.55 vs 3.42 mm, P = .001). Conclusions Variations in the AEA pathway occur more in male patients and those with higher Keros classifications. The distance between the variant AEA and the skull base increases with higher Keros classification. Keros classification can yield insight to the location of the AEA.

Comparison of major lymphocyte subpopulations and recent thymic emigrants in patients with ataxia telangiectasia and age-matched healthy groups

BACKGROUND: Ataxia telangiectasia (A-T) is a genetic disorder caused by the homozygous mutation of the A-T mutated gene. It is frequently associated with variable degrees of cellular and humoral immunodeficiency. However, the immune defects in A-T patients are not well characterized. To the best of our knowledge, no studies have focused on the major lymphocyte subpopulations and recent thymic emigrants of A-T patients in comparison with age-matched healthy controls. METHODS: Following the European Society for Immunodeficiencies criteria, 17 patients diagnosed with A-The, and 12 age-matched healthy children were assigned to the study. Both patients and healthy controls were grouped as 1-5, 6-10, 11-15, and 15+ years. By using a flow cytometer, major lymphocyte subpopulations and CD4+CD45RA+CD31+ recent thymic emigrants were determined as percentage and absolute cell numbers and compared. RESULTS: No significant differences in all lymphocyte subpopulations were observed between the age groups of A-T patients. Compared to the healthy controls, there was a decrease in T cells, effector memory T4 cells, B cells, naïve B cells, naïve T4 cells, switched B cells, and recent thymic emigrants and an increase in active T8 cells and non-switched B cells in the percentage and absolute number of some cell populations in the A-T group. CONCLUSIONS: This study showed that effector functions in some cell lymphocyte populations were decreased in A-T patients

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Acquired IgE-mediated food allergy after liver transplantation in children

BACKGROUND: In recent years, the number of studies regarding newly-diagnosed food allergies after liver transplantation has been increasing. In this study, we aimed to investigate the frequency, aetiology, risk factors, and severity of IgE-mediated food allergies after liver transplantation in children. METHODS: Paediatric patients who underwent liver transplantation at Inonu University Faculty of Medicine, Organ Transplantation Institute were included in the study. RESULTS: Forty-nine paediatric patients were enrolled in the study; 26 (53.1%) were female, the median age at transplantation was five years, and median follow-up time after transplantation was 16 months. Six patients (12.2%) developed IgE-mediated food allergies after transplantation; four had urticaria and/or angio-oedema and two developed anaphylaxis after food intake. Patients with and without IgE-mediated food allergies were similar in terms of sex, age at transplantation, comorbid atopic disease, immunosuppressant therapy with tacrolimus, and blood tacrolimus level (p > 0.05 for each). Serum total IgE levels ≥100 IU/mL (p = 0.02) and peripheral eosinophilia (p = 0.026) were more common in the patients who developed IgE-mediated food allergies. In five of the six patients who developed IgE-mediated food allergies, reaction occurred within the first year after transplantation; the risk of developing a reaction was 2.7 times higher within the first year after transplantation than in subsequent years (95% CI, 1.546-4.914; p = 0.026). No Epstein-Barr virus or cytomegalovirus infections were detected in any of the patients who developed IgE-mediated food allergies after liver transplantation. CONCLUSION: The risk of developing IgE-mediated food allergies is approximately three times higher within the first year after transplantation than in subsequent years

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Report: Osteocyte enhancement function of bisphosphonates in prosthetic replacement.

Aseptic loosening after prosthetic replacement is the primary cause of shortened service life and lowered stability of prosthesis, and increased revision rate after joint replacement. Factors of causing the loosening of joint prosthesis include mechanical factors and biological factors. The mechanical effect of bisphosphonates (BP) is quite obvious, which can enhance osteocyte function, accelerate the generation of new bone and lower bone resorption activity of osteoclast and macrophage. In animal experiment and adjuvant therapy of patients after joint replacement, BP also shows up the functions of reducing osteolysis induced by wear debris, preventing stress shielding and interface fretting and enhancing bone density. This paper elaborated the mechanism of BP adjusting bone metabolism, and analyzed the action principle and the vital function of it in prosthetic replacement. It has proved that BP can effectively reduce the early peri-prosthesis bone absorption after total hip replacement and improve bone mass peri-prosthesis. It is currently the significant choice of preventing bone lose of peri-prosthesis after operation.

