The Yearly Periodicity of Operative Upper Extremity Trauma: A Retrospective Study of "Trauma Season".

BACKGROUND: Upper extremity (UE) trauma requiring operative care increases during the summer and fall months, which the authors colloquially refer to as "trauma season." METHODS: CPT databases were queried for codes related to acute UE trauma at a single level-1 trauma center. Monthly CPT code volume was tabulated for 120 consecutive months and average monthly volume was calculated. Raw data were plotted as a time series and transformed as a ratio to the moving average. Autocorrelation was applied to the transformed data set to detect yearly periodicity. Multivariable modeling quantified the proportion of volume variability attributable to yearly periodicity. Subanalysis assessed presence and strength of periodicity in four age groups. RESULTS: A total of 11,084 CPT codes were included. Monthly trauma-related CPT volume was highest in July through October and lowest in December through February. Time-series analysis revealed yearly oscillation in addition to a growth trend. Autocorrelation revealed statistically significant positive and negative peaks at a lag of 12 and 6 months, respectively, confirming yearly periodicity. Multivariable modeling revealed R 2 attributable to periodicity of 0.53 ( P < 0.01). Periodicity was strongest in younger populations and weaker in older populations. R 2 was 0.44 for ages 0 to 17, 0.35 for ages 18 to 44, 0.26 for ages 45 to 64, and 0.11 for ages 65 and older. CONCLUSIONS: Operative UE trauma volumes peak in the summer and early fall and reach a winter nadir. Periodicity accounts for 53% of trauma volume variability. The authors' findings have implications for allocation of operative block time and personnel and expectation management over the course of the year.

IgA nephropathy diagnosed as a result of acute exacerbation due to G-CSF administration.

Granulocyte colony-stimulating factor (G-CSF) is commonly used to stimulate bone marrow production. G-CSF is usually safe but sometimes causes serious adverse effects and, in rare cases, exacerbates glomerulonephritis. We report a case of immunoglobulin A (IgA) nephropathy that was aggravated by G-CSF. A 56-year-old Japanese man with no relevant medical history was admitted to our hospital as a donor of peripheral blood stem cells (PBSCs) for transplantation. To mobilize PBSCs, he received subcutaneous G-CSF (lenograstim), 500 µg for 4 days. Three days after the first dose of lenograstim, gross hematuria appeared, and after administration on the fourth day, renal dysfunction and nephrotic-range proteinuria were observed. Renal biopsy and light microscopic study revealed mild mesangial proliferation with expansion in association with the presence of cellular segmental crescents. Immunofluorescence study revealed diffuse, granular staining in the mesangium for IgA, complement component 3 (C3), and lambda light chains. We diagnosed highly active IgA nephropathy and initiated treatment with prednisolone and azathioprine. Three months later, renal function returned to normal. Screening for hidden chronic glomerulonephritis should be performed when G-CSF is administered, as in PBSC donors. Immunosuppressant therapy, such as prednisolone or azathioprine, is considered for exacerbations of highly active glomerulonephritis.

A case of juvenile-onset fibrillary glomerulonephritis diagnosed by mass spectrometry and immunohistochemistry of DNAJB9.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. FGN is characterized by the deposition of randomly arranged, nonbranching microfibrils in the mesangium and glomerular basement membrane. The discovery of DNAJ homolog subfamily B member 9 (DNAJB9) in 2017 was a breakthrough, and DNAJB9 has been proven to be extremely useful for the definitive diagnosis of FGN. While FGN often occurs in middle-aged individuals, this case was diagnosed at a relatively young age of 17. We performed renal biopsy, and light microscopic study revealed mesangial proliferation with expansion and subepithelial deposits. Electron microscopic study showed glomerular deposition of randomly oriented nonbranching fibrils with a mean of 20 nm. However, direct first scarlet stain for amyloidosis was weakly positive. Therefore, we confirmed the diagnosis of FGN and eliminated the presence of amyloidosis with mass spectrometry. This is the first case in Japan in which the complication of amyloidosis was ruled out with mass spectrometry and FGN was diagnosed using immunostaining and mass spectrometry of DNAJB9. We began treatment with cyclosporine A. One and a half years after the start of the treatment, kidney function continues to be normal.

