Comparative study of sitagliptin with pioglitazone in Japanese type 2 diabetic patients: the COMPASS randomized controlled trial.

AIMS: To compare the efficacy and safety of these two agents and the impact on surrogate markers related to diabetic complications in Japanese type 2 diabetic patients. METHODS: In a multicenter, open-label trial, 130 patients whose diabetes had been inadequately controlled (HbA1c, 6.9-9.5%) with metformin and/or sulphonylurea were randomly assigned to a sitagliptin group (50 mg/day) or a pioglitazone group (15 mg/day) and were followed up for 24 weeks. At 16 weeks, if the patient's HbA1c level was ≥6.5%, the dose of sitagliptin or pioglitazone was increased up to 100 or 30 mg/day, respectively. Main outcome measure was the difference in the mean changes in the HbA1c level from baseline at 24 weeks between these two groups. RESULTS: Of the 130 patients who were enrolled, 115 subjects (sitagliptin group: 58 patients, pioglitazone group: 57 patients) completed this trial. At 0 weeks, the mean HbA1c level was 7.47 ± 0.66% in the sitagliptin group and 7.40 ± 0.61% in the pioglitazone group. At 24 weeks, the mean changes in the HbA1c level from baseline were -0.86 ± 0.63% versus -0.58 ± 0.68% (p = 0.024). Hypoglycaemia (2 patients, 3.4% vs. 2 patients, 3.5%), gastrointestinal symptoms (3 patients, 5.2% vs. 1 patient, 1.8%) and pretibial oedema (0 patients, 0% vs. 39 patients, 68.4%, p < 0.001) were observed for 24 weeks. CONCLUSIONS: Sitagliptin was not only more tolerable, but also more effective than pioglitazone in Japanese type 2 diabetic patients who had been treated with metformin and/or sulphonylurea.

Changes in autonomic nervous activity prior to spontaneous coronary spasm in patients with variant angina.

Although the autonomic nervous system has been implicated in the genesis of coronary spasm, the precise mechanism by which it serves as the trigger of coronary spasm remains unclear. The aim of this study was to investigate changes in autonomic nervous activity associated with ischemic episodes in patients with variant angina (VA). Heart rate variability (HRV) on Holter monitoring was analyzed during 17 ischemic episodes in 11 patients with VA. The parameters of HRV were measured during a 2-min period at various time intervals prior to the onset of ST-segment elevation. The low frequency (LF) and high frequency (HF) components of the HRV, LF/HF ratio, mean RR interval, and the coefficient of the RR interval variation (CV) were calculated for each time interval. Both the HF and the CV increased significantly in the 2 min prior to the onset of ST-segment elevation, suggesting heightened vagal activity. The LF/HF ratio, a measure of cardiac sympatho-vagal balance, did not change. The LF, a measure of sympathetic activity with vagal modulation, also did not change. The RR interval decreased significantly in the 2 min prior to the onset of ST-segment elevation. These results suggest that enhancement of both the vagal and the sympathetic nervous activity plays an important role in the initiation of coronary spasm.

Pseudoxanthoma elasticum-like papillary dermal elastolysis: report of four Japanese cases and an immunohistochemical study of elastin and fibrillin-1.

We report four patients with pseudoxanthoma elasticum-like papillary dermal elastolysis (PDE). Multiple small papules on the neck, clinically resembling pseudoxanthoma elasticum, and loss of the elastic fibre network in the papillary dermis were found in each case. Immunohistochemical staining for elastin and fibrillin-1 in one patient demonstrated the disappearance of elastin and fibrillin-1 in the papillary dermis. Site-matched normal skins of the elderly showed intact elastin but a lack of fibrillin-1 in the papillary dermis. The younger normal skins revealed intact elastin and fibrillin-1. The results suggest that fibrillin-1 is absent from the papillary dermis of the normal-appearing neck skin of the elderly and that the primary defect in PDE may be in elastin rather than in fibrillin-1.

Correlation between initial potentials on a signal-averaged P-wave and indice of electrophysiologic measurements in the right atrium.

The aim of this study was to determine whether initial potentials of the P-wave on a signal-averaged electrocardiogram (SAE) during sinus rhythm reflect indices of electrophysiologic measurements in the high lateral right atrium. A total of 67 patients underwent P-wave signal averaging during electrophysiologic testing. The correlation between root mean square voltages for the initial 10