Phytochemical evaluation and in vitro antioxidant and photo-protective capacity of Calendula officinalis L. leaves / Avaliação fitoquímica e capacidade antioxidante e fotoprotetora in vitro das folhas de Calendula officinalis L

ABSTRACT The plant Calendula officinalis L. is widely applied due to its medicinal properties, which are mainly dermatological and ornamental. The goal of this study is to assess the phytochemical components in a hydroethanolic extract (HECO) from the leaves of Calendula officinalis L. using UV-VIS spectrophotometry and thin layer chromatography (TLC), as well as to identify and quantify the components related to its antioxidant capacity employing high performance liquid chromatographic (HPLC). The antioxidant capacity evaluation was performed using the DPPH method for superoxide and hydroxyl radicals. The photo-protective capacity was evaluated by UVspectrophotometry in order to determine the in vitro Sun Protection Factor(SPF). The results show the plant’s strong antioxidant activity (DPPH and hydroxyl methods), which we believe to be related to the presence of flavonoids (24.67 mg/g), polyphenols (33.90 mg/g), condensed tannins (27.30 mg/g), and the amount of rutin (37.25 mg/g), and quercetin (6.09 mg/g) found during the study. The HECO presented a good antioxidant capacity, most likely due to the polyphenols, flavonoids, and tannins in its contents. However, the obtained SPF of 1.89 ± 0.05 does not allow the plant to be classified as a stand-alone sunscreen, and more studies are needed in order to test its ability to enhance sunscreens in existing cosmetic formulations.

RESUMO A Calendula officinalis L. é uma planta amplamente utilizada por suas propriedades medicinais, principalmente dermatológica e ornamental. O objetivo deste estudo é avaliar constituintes fitoquímicos do extrato hidroetanólico das folhas de Calêndula officinalis L. (HECO) por espectrofotometria UV-visível e cromatografia em camada delgada (CCD), bem como detectar e quantificar os componentes relacionados com a capacidade antioxidante por Cromatografia Líquida de Alta Eficiência (CLAE). Posteriormente, foi avaliada a capacidade antioxidante pelo método do DPPH, radicais superóxido e hidroxila. Além disso, a capacidade fotoprotetora foi avaliada através de espectrofotometria UV para determinação do Fator de Proteção Solar in vitro (FPS). Os resultados evidenciaram que a planta apresentou uma excelente atividade antioxidante para o método do DPPH e do radical hidroxila, o que pode estar relacionada com a presença de flavonoides (24,67 mg/g), polifenóis (33,90 mg/g) e taninos condensados (27,30 mg/g) e da quantidade de rutina (37,25 mg/g) e quercetina (6,09 mg/g) encontrados neste estudo. O HECO apresentou uma notável capacidade antioxidante, provavelmente devido à presença de polifenóis, flavonoides e taninos. O valor do FPS encontrado (1,89 ± 0,05), não classifica a planta como um protetor solar isolado. No entanto, mais estudos são necessários para testar a capacidade de potencializar filtros solares em formulações cosméticas.

Nonenzymatic continuous glucose monitoring in human whole blood using electrified nanoporous Pt.

This paper describes the first devised method for the nonenzymatic and electrochemical glucose monitoring in 100% human whole blood and serum. The nanoporous Pt electrode allows for the selective amplification of glucose oxidation in the presence of electroactive interfering species without the need for enzymatic reaction. The outer membrane was particularly optimized to allow glucose molecules to be electrochemically detected against the numerous constituents of human blood. The proposed sensor provided reproducible amperometric responses to glucose in human serum and whole blood. Its sensitivity was maintained for at least 7h under constantly electrified conditions, and continued to work properly after 30 days of storage in human whole blood and serum. Unlike the enzyme-based glucose sensors, it was found to be minimally affected by thermal fluctuation, so as to remain successful even after steam sterilization at high temperature (134 °C) and pressure (0.22 Mpa). The unprecedented long-term stability and sterilization compatibility observed herein suggest a promising alternative to conventional enzymatic glucose sensors for many analytical and clinical applications, particularly for continuous glucose monitoring devices designed to potentially lead to a closed-loop artificial pancreas by combining them with an insulin pump.

Electrochemical nanoneedle biosensor based on multiwall carbon nanotube.

We report the fabrication and analytical functions of a biosensor based on a nanoneedle consisting of a multiwall carbon nanotube attached to the end of an etched tungsten tip. The devised electrode is the smallest needle-type biosensor reported to date. The nanoneedles prepared in this work are 30 nm in diameter and 2-3 microm in length. Dopamine and glutamate, which are physiologically important neurotransmitters, were successfully detected using these nanoneedles. Bare nanoneedles detected dopamine in the range from 100 to 1000 microM by differential pulse voltammetry, and enzyme-modified nanoneedles were able to respond to glutamate in the 100-500 microM range by potentiostatic amperometry.

Glucose sensor based on glucose oxidase immobilized by zirconium phosphate.