Square-root Palatoplasty: Comparing a Novel Modified-Furlow Double-opposing Z-palatoplasty Technique to Traditional Straight-line Repair.

The purpose of this study was to introduce a modification of the Furlow double-opposing Z-plasty (DOZ)-the square-root palatoplasty (SRP)-and critically evaluate outcomes compared to children who underwent straight-line repair (SLR). METHODS: A retrospective review was performed of all nonsyndromic children undergoing primary cleft palate closure either by SRP or SLR at our institution between 2009 and 2017. Outcomes of interest included rates/location of oronasal fistula, secondary surgery, speech delay/deficits, resonance, nasal air emission (NAE), articulation errors, and velopharyngeal function. Logistic regression was used to assess for the effect of surgery type on outcomes while controlling for Veau cleft type, age, and gender. RESULTS: Seventy-eight patients were included; 46 (59%) underwent SRP, and 32 (41%) underwent SLR. The mean follow-up was 4.07 years. When compared to SLR, children who underwent SRP were less likely to have oronasal fistula [odds ratio (OR) 4.8, P = 0.0159], speech delay/deficits (OR 7.7, P < 0.001), NAE (OR 9.7, P < 0.001), articulation errors (OR 10.2, P < 0.001), or need for secondary speech surgery (OR 13.2, P < 0.0002). Patients who underwent SRP were also more likely to have normal resonance (78.26% versus 43.75%, respectively; P = 0.0043) and good VP function (84.78% versus 56.25%, respectively; P = 0.0094). CONCLUSIONS: This study describes and evaluates outcomes following a modified-Furlow DOZ technique-the SRP. After adjusting for Veau classification, age, and gender in nonsyndromic children, SRP is associated with significantly less speech delay/deficits, NAE, articulation errors, and need for secondary speech surgery when compared to children who underwent SLR.

No Longer a Pain in the Neck: Use of Operating Microscope for Palatoplasty.

For craniofacial surgeons, cleft palate repair is an intricate and difficult operation positionally. Historically, use of loupe magnification and a headlight can cause significant strain to the surgeon's neck and, at times, subpar optics for both the operator and the assistant. The use of an operating microscope was first advocated by Sommerlad in 2003. By using the operating microscope for cleft palate closure, there are improved ergonomics for the surgeon and assistant by allowing for straight in-line back and neck posture with excellent visualization of the surgical field for the entire surgical team. The available zoom and focus improve the ability to isolate and repair the levator veli palatini muscle. Proper posture with a neutral cervical spine will help prolong a surgeon's career and ability to care for their patients.

Unique pathological changes in the pancreas of fulminant type 1 diabetes.

Distinct features of the pancreas of fulminant type 1 diabetes (FT1DM) include (1) enterovirus infection of the islets and exocrine acinar tissue. (2) Activated innate immune responses: MDA5 and RIG-I expression and TLR4 and TLR9 expression in the islets of FT1DM. (3) Combined activation of the STAT/JNK and NFkB pathways, resulting in Type I interferon (IFN) and proinflammatory cytokine (i.e., IFNγ) expression in islet beta cells and MHC class I hyper-expression. (4) Activation of dendritic cells followed by effector cell infiltration of CD8+ T cells and CD68+ macrophages, resulting in apoptosis and neurosis of islet cells and exocrine acinar cells. (5) Many chemo-attractants (i.e., CXCL10) and chemotactic activators (i.e., l-plastin) were induced by a viral infection. (6) Mutual stimulating effect of cytokines expressed in beta cells in autocrine and paracrine mechanisms may enhance beta-cell destruction through the STA1-caspase pathway. (7) Proteomics analysis using laser capture microdissection followed by mass spectrometry found 38 molecules in inflamed islets of FT1DM, which were not highlighted before. Our pathologically verified model of beta-cell destruction in FT1DM will contribute to anti-virus therapy of type 1 diabetes in the near future.

