The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants.

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.

Pulmonary artery leiomyosarcoma: an unusual cause of shortness of breath.

INTRODUCTION: Primary leiomyosarcomas of the pulmonary artery are very rare tumours with 30 cases reported in the English literature. Herein, we report the first case with evidence of a renal metastasis. MATERIALS AND METHODS: The tumour was discovered at autopsy in a 61-year-old woman who had presented with shortness of breath and chest pain. It was located in the pulmonary trunk with extension into the adjacent pericardial cavity. Separate nodules were found in the pulmonary valve, the left pulmonary artery and the left kidney. RESULTS: On microscopic examination, the tumour was composed of spindle cells with cigar-shaped nuclei immunoreactive for vimentin, desmin, CD68 and α-smooth muscle actin. CONCLUSIONS: Primary pulmonary artery leiomyosarcoma is easily confused clinically with pulmonary thromboembolism and most cases are diagnosed post mortem. Most tumours arise in the pulmonary trunk and metastases are only rarely described. The management of patients with this rare tumour depends on early surgical resection and the prognosis is unfavourable.

Activated protein C resistance (APCR) and placental fibrin deposition.

Activated protein C resistance (APCR) results in an ineffective anticoagulant response leading to an increased risk of thrombosis, particularly during pregnancy. Adverse pregnancy outcomes including pre-eclampsia (PET), intrauterine growth restriction (IUGR), recurrent miscarriage and placental abruption have been linked with thrombotic lesions compromising the utero-placental circulation. Using histological staining including Martius Scarlet Blue (MSB) and Haematoxylin and Eosin (H&E) and microscopy, we studied placental fibrin deposition and histological abnormalities in subjects (n=23) with APCR (APCR group), based on a ratio of less than or equal to 2.1s with the Coatest classic test and subjects (n=11) with an APC ratio in the normal range, greater than 2.1s (APCN group). Fibrin deposition was significantly higher (3.3-fold) in the APCR group compared to the APCN group. An inverse correlation between APC ratio and placental fibrin deposition was determined for the study group. Histological abnormalities were more than 2-fold higher in the APCR group compared to the APCN group. Molecular screening identified common thrombophilic mutations, FVL and FII-G20210A in the APCR group but not in the APCN group.

Small cell neuroendocrine carcinoma of the breast: a report of three cases and review of the literature.

Small cell neuroendocrine carcinoma of the breast is a rare tumour with less than 30 cases reported in the literature. The clinicopathological findings of three cases of primary neuroendocrine carcinoma of the breast and a review of the pertinent literature are presented. The morphological and immunohistochemical patterns of this tumour are similar to its pulmonary counterpart. Expression of neuroendocrine markers is inconsistent, so morphology is the mainstay of diagnosis. Size is a very important prognostic factor in this tumour, as in breast carcinomas of the usual type.

Aneursymal bone cyst of the proximal phalanx of the thumb in a child.

Aneursymal Bone Cysts (ABCs) involving the hand are a rare occurrence. We report a case of an ABC of the proximal phalanx of the thumb in a boy which was treated successfully with curettage and autologous bone grafting. When the diagnosis of ABC of the small bones of the hand is entertained, prompt therapeutic intervention is indicated because of the potential for aggressive local behaviour. In the paediatric patient, simple surgery to preserve the growth plate is recommended.

Internal displacement in Burma.

The internal displacement of populations in Burma is not a new phenomenon. Displacement is caused by numerous factors. Not all of it is due to outright violence, but much is a consequence of misguided social and economic development initiatives. Efforts to consolidate the state by assimilating populations in government-controlled areas by military authorities on the one hand, while brokering cease-fires with non-state actors on the other, has uprooted civilian populations throughout the country. Very few areas in which internally displaced persons (IDPs) are found are not facing social turmoil within a climate of impunity. Humanitarian access to IDP populations remains extremely problematic. While relatively little information has been collected, assistance has been focused on targeting accessible groups. International concern within Burma has couched the problems of displacement within general development modalities, while international attention along its borders has sought to contain displacement. With the exception of several recent initiatives, few approaches have gone beyond assistance and engaged in the prevention or protection of the displaced.

Australia's oldest human remains: age of the Lake Mungo 3 skeleton.