Amperometric glucose sensors were fabricated using glucose oxidase (GOx) entrapped in zirconium hydrogenphosphate (ZrP), and their performance was evaluated. Reportedly, alpha-ZrP is one of the candidates that are expected to improve the stability of enzymes immobilized on solid surfaces. We intercalated GOxs into ZrP (GOx/ZrP), cast the GOx/ZrP suspension in polyvinylalcohol on a platinum electrode, and dried it in a vacuum oven. The morphological layered structure was investigated by scanning electron microscopy. The enzymatic activities, which were determined by open-circuit potentiometric technique, reached the highest when GOxs were immobilized in ZrP at ca. pH 5. In vitro tests showed good linear responses in the 0-25 mM range and the sensitivity of 0.14 nA mM(-1) at 0.4 V vs. Ag/AgCl. The sensors, as made, were stable for more than 3 days within a limited deterioration.

In vitro and short-term in vivo characteristics of a Kel-F thin film modified glucose sensor.

A new outer layer composition, consisting of polytetrafluoroethylene (PTFE), Kel-F oil, and Nafion, is suggested to minimize the detrimental effect of dissolved oxygen and to extend the linear response range of a glucose oxidase(GOx)-based sensor using nonconducting polymer. The morphology of Kel-F/PTFE/Kel-F/Nafion polymeric laminate was followed during fabrication by SEM. When Kel-F film was formed on the PTFE outer layer, the linear response was extended to 21 mM, at a sensitivity of 2.8 +/- 0.8 nA/mM mm2. We demonstrate that a sensor without Kel-F/PTFE/Kel-F/Nafion outer layer is relatively oxygen dependent, whereas by comparison a sensor with Kel-F/PTFE/Kel-F/Nafion outer layer is oxygen independent. The current of such a glucose sensor implanted in the subcutaneous tissue stabilized within 60 min, and the lag between blood glucose changes and sensor output was within 1 min. The in vivo characteristics of the glucose sensor described show great promise for one-point in vivo calibration.

In vivo calibration of the subcutaneous amperometric glucose sensors using a non-enzyme electrode.

A new two-point calibration method for the subcutaneous amperometric continuous glucose sensor is reported. The proposed method is based on direct measurement of the background current (I(o)) using a non-enzyme electrode. For in vivo test, three electrodes were implanted in rabbits. Two of the three were identical needle-type enzyme electrodes with perfluorinated polymer outer layers (Pt/enzyme layer/Kel-F/PTFE/Kel-F/Nafion) that were placed in subcutaneous tissue and in a vessel (ear artery), respectively. And one non-enzyme electrode with exactly the same membrane composition as those of other two was in the subcutaneous layer to measure the background current. Implantation in the subcutaneous layer generated many crevices on the protecting layers of the electrodes. The signals from enzyme electrodes were effectively corrected by the measured background current from the non-enzyme electrode. In addition, a telemetric monitoring system was developed and evaluated for in vivo continuous glucose monitoring in order to alleviate the problems of motion artifact.

Human obesity: an evolutionary approach to understanding our bulging waistline.

The unique worldwide spread of the human species and the remarkably long post-reproductive survival show that our genome permits excellent adaptation to vastly different environments. Moreover, the main scourges of later age, namely malignant growths and atherosclerosis, appear in humans later than in shorter-living animals. In recent years, excess weight and obesity have become mass phenomena with a pronounced upward trend in all developed countries. However, despite the detrimental effects of being overweight, these populations live longer than ever, which in part may be explained by the availability of better medical treatment. The prevalence and predicted further spread of obesity can be understood in the light of evolution. In all animal species energy metabolism is asymmetric with energy accumulation ('thrifty genotype') being the necessary condition of survival during hard times. For humans, which are no different to other animals in this respect, this genetic programming was necessary for survival because during the course of history, including the recorded history in the more developed Middle East, Europe or China, there was never a long period of uninterrupted food abundance, whereas famines were regular and frequent. Therefore fat accumulation, when food was available, meant survival at times of shortage, while the possible detrimental effects of overindulgence in food and being overweight expressed in unrealistically old age were irrelevant. It is the central, mostly intra-abdominal fat (in both humans and animals) that is more medically important than the subcutaneous truncal fat, and the accumulation of both types of fat is conditioned by high food consumption; therefore it is a historic novelty for human populations. In contrast, lower-body fat in human females is unique in the animal kingdom: it is much less metabolically active, it is of much lower pathologic significance than central fat, and it is programmed to be mobilized mostly during pregnancy and lactation. In view of all this, norms of desired weight should be based on hard mortality and morbidity statistics and not on theoretical, esthetic or fashion considerations. By this criterion, the upper limit of desirable weight is likely to be body mass index (BMI) 27 or 28, but specified for different populations (sex, race, ethnic origin); moreover, with aging, the detrimental effects of obesity diminish and finally disappear. Risks of other pathologies related to obesity (e.g. diabetes, hypertension and coronary disease) are also population-specific. However, total fatness, measured by BMI, is insufficiently sensitive as a risk factor, and fat distribution (upper-body versus low-body type, as reflected by waist circumference and waist:hip ratio) plays at least as prominent a role. Therefore the detailed norms, not yet available, should take into account both general obesity and fat distribution and be specific for different populations. Since long-term weight loss in adults is rarely achievable, public health measures should be aggressively directed at the prevention of obesity from childhood.