Use of Postmastectomy Radiation in Patients Treated for Invasive Breast Cancer with Mastectomy and Immediate Reconstruction.

Immediate reconstruction after mastectomy helps women manage the psychological impact of deforming surgery. Postmastectomy radiation therapy (PMRT) can negatively impact the aesthetic result after breast reconstruction. We performed this study to achieve a better understanding of how PMRT is used after reconstruction in our institution. We conducted a retrospective review of a prospectively maintained database of all women who underwent mastectomy for invasive breast cancer followed by immediate reconstruction from 2006 to 2017. Patients were divided into two groups depending on whether PMRT was included in their treatment, and we compared clinical and pathologic characteristics to determine which factors were likely to lead to PMRT. A total of 315 women treated with mastectomy and immediate reconstruction were identified. A total of 96 were treated with PMRT; 219 had mastectomy and immediate reconstruction without radiotherapy. Tumor characteristics, tumor stage, demographics, and comorbidities did not predict the use of PMRT. Neoadjuvant chemotherapy (NAC) was the most powerful predictor for using PMRT. In 47 of 81 (58%) patients treated with NAC, PMRT was used. Whereas 49 of 234 (21%) patients who did not receive NAC were treated with PMRT (P = 0.0001, risk ratio 2.77, 95 per cent confidence interval 2.03-3.77). In our institution, patients treated with NAC followed by mastectomy and immediate reconstruction are significantly more likely to receive PMRT. The increased use of PMRT after NAC should be factored into the preoperative discussion with patients choosing mastectomy and immediate reconstruction.

Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy.

AIMS: We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy. METHODS: We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search. RESULTS: Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile-third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4-9.4) µg/day, and 0.46 (0.20-0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive. CONCLUSIONS: Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.

Genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in CSAD/lnc-ITGB7-1 on Chromosome 12q13.13 Associated With Susceptibility to Fulminant Type 1 Diabetes.

The first genome-wide association study of fulminant type 1 diabetes was performed in Japanese individuals. As previously reported using a candidate gene approach, a strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region (P = 1.56 × 10-23, odds ratio [OR] 3.18). In addition, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level (P = 7.58 × 10-9, OR 1.96). Fine mapping of the region revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value (P = 4.60 × 10-9, OR 1.97 [95% CI 1.57-2.48]). The risk allele of rs3782151 is a cis expression quantitative trait locus for ITGB7 that significantly increases the expression of this gene. CSAD/lnc-ITGB7-1 was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.

Diffusion-weighted magnetic resonance imaging in the pancreas of fulminant type 1 diabetes.

Abrupt disease onset and severe metabolic disorders are main characteristics of fulminant type 1 diabetes. Diffusion-weighted magnetic resonance imaging (DWI) is an imaging technique that reflects restricted diffusion in organs and can detect mononuclear cell infiltration into the pancreas at the onset of the disease. Fourteen patients with fulminant type 1 diabetes who underwent abdominal magnetic resonance imaging were recruited for the measurement of apparent diffusion coefficient (ADC) values of the pancreas that were compared with those of 21 non-diabetic controls. The ADC values of all parts of the pancreas were significantly lower in fulminant type 1 diabetes than in controls (head, 1.424 ± 0.382 × 10-3 vs. 1.675 ± 0.227 × 10-3 mm2/s; body, 1.399 ± 0.317 × 10-3 vs. 1.667 ± 0.170 × 10-3 mm2/s; tail, 1.336 ± 0.247 × 10-3 vs. 1.561 ± 0.191 × 10-3 mm2/s; mean, 1.386 ± 0.309 × 10-3 vs. 1.634 ± 0.175 × 10-3 mm2/s) (p < 0.01). The best cut-off value indicated that the sensitivity was 86% and the specificity was 71% when using DWI, which was also efficient in two atypical patients with fulminant type 1 diabetes without elevated levels of exocrine pancreatic enzymes or with high HbA1c levels due to the preexistence of type 2 diabetes. The ADC values were significantly correlated to plasma glucose levels and arterial pH, and tended to increase with the lapse of time. DWI may be an additional tool for making an efficient diagnosis of fulminant type 1 diabetes.