We have carried out a comprehensive ESR and U-series dating study on the Lake Mungo 3 (LM3) human skeleton. The isotopic Th/U and Pa/U ratios indicate that some minor uranium mobilization may have occurred in the past. Taking such effects into account, the best age estimate for the human skeleton is obtained through the combination of U-series and ESR analyses yielding 62,000+/-6000 years. This age is in close agreement with OSL age estimates on the sediment into which the skeleton was buried of 61,000+/-2000 years. Furthermore, we obtained a U-series age of 81,000+/-21,000 years for the calcitic matrix that was precipitated on the bones after burial. All age results are considerably older than the previously assumed age of LM3 and demonstrate the necessity for directly dating hominid remains. We conclude that the Lake Mungo 3 burial documents the earliest known human presence on the Australian continent. The age implies that people who were skeletally within the range of the present Australian indigenous population colonized the continent during or before oxygen isotope stage 4 (57,000-71,000 years).

Papillary carcinoma in a thyroglossal duct remnant--a review of thyroglossal surgery in a regional centre in the west of Ireland.

A review of thyroglossal duct remnants presenting to a regional centre in the West of Ireland was undertaken. Over a 15 yr period, 25 patients were operated on for duct remnants. The mean age was 19.6 yr and ranged from 3 to 68 yr. There were 16 (64 per cent) males and 9 (36 per cent) females. Seventeen (68 per cent) patients were less than 20 years at the time of surgery. Four patients presented with a sinus and the remainder with a cystic lesion. Two patients experienced recurrent disease. One patient, a 41 yr old female, had a papillary carcinoma of a thyroglossal cyst. There were no clinical features distinguishing this patient from those with benign cystic remnants of the thyroglossal duct. The possibility of carcinoma in older patients, in particular females, presenting with thyroglossal cysts emphasises the importance of performing a formal Sistrunk's operation. It reduces the risk of recurrence of the cyst and may reduce the risk of recurrence of the tumour as the duct may provide a route for the spread of tumour.

Massive thymic hemorrhage in a neonate: an entity revisited.

The authors describe a case of early neonatal death of a full-term infant who had respiratory distress and anemia after fetal distress during labor. Postmortem examination disclosed mediastinal compression by a large fresh hemorrhage into the left lobe of the thymus. Massive thymic hemorrhage is an extremely rare but sometimes lethal occurrence; it may represent a manifestation of early-onset hemorrhagic disease of the newborn.

Clinical evaluation of near-continuous oral micronized progesterone therapy in estrogenized postmenopausal women.

In an open non-comparative prospective trial of 12 months' duration, we investigated the role of a novel hormone replacement therapy regimen in 40 post-menopausal women who sought hormone replacement therapy. The regimen consisted of continuous administration of 0.625 mg of conjugated equine estrogen coupled with a fixed low-dose of micronized oral progesterone administered for 23 days every calendar month. The regimen was well-tolerated, producing no major side-effects and was effective in relieving menopausal symptoms. The study showed that 40% of the women experienced side-effects and 20% withdrew from the study. Half of the 20% of the women who dropped out did so for reasons not related to treatment. All symptomatic women experienced improvement after the 1st month, and virtually all were asymptomatic by the 3rd month of treatment, persisting until the end of the trial with the average number of hot flushes per day declining from the pretreatment levels by 96%. Amenorrhea was observed in 47% of patients, amenorrhea and minimal vaginal bleeding in 78% but acyclic bleeding was present in 28% of those in whom bleeding was re-established. Endometrial atrophy was induced in the majority of patients and no atypical endometrial hyperplasia was encountered. No significant changes were observed in blood glucose or liver enzymes. The mean percentage changes from baseline for serum cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoproteins (LDL) and LDL/HDL ratio were -6%, +32% (p < 0.001), -16% (p < 0.05), +15% (p < 0.05) and -23% (p < 0.05), respectively. The regimen was clinically effective and its apparent lack of major side-effects, the protective effect on the endometrium, the added advantage of minimal vaginal bleeding and the beneficial effect on lipid/lipoprotein levels, offer an attractive therapy and improved compliance with postmenopausal hormone replacement therapy.

Unexplained stillbirths and sudden infant death syndrome.

Comparison of necropsy records, clinical details and epidemiological data of 93 unexplained stillbirths and 149 cases of sudden infant death syndrome provides compelling evidence that these disorders represent a continuum of a single spectrum of disease. Regarding them as a single disease entity could lead to a clearer understanding of both.

