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Objective The primary objective of this review is to analyze and synthesize the best available evidence on the experiences and perceptions of psychological stress reported by pancreatic cancer patients at any time point from pre-diagnosis, diagnosis, treatment, post-treatment and/or follow-up care. Introduction A cancer diagnosis is known to be life-threatening, altering and limiting, and negatively affects an individual's activities of daily living. Despite developments in treatment options for pancreatic cancer patients, it represents the highest mortality and morbidity among cancers. Stress is a subjective phenomenon that negatively impacts an individual's psychological and emotional well-being, and interferes with the ability to cope with cancer symptoms and treatments. Identifying a patient's experience of stress could facilitate educational, spiritual and social resources to address his or her emotional and psychological needs. Inclusion criteria Qualitative studies that include individuals with pancreatic cancers, regardless of age, sex or ethnicity, will be considered for inclusion in this review. Methods The databases to be searched include PubMed, CINAHL, Cochrane, Web of Science, Embase, Scopus, BioMed Central and PsycINFO. The search for gray literature will include Biosis, OpenGrey, Open Access Theses and Dissertations, and WorldCat. This systematic review will consider all published and unpublished studies with no date limitations. Selected studies will be assessed for methodological quality by two independent reviewers. Coding will be assigned to synthesize any differences in the experiences and perceptions of psychological stress at four time points. Where textual pooling is not possible, conclusions will be presented in narrative form.

Retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP) have no treatment. Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. We investigated a novel approach in which human retinal progenitor cells (RPCs) derived from primitive mesenchymal stem cells (pMSCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Intravitreally transplanted cells improved retinal function and significantly increased retinal thickness. Transplanted cells homed, survived, and integrated to various retinal layers. They also induced anti-inflammatory and neuroprotective responses and upregulated neurogenesis genes. We found that RPCs were more efficacious than pMSCs in improving the retinal structure and function. RNA analyses suggest that RPCs promote neuroprotection and neuronal differentiation by activating JAK/STAT and MAPK, and inhibiting BMP signaling pathways. These promising results provide the basis for clinical studies to treat RDD using RPCs derived from pMSCs.

Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)

Objective Bicuspid aortic valve (BAV) is associated with high incidence of ascending aortic aneurysm. In BAV sporadic form, changes in outflow's hemodynamic secondary to the valvular morphotype are said to play a prominent role in the aortic dilatation. We aimed at comparing the different ascending aorta segment diameters according to the morphotype and the function of the BAV. Methods We evaluated 174 patients with sporadic BAV by transthoracic echocardiography. The valvular function was defined as either Aortic Insufficiency (AI) if Grade ≥ 2 and aortic Stenosis (AS) if mean gradient > 20 mmHg. Aortic diameters were measured at the Valsalva sinus, tubular ascending aorta and at the aortic arch. Kruskal-Wallis, Mann–Whitney and Spearman tests were used for comparisons. Results Among the non-operated patients, Sievers’ morphotype was type 1LR for 63%, type 1NR for 18%, and other types counted for 19%. The Valsalva sinus diameter did not differ according to the Sievers’ type (P = 0.78). The type 1LR type compared to the type1NR appeared to have a wider tubular aorta, but not significantly (42.3 ± 8.5 vs. 36.4 ± 7.3 mm; P = 0.06). Aortic valve function was distributed as follows: AI: 39%, AS: 20%, Both: 9%, Normal: 32%. Comparison of the different valve dysfunctions revealed a difference at the Valsalva (P Conclusion Our results showed the tremendous role of AI in the aortic dilation of all segments except the arch. However no influence of BAV morphotype was noticed on aortic diameters. Our results give rise to the relatively limited influence of the valvular morphology in the development of aortic dilation.

Acute erythroleukemia is a relatively rare disorder of a multilineal nature. Patients with this type of leukemia traditionally have been treated with a standard myeloid protocol, with a wide variation in prognosis between M6a, which has a similar prognosis to acute myelogenous leukemias, and M6b, with an extremely poor outcome despite aggressive therapy. Forty-eight archival cases of acute erythroleukemia, subtypes M6a (the traditional FAB-M6), M6b (pure erythroleukemia), and M6c (>30% myeloblasts and >30% pronormoblasts by FAB exclusion criteria), were evaluated for multidrug resistance gene (MDR-1) status. Findings were correlated with clinical course and karyotypes. Immunohistochemical stain for the protein product of MDR-1, P-glycoprotein, was variably positive in 11 of 23 patients with M6a, as well as in all of the patients with M6b (strongly positive) and M6c (weakly positive). P-glycoprotein expression positively correlated with unfavorable cytogenetic aberrations, poor response to chemotherapeutic agents, and short survival. Most significant was that P-glycoprotein expression demonstrated a negative additive effect on response to treatment and prognosis with unfavorable cytogenetic anomalies. P-glycoprotein expression and multiple cytogenetic anomalies most probably contribute to the resistance to chemotherapy and poor survival characteristic of the patients with M6b (mean survival, 3.15 +/- 4.2 mo) and M6c (mean survival, 10.5 +/- 12.7 mo). Because patients with M6b and M6c have increased numbers of pronormoblasts in their bone marrow and past chemotherapeutic attempts have failed, chemotherapy directed at these cells is appropriate. Additional therapy directed toward the MDR-1 gene and its protein product seems indicated from our findings.