Homogeneity of the age at diagnosis in sibs with Type 2 diabetes: implications for sib-pair analysis.

Homogeneity of the age at diagnosis of Type 2 diabetes was studied in 1,228 sibs in 300 unrelated families: 100 consecutive single-affected and 200 consecutive multiple-affected ones. There were 635 diabetic sibs. The mean and median age at diagnosis in all affected individuals was 50 years (range, 19-75 years). The mean age at diagnosis in the multiply affected families was 49 years (median 50); the between-sibs range of age at diagnosis within multiple-affected families was (mean and median) 17 years (range, 0-55), with 42% of these diagnosed within a 5-year age span, 66% within 10 years, and 90% within 13 years. When one parent had diabetes, it was more often the mother (79% P = 0.0023). In order to examine this apparent tendency toward homogeneity of age at diagnosis within families, with full regard for and parsimonious to right-censored data, we employed a Cox proportional-hazards survival analysis, with family as the explanatory variable. Deviance residuals resulting from that model were analyzed in a variance components, random effects model ANOVA which indicated a significant (P << 0.001) effect of family on age of diagnosis, with an intraclass correlation of 0.29. In many families the clustering of age at diagnosis appeared very tight, with single outliers, and in 20 families with the longest history, diabetes was diagnosed in 68 sibs within the span of 8 +/- 7 years, whereas 38 unaffected sibs remain free of diabetes 25 +/- 8 years later. The wide differences of the age at diagnosis between families and its intrafamilial homogeneity should be considered in planning genetic analysis of Type 2 diabetes.

Mitogenic factors accelerate later-age diseases: insulin as a paradigm.

Some genes are expressed differently in earlier and later generations of most cell lines. Many diseases become clinically expressed only later in life, and show clustering of the age at onset in the affected siblings, which may be related to the changing expression with age of the genes involved. Because insulin and its receptor are extremely ancient and well preserved structures with almost universal mitogenic effects, insulin may serve a paradigm of this process. It is suggested that by stimulating cell proliferation, hyperinsulinemia speeds up the appearance of later generations of cells with different expression of the genes. Insulin resistance, accompanying any hyperinsulinemia and considered to be a pathogenetic factor of some common later-age diseases, involves only some biochemical, but not mitogenic effects of the hormone. In humans, high levels of insulin in blood are encountered both physiologically after meals and in many pathological conditions: insulin therapy inevitably causes peripheral hyperinsulinemia; in type 2 diabetes hyperinsulinemia precedes hyperglycemia by many years; hyperinsulinemia is an independent risk factor of atherosclerosis, of type 2 diabetes itself, of some forms of dementia and other diseases; obesity is an obligatory hyperinsulinemic condition. The opposite of hyperalimentation, i.e. calorie restriction (at least, in rodents) may exert its life-prolonging effects through decreasing insulinemia and therefore the rate of cell proliferation. Insulin is only one example, and different mitogens regulate proliferation of different cells. It is likely that growth factors in general accelerating the replication of cells, play a role in speeding up the appearance of later-age diseases involving these cells.

In most poorly controlled glyburide-treated type 2 diabetic patients drug withdrawal causes further increase in glycemia not accompanied by changes in insulin secretion.

To find out whether the secondary failure of glyburide in type 2 diabetes is complete or partial, we studied 38 patients, age (M +/- SD) 69 +/- 9 years, suffering from diabetes from 13.5 +/- 8.4 years and treated with glyburide for 5-13 years, with poor glycemic control (glycohemoglobin 10.6 +/- 2.6%). Serum glucose, insulin and C-peptide were assayed before and 1 h and 2 h after a simulated meal load (355 Cal), after which the drug was replaced with placebo for 4 weeks, and the test repeated. After glyburide withdrawal, fasting glycemia increased from 10.3 +/- 3.3 to 15.1 +/- 4.4 mmol/L (p < 0.001), but in 3/38 patients, it even decreased and in five others the changes were less than +/- 2 mmol/L. These changes negatively but only weakly correlated with initial glycemia: r = 0.4123, p < 0.010. The mean post-meal glycemia at 1 h and 2 h increased respectively by 3.3 and 5.9 mmol/L (both p < 0.001). Neither the levels of glycemia nor its changes after the glyburide withdrawal correlated with the levels of, or changes in, insulin or C-peptide. We conclude that in most but not all type-2 diabetic patients, poorly controlled with glyburide, the drug still retains some limited therapeutic effectiveness, and therefore its withdrawal causes further deterioration of control with the almost equal increases in fasting and post-meal levels of glycemia. These changes are not accompanied by decrease in insulin secretion.