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S).

INTRODUCTION: We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the ß-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA). METHODS: In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used. RESULTS: On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased. CONCLUSION: The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the ß-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors. CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry UMIN000003693.

Association Between Compliance with Triage Directions from an Organized State Trauma System and Trauma Outcomes.

BACKGROUND: The Louisiana Emergency Response Network (LERN), a statewide trauma system, has a single communication center with real-time data on hospital capacity across the state. With these data, scene information, and a standardized triage protocol, prehospital providers are directed to the most appropriate hospital. The purpose of our study was to compare outcomes between those patients who complied with the LERN communication center direction and those who did not. STUDY DESIGN: Trauma patients directed by LERN from the field in 2014 were included. Patients who followed the LERN communication center direction were considered the compliant group. Patients brought to a hospital inconsistent with the LERN direction were considered the noncompliant group. Chi-square analysis was used to compare differences between groups and a p value of <0.05 was considered statistically significant. RESULTS: During the study period, LERN directed 14,071 patients to a destination hospital. Prehospital providers were compliant with the LERN direction in 13,037 (92.7%) patients and noncompliant in 1,034 (7.3%) patients. There were fewer patients in the compliant group (570 of 13,037 [4.3%]) requiring transfer to a second hospital than in the noncompliant group (312 of 1,034 [30.2%]) (p < 0.01). The mortality rate was lower in the compliant group (81 of 13,037 [0.6%]) than in the noncompliant group (21 of 1,034 [2.03%]) (p < 0.01). CONCLUSIONS: Following direction from a central communication center with real-time hospital capacity data yielded a 6-fold decrease in secondary transfer and a 3-fold decrease in mortality. These data emphasize the value of an organized statewide trauma network that routes patients to the appropriate facilities.

Insufficient Humidification of Respiratory Gases in Patients Who Are Undergoing Therapeutic Hypothermia at a Paediatric and Adult Intensive Care Unit.

For cooled newborn infants, humidifier settings for normothermic condition provide excessive gas humidity because absolute humidity at saturation is temperature-dependent. To assess humidification of respiratory gases in patients who underwent moderate therapeutic hypothermia at a paediatric/adult intensive care unit, 6 patients were studied over 9 times. Three humidifier settings, 37-default (chamber-outlet, 37°C; Y-piece, 40°C), 33.5-theoretical (chamber-outlet, 33.5°C; Y-piece, 36.5°C), and 33.5-adjusted (optimised setting to achieve saturated vapour at 33.5°C using feedback from a thermohygrometer), were tested. Y-piece gas temperature/humidity and the incidence of high (>40.6 mg/L) and low (<32.9 mg/L) humidity relative to the target level (36.6 mg/L) were assessed. Y-piece gas humidity was 32.0 (26.8-37.3), 22.7 (16.9-28.6), and 36.9 (35.5-38.3) mg/L {mean (95% confidence interval)} for 37-default setting, 33.5-theoretical setting, and 33.5-adjusted setting, respectively. High humidity was observed in 1 patient with 37-default setting, whereas low humidity was seen in 5 patients with 37-default setting and 8 patients with 33.5-theoretical setting. With 33.5-adjusted setting, inadequate Y-piece humidity was not observed. Potential risks of the default humidifier setting for insufficient respiratory gas humidification were highlighted in patients cooled at a paediatric/adult intensive care unit. Y-piece gas conditions can be controlled to the theoretically optimal level by adjusting the setting guided by Y-piece gas temperature/humidity.