Acute erythroleukemia is an aggressive leukemia derived from a multipotential stem cell. Three subtypes have been described: (1) M6a with greater than or equal to 30% blasts of the nonerythrocytic component, (2) M6b with greater than or equal to 30% pronormoblasts of the erythrocytic elements, and (3) M6c with greater than or equal to 30% blasts and greater than or equal to 30% pronormoblasts by the aforementioned exclusion criteria. The poor prognosis associated with this disorder positively correlates with a high pronormoblast:myeloblast ratio; unfavorable cytogenetic aberrations; a high proliferative index; and the presence of P-glycoprotein expression (multidrug resistance phenotype). Chemotherapeutic regimens directed toward these specific parameters should be devised in order to improve the characteristically poor outcome of this patient population.

Acute erythroleukemia (FAB M6) is a rare heterogeneous disease with an increase in red cell precursors and myeloblasts. Three subsets have been described: M6A (myeloblast-rich erythroleukemia); M6B (proerythroblast-rich erythroleukemia); and M6C (myeloblast- and proerythroblast-rich mixed variant). This study was undertaken to define and compare the clinical courses and survival outcomes among M6A, M6B, and M6C variants of erythroleukemia. Sixty-nine cases of M6 leukemia were categorized as consisting of ≥50% erythroid of all nucleated cells and M6A with ≥30% myeloblasts/nonerythroid component; M6B with ≥30% proerythroblasts/erythroid component; and M6C with ≥30% myeloblasts and ≥30% proerythroblasts. The demographics, cell type distribution, and survival (mean ± sd) of these groups were compared. There were 32 M6A, 26 M6B, and 11 M6C patients. No significant difference was seen among the groups in age, sex, or treatment. Compared to M6A, both the M6B (P< 0.0001) and M6C (P< 0.0001) variants showed a statistically significant increase in the percentage of bone marrow erythroid cells, proerythroblasts, and the proerythroblasts/erythroid ratios. Comparing the groups for survival, M6B (3 ± 3.6 months) versus M6A (25 ± 28 months), P< 0.002, and M6C (10 ± 13 months) versus M6A, P< 0.01 had a poorer prognosis. Calculating the proerythroblasts as a component of total bone marrow erythroids provides a complimentary method for delineating the pure red cell erythroleukemia (M6B) and mixed variant (M6C), similar to that for the myeloid/erythroid (M6A) leukemia. Now that it is possible to delineate erythroleukemia subtypes, innovative treatments are indicated to target the malignant erythroid population, which is resistant to myeloid-based therapies. Am. J. Hematol. 65:5–13, 2000. © 2000 Wiley-Liss, Inc.

BACKGROUND: Acne vulgaris is a complex, chronic, and common skin disorder of pilosebaceous units. The major pathogenic factors involved are ductal hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. AIM: The aim of the study was to investigate the therapeutic effects of resveratrol, a natural phytoalexin produced by some spermatophytes, such as grapes and other plants, on acneic skin. METHODS: Resveratrol was incorporated in a carboxymethylcellulose-based gel. The chemical stability of resveratrol after storage at 4°C for 30 days was investigated by high-performance liquid chromatography (HPLC). The resveratrol-containing hydrogel was administered to 20 patients affected by acne vulgaris enrolled in this single-blind study. The resveratrol-containing formulation was applied daily as a solo treatment on the right side of the face for 60 days, while the hydrogel vehicle was applied to the left side of the face as a control. To objectively evaluate the results, a digital photographic database was used to collect images. The number and type of lesions were recorded for each patient, to compare the Global Acne Grading System (GAGS) score before treatment with that obtained at the end of the study. Moreover, with the innovative technique of follicular biopsy, areas of acneic skin were prepared for histopathology. The average area occupied by microcomedones at baseline was compared with that at the end of treatment. RESULTS: HPLC analysis demonstrated that resveratrol, upon incorporation into the gel, did not convert to its cis-isomer when stored at 4°C for 30 days. All patients were satisfied with the active treatment and none experienced adverse effects. Clinical evaluation showed a 53.75% mean reduction in the GAGS score on the resveratrol-treated sides of the face compared with 6.10% on the vehicle-treated sides of the face. These data were supported by histologic analysis, which showed a 66.7% mean reduction in the average area of microcomedones on the resveratrol-treated sides of the face. The comparison with the vehicle-treated side of the face (9.7% reduction) showed a clinically relevant and statistically significant decrease of lesions in areas treated with resveratrol-containing hydrogel. CONCLUSION: This pilot study showed positive results for resveratrol gel in acne, and should be considered a valid starting point for further testing of the effectiveness of this molecule in different concentrations and formulations and in a larger group of patients.