Aberrant thyroglossal cyst.

A case is presented of a laterally occurring thyroglossal cyst. In conventional teaching, thyroglossal duct remnants occupy the midline, or a position adjacent to the midline, and are found in a line marking the descent of the thyroid anlage and move upwards on protruding the tongue. Laterally presenting thyroglossal duct remnants are unusual.

Cell proliferation in breast tumours: analysis of histological parameters Ki67 and PCNA expression.

Ki67 and Proliferating Cell Nuclear Antigen (PCNA) are antigens expressed in the nucleus during various phases of cell division, which can be detected immunohistochemically using monoclonal antibodies. Thirteen fibroadenomas and 39 carcinomas were examined for expression of Ki67 and PCNA. A staining index was calculated for each tumour as the percentage of positive cells in the areas of highest density. The mean index for both antibodies was significantly lower in fibroadenomas than in malignant tumours. A wide range of proliferation rates was seen in the malignant group; the mean Ki67 index of Grade I carcinomas was 9% +/- 4.4 (mean +/- SD), of Grade II 14.3 +/- 8.7 and of Grade III 26.2 +/- 15.7. These differences are statistically significant. In malignant tumours there was a good correlation between the mitotic count and the Ki67 index (r = 0.61, p < 0.005) but none between the mitotic count and PCNA index. There was a weak correlation between the Ki67 and the PCNA indices (r = 0.38 p < 0.005), but no correlation was found between either index and oestrogen receptor status, patient age or tumour size. Ki67 immunohistochemistry is a convenient method for assessing cell proliferation, applicable in most laboratories. The validity of measuring proliferation in this way has yet to be established but the wide variation of expression even within the conventional grading categories may help to discriminate prognostically distinct subgroups. Expression of PCNA appears to correlate poorly with Ki67 expression in breast tumours and not with mitotic count; therefore its usefulness as a marker of proliferative activity, on current evidence, appears to be limited.

Patterns of cytokeratin expression by neoplastic and non-neoplastic epithelium.

Eighty-one epithelial lesions were studied immunohistologically for cytokeratin protein expression using three anticytokeratins CAM 5.2, NCL5D3 and RCK102. Consistent differences were noted between squamous and glandular neoplasms. Squamous and cutaneous carcinomas were found to preferentially express higher molecular weight cytokeratins than adenocarcinomas. In addition, tumours of similar morphology from different sites showed differences in expression of these markers. Differences in pattern were also found between benign and malignant lesions in the case of liver and urinary bladder. Thus the value of cytokeratin profile analysis in characterisation of epithelial neoplasms is confirmed and may be useful in distinguishing benign from malignant tumours in some instances.

Low-dose progesterone therapy in oestrogenised postmenopausal women: effects on plasma lipids, lipoproteins and liver function parameters.

BACKGROUND: Cardiovascular disease among older women is a major health problem and is the leading cause of death in this group in developed countries. The risk is reduced in oestrogen users secondary to favourable lipid changes, but the beneficial effect of oestrogen may be counteracted when concomitant progestogens are administered. OBJECTIVE: To study the effects of a novel hormone replacement therapy regimen on liver enzymes, lipids and lipoproteins in postmenopausal women. DESIGN: Prospective open, non-comparative trial for 12 months. METHODS: 40 healthy postmenopausal women, (mean age +/- S.D.), 53.5 +/- 3 years received 0.625 mg of conjugated equine oestrogen daily and 100 mg of micronised oral progesterone (P) for the first 23 days every calendar month for 12 months without interruption. MAIN OUTCOME MEASURE: Gonadotrophins, liver function parameters and lipoproteins were measured before treatment and at the 6th, 9th and 12th months of treatment. RESULTS: Compliance with treatment was confirmed by a 33% decrease in mean serum level of follicle stimulating hormone at the end of 1 year of treatment. In the same period, the mean serum cholesterol, LDL and LDL/HDL ratio decreased by 6%, 16% and 23% of the base line levels, respectively. The percentage changes in triglycerides and HDL from the basal levels were +32% (P < 0.001) and +15% (P < 0.05), respectively. CONCLUSION: These results indicate that near continuous administration of fixed low-dose of P has no adverse effects on the lipid milieu of postmenopausal women when combined with long-term continuous oestrogen replacement therapy provided women with borderline triglyceridaemia are excluded.