Clinical features of cases of seroconversion of anti-glutamic acid decarboxylase antibody during the clinical course of type 2 diabetes: a nationwide survey in Japan.

The pathogenesis of type 1 diabetes is different from that of type 2 diabetes, and anti-glutamic acid decarboxylase antibody (GADA) helps to diagnose autoimmune type 1 diabetes. Some studies reported that GADA seroconversion occurs during the clinical course of type 2 diabetes, leading to development of "type 1 on type 2 diabetes". To clarify the clinical characteristics and triggers of GADA seroconversion, we performed a nationwide questionnaire survey for clinical cases identified by literature search, and obtained information on 38 cases (24 with insulin therapy and 14 without it). The diabetes duration up to determination of GADA seroconversion was significantly longer in the group with insulin therapy than that without it. This finding was particularly noted in insulin-treated non-obese patients with lower serum C-peptide levels. In these patients, insulin therapy could have masked sudden increases in plasma glucose and HbA1c levels, possibly leading to delayed determination of GADA seroconversion. In non-obese patients without insulin therapy, an abrupt rise in the plasma glucose and HbA1c levels was observed at immediately before the determination, a finding which may help to predict GADA seroconversion. From the results of the present survey, we could not determine apparent triggers of GADA seroconversion. Thus, physicians may need to consider the possibility of concurrent type 1 diabetes during the therapeutic course of type 2 diabetes; GADA measurement should be considered when non-obese type 2 diabetic patients not receiving insulin therapy experience unexpected abrupt hyperglycemia and when those receiving insulin therapy show low serum C-peptide levels.

The Impact of Chemotherapy on Complications Associated with Mastectomy and Immediate Autologous Tissue Reconstruction.

We performed this study to evaluate the impact of chemotherapy on the outcomes associated with immediate autologous tissue reconstruction (IATR) in the treatment of breast cancer. Patients were divided into two groups: Group 1 received chemotherapy before surgery and Group 2 did not receive chemotherapy. Records were reviewed to identify demographics, comorbidities, histology, and wound healing complications. Groups were compared using Kruskal-Wallis and Fisher exact tests as appropriate. A total of 128 patients were identified: 29 received chemotherapy before surgery (Group 1) and 99 did not receive chemotherapy (Group 2). Group 1 patients were more likely to have diabetes 27 per cent versus 6 per cent (P = 0.005) despite both groups having a mean body mass index of 30. Group 2 patients had less advanced stage disease as expected because they did not receive chemotherapy; 37 per cent of Group 2 patients had stage 0 breast cancer (P < 0.001). The incidence of wound complications was 17 per cent in Group 1 and 12 per cent in Group 2 (P = NS). Preoperative chemotherapy for breast cancer followed by IATR was associated with no increased risk of healing complications. IATR can be offered to patients who require preoperative chemotherapy, and their healing will not be impaired as a result of the chemotherapy.

Use of Normothermic Default Humidifier Settings Causes Excessive Humidification of Respiratory Gases During Therapeutic Hypothermia.