The diagnosis of granular acute lymphoblastic leukemia (ALL) can be problematic as the cytoplasmic granules found in many blast cells may mimic those seen in acute myelogenous leukemia (AML). This rare variant of B-cell ALL is more commonly diagnosed in children, but may occur in adults. We report a case of granular B-ALL in a 56-year-old female and review the literature.

Recent studies of acute erythroleukemias have reaffirmed DiGuglielmo's syndrome (M6a, myeloblast-predominant) and disease (M6b, pronormoblast-predominant). M6c (mixed myeloblast/pronormoblast) has also been described. However, MDS is still defined according to the percentage of myeloblasts (% myeloblasts) without including the pronormoblast count. A 20-year retrospective study was performed to identify cases demonstrating >or=50% erythrocytic component and

The mechanism by which the immune system of a tumor-bearing host acquires tolerance toward tumor antigens is still elusive. Antigen-presenting cells (APCs) are critical regulators of the decision between immune response and tolerance. APCs that express the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) have been found to inhibit T-cell responses both in vitro and in vivo. We hypothesized that malignant tumors exploit this mechanism by recruiting IDO-expressing APCs to the tumor-draining lymph nodes. To test this hypothesis, archival tissues and records of 26 cases of lymph node dissection for invasive cutaneous melanoma were obtained. IDO immunohistochemistry was performed on 14 cutaneous tumors and 328 regional lymph nodes. Abnormal accumulations of IDO-positive cells with a monocytoid or plasmacytoid morphology were identified in the perisinusoidal regions of draining lymph nodes in 45% of nodes studied. Recruitment of IDO-positive cells was seen in nodes with and without malignancy. We hypothesize that these IDO-positive APCs may contribute mechanistically to acquired tolerance to tumor antigens. Immunostaining of tumor-draining lymph nodes for abnormal accumulation of IDO-expressing cells might thus constitute an adverse prognostic factor and could contribute to the decision process and the appropriate care of patients with this deadly disease.

T patient was a 47-year-old man whose past medical history was significant for renal transplant, as well as refractory anemia with ringed sideroblasts (Figure 1) diagnosed 1 year previously. He re-presented to his hematologist/oncologist with fatigue and weight loss. The only medications he was taking at the time of presentation were cyclosporine and prednisone. Physical examination was noncontributory. A complete blood count revealed anemia, thrombocytopenia, and rare blasts. A bone marrow aspirate and biopsy were performed and revealed 51% erythrocytic precursors (Figure 2). Characteristic features included the presence of 41% pronormoblasts by FrenchAmerican-British (FAB) exclusion criteria, with marked dysplastic change and ‘‘block-and-blush’’ periodic acid– Schiff positivity (Figure 3) of the erythroid cell lineage. There were 22% myeloblasts by FAB exclusion criteria, with minimal dysplasia of the granulocytic cell line. A diagnosis of acute erythroleukemia, M6b (pure erythroleukemia, Di Guglielmo disease) was established. Cytogenetic analysis demonstrated a complex karyotype with abnormalities of both chromosomes 5 and 7. Review of the previous bone marrow slides confirmed the original diagnosis. The patient underwent 6 cycles of arabinosylcytosine (cytarabine)/daunorubicin therapy. Sequential intrachemotherapy and postchemotherapy bone marrow specimens revealed ablation of all hematopoietic elements, with the exception of the pronormoblasts. The patient died 21⁄2 months after initial diagnosis. A leukemia composed of purely erythrocytic precursors was first described by Di Guglielmo in 1926 and was designated Di Guglielmo disease. Until recently, this fulminant acute leukemia was alternately classified as a myeloproliferative disorder or a myelodysplastic syndrome. Nevertheless, a number of articles and books have described the complex cytogenetics and extremely poor outcome associated with this disease, which represents a distinct leukemic entity.1–4 The overall presentation and outcome of the patient described here are in keeping with previous descriptions of this condition.1,2 Investigators studying this leukemic process proposed that this disorder be renamed

We report a rare case of testicular histiocytoid hemangioma. Pathological features and differential diagnosis of this neoplasm are discussed. Testicular vascular tumors are rare, and include cavernous hemangioma,' capillary hemangioma? papillary endothelial hyperplasia3 and hemangioend~thelioma.~*~ The term histiocytoid hemangioma was proposed by Rosai et a1 to refer to certain vascular proliferations of skin, soft tissue, large blood vessels, bone and heart.6 The microscopic marker of these lesions is the proliferation of plump endothelial cells with bland nuclear features accompanied by a mixed inflammatory cell infiltrate. Histiocytoid hemangioma has rarely been described in the We report an additional case of histiocytoid hemangioma of the testis. CASE REPORT A 33-year-old white man consulted a urologist after palpating a mass in the right testis. The patient had no history of trauma or infection and no other symptoms. Medical and family histories were unremarkable. His wife had recently given birth to their second child. Physical examination was unremarkable except for a hard, approximately 2 cm. mass in the right testis with no significant testicular enlargement. Ultrasound revealed a 1.7 cm. mass in the upper half of the right testis. Findings were most consistent with a neoplastic process and radical inguinal orchiectomy was subsequently performed. Convalescence was uneventful. PATHOLOGICAL FINDINGS

Background Rapid detection of bloodstream infections (BSIs) can be lifesaving. We investigated the sample processing and assay parameters necessary for highly-sensitive detection of bloodstream bacteria, using Staphylococcus aureus as a model pathogen and an automated fluidic sample processing – polymerase chain reaction (PCR) platform as a model diagnostic system. Methodology/Principal Findings We compared a short 128 bp amplicon hemi-nested PCR and a relatively shorter 79 bp amplicon nested PCR targeting the S. aureus nuc and sodA genes, respectively. The sodA nested assay showed an enhanced limit of detection (LOD) of 5 genomic copies per reaction or 10 colony forming units (CFU) per ml blood over 50 copies per reaction or 50 CFU/ml for the nuc assay. To establish optimal extraction protocols, we investigated the relative abundance of the bacteria in different components of the blood (white blood cells (WBCs), plasma or whole blood), using the above assays. The blood samples were obtained from the patients who were culture positive for S. aureus. Whole blood resulted in maximum PCR positives with sodA assay (90% positive) as opposed to cell-associated bacteria (in WBCs) (71% samples positive) or free bacterial DNA in plasma (62.5% samples positive). Both the assays were further tested for direct detection of S. aureus in patient whole blood samples that were contemporaneous culture positive. S. aureus was detected in 40/45 of culture-positive patients (sensitivity 89%, 95% CI 0.75–0.96) and 0/59 negative controls with the sodA assay (specificity 100%, 95% CI 0.92–1). Conclusions We have demonstrated a highly sensitive two-hour assay for detection of sepsis causing bacteria like S. aureus directly in 1 ml of whole blood, without the need for blood culture.

Cryptococcal meningitis following autologous stem cell transplantation in a patient with multiple myeloma