Adult patients frequently suffer from serious respiratory complications during therapeutic hypothermia. During therapeutic hypothermia, respiratory gases are humidified close to saturated vapor at 37°C (44 mg/L) despite that saturated vapor reduces considerably depending on temperature reduction. Condensation may cause serious adverse events, such as bronchial edema, mucosal dysfunction, and ventilator-associated pneumonia during cooling. To determine clinical variables associated with inadequate humidification of respiratory gases during cooling, humidity of inspiratory gases was measured in 42 cumulative newborn infants who underwent therapeutic hypothermia. Three humidifier settings of 37-default (chamber outlet, 37°C; distal circuit, 40°C), 33.5-theoretical (chamber outlet, 33.5°C; distal circuit, 36.5°C), and 33.5-adjusted (optimized setting to achieve 36.6 mg/L using feedback from a hygrometer) were tested to identify independent variables of excessively high humidity >40.7 mg/L and low humidity <32.9 mg/L. The mean (SD) humidity at the Y-piece was 39.2 (5.2), 33.3 (4.1), and 36.7 (1.2) mg/L for 37-default, 33.5-theoretical, and 33.5-adjusted, respectively. The incidence of excessive high humidity was 10.3% (37-default, 31.0%; 33.5-theoretical, 0.0%; 33.5-adjusted, 0.0%), which was positively associated with the use of a counter-flow humidifier (p < 0.001), 37-default (compared with 33.5-theoretical and 33.5-adjusted, both p < 0.001) and higher fraction of inspired oxygen (p = 0.003). The incidence of excessively low humidity was 17.5% (37-default, 7.1%; 33.5-theoretical, 45.2%; 33.5-adjusted, 0.0%), which was positively associated with the use of a pass-over humidifier and 33.5-theoretical (both p < 0.001). All patients who used a counter-flow humidifier achieved the target gas humidity at the Y-piece (36.6 ± 0.5 mg/L) required for 33.5-adjusted with 33.5-theoretical. During cooling, 37-default is associated with excessively high humidity, whereas 33.5-theoretical leads to excessively low humidity. Future studies are needed to assess whether a new regimen with optimized Y-piece temperature and humidity control reduces serious respiratory adverse events during cooling.

Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan.

AIMS: Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan. METHODS: We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated. RESULTS: Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml. CONCLUSIONS: Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM.

Rapid Normalization of High Glutamic Acid Decarboxylase Autoantibody Titers and Preserved Endogenous Insulin Secretion in a Patient with Diabetes Mellitus: A Case Report and Literature Review.

A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.

Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM).

AIMS: Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear. MATERIALS AND METHODS: Patients were subdivided as follows: patients with high GADA titers [≥10 U/ml (≥180 WHO U/ml): high GADA] (group 1, n = 37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n = 33); those without GADA and with islet cell antibodies (ICA) (group 3, n = 8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n = 6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107 months from entry. RESULTS: The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45 years, duration of diabetes <24 months, body mass index (BMI) <22.0 kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state. CONCLUSIONS: SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.

Risk factors for sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus.

AIMS: The onset of fulminant type 1 diabetes mellitus is sometimes accompanied by sudden death or cardiac arrest. The aim of this study was to determine the risk factors for the development of these conditions at the onset of fulminant type 1 diabetes mellitus. METHODS: We conducted a search of the literature on fulminant type 1 diabetes and sudden death or cardiac arrest published up to 2012 in PubMed and Ichushi (a Japanese article database), and a questionnaire survey was administered to the authors of the articles and to diabetes specialists affiliated to the Japan Diabetes Society. We analyzed the clinical data at disease onset of 17 patients with fulminant type 1 diabetes mellitus who experienced sudden death or cardiac arrest, and those of 257 patients who did not develop these conditions. RESULTS: Patients with sudden death or cardiac arrest were younger, had a higher rate of impaired consciousness, more severe acidosis, hyperglycemia, hyponatremia, hyperkalemia, and hypochloremia, a higher serum blood urea nitrogen level, a higher serum creatinine level, and a higher plasma osmolality level than the other patients. In multiple logistic regression analyses, plasma glucose level was positively associated with sudden death or cardiac arrest. Receiver operating characteristic curve analyses showed that patients with a plasma glucose level over 1000 mg/dl (55.5 mmol/l) were at a high risk of cardiac arrest. CONCLUSIONS: Severe metabolic derangement, especially a high plasma glucose level, is associated with sudden death or cardiac arrest at the onset of fulminant type 1 diabetes mellitus.