The following abstracts are compiled from Check Sample exercises published in 2008. These peer-reviewed case studies assist laboratory professionals with continuing medical education and are developed in the areas of clinical chemistry, cytopathology, forensic pathology, hematology, microbiology, surgical pathology, and transfusion medicine. Abstracts for all exercises published in the program will appear annually in AJCP. # 1 Fetal Lung Maturity Testing Clinical Chemistry No. CC 08-1 (CC-367) {#article-title-2} Neonatal respiratory distress syndrome (RDS) is a disorder of pulmonary immaturity with a high mortality characterized by low levels of pulmonary surfactant. Gestational age determines risk based on concentration of pulmonary surfactant, ie, as gestation progresses the concentration of pulmonary surfactant increases. As a result, newborns delivered at fewer than 28 weeks have a more than 60% risk of RDS, whereas those delivered at more than 34 weeks have a less than 5% risk of RDS. In situations where gestational age alone is not sufficient to determine RDS risk and preterm delivery is medically needed, amniotic fluid analysis can be performed to determine pulmonary surfactant concentration. Four common methods are the lecithin-sphingomyelin ratio, phosphatidylglycerol measurement, surfactant-albumin ratio, and lamellar body count. All of these tests have excellent negative predictive values but poor positive predictive values, ie, they are great at confirming maturity but poor at confirming immaturity. # 2 Alkaline Phosphatase Isoenzyme Analysis: Guiding the Differential Diagnosis of Elevated Serum Total Alkaline Phosphatase Clinical Chemistry No. CC 08-2 (CC-368) {#article-title-3} The measurement of alkaline phosphatase (ALP) has long been used in clinical medicine, primarily to aid the diagnosis and monitoring of liver and bone diseases. Its diagnostic utility is limited by the enzyme’s wide tissue distribution and by a variety of potential nonpathologic causes. Isoenzyme analysis is one of several tools available to the clinician hoping to further characterize an elevated total ALP. It provides differentiation among liver, bone, intestinal, placental, and tumor-related forms as the cause of an elevation. The case presents a patient with persistent elevated ALP and atypical bands in the isoenzyme electrophoresis gel. An atypical ALP may be the result of a macroenzyme, which, if present, complicates interpretation of the test result and may cause additional, unnecessary testing or procedures. Recognizing and reporting a macroenzyme is an important service the clinical laboratorian can provide a clinician. # 3 Indirect Phlebotomy: Is It Good Practice? Clinical Chemistry No. CC 08-3 (CC-369) {#article-title-4} Indirect phlebotomy, the collection of blood samples through vascular infusion devices, is a common practice adopted to minimize needle-stick pain and discomfort in hospitalized patients. However, this practice can lead to alteration of the specimen and medical errors associated with misrepresentation of the blood test values. Among the possible problems, dilution or concentration of a particular analyte may occur, depending on the contents of the line’s infusate. Although some studies may indicate that blood collection from lines can be acceptable for isolated laboratory tests, there are insufficient data to demonstrate the reliability of line draws as routine practice. Use of lines for specimen collection should be reserved only for those patients with truly poor vascular access or those patients who require multiple phlebotomies in a short time period. Samples should be collected from lines only under a direct physician order, with careful attention to technique and established protocols that take many variables into account, including the analytes, contents of the line, type of line, discard blood volume, time interval between interruption of infusion and sampling, and catheter size. Even with careful attention to these details, clinicians must remain wary of the potential for medical errors related to misinterpretation of laboratory test results based on such samples.

Case: A 73 year old male with no significant past medical history presented with chronic fatigue. A routine CBC revealed an H/H of 6.8/19, MCV 103, WBC 4,100 and platelet count 92,000. Reticulocyte count was 0.6%. Serum iron, B12 and red cell folate studies were within normal limits. A bone marrow aspiration and biopsy were performed. Bone Marrow Findings: The bone marrow aspirate showed an M:E ratio of 1.8:1, with 33% erythrocytic elements. There was markedly left shifted erythropoiesis, with 57% of erythrocytic precursors being pronormoblasts. 1.2% blasts were present. Moderate erythrocytic dysplasia was present, with mild granulocytic and megakaryocytic changes. Vacuolated pronormoblasts were readily identified. No ringed sideroblasts were present. A diagnosis of MDS, NOS was rendered. No cytogenetics were obtained. Follow-up: The patient was transfused 4 units of packed red cells. Due to the patient’s rapidly deteriorating condition, comfort measures only were provided. The patient died 2.5 weeks after the bone marrow procedure. No autopsy was performed. The cause of death was listed as MDS. Discussion: This case is an extremely rare instance of left shifted erythropoiesis in the absence of the requisite number of erythrocytic elements for consideration of acute erythroleukemia (50%). By current definitions, this is an example of a fulminant MDS. However, this case does beg the question of whether or not pronormoblasts should be included in the assessment of malignant disorders of bone marrow.

Measurements were made of the changes in the monophasic action potential, excitability, durations of the refractory periods and conduction times in an area of left ventricular muscle during the development of ischemia subsequent to ligation of the ramus descendens anterior. The degree and duration of the ischemia produced varied greatly and effects were related thereto. It was found that action potentials shortened as did the refractory periods; thresholds fell momentarily and then rose progressively as tissue responsiveness failed due to continuing ischemia. Latency of responses increased, the action potentials decreased in amplitude and alternation occurred before the tissue became completely unresponsive. Early re-establishment of a blood supply caused a reversal of the abnormalities. The significance of these changes to the origin of arrhythmias is discussed.

The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes.The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied.The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100,000/year vs 5/100,000/year), were included in the later onset group (180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6).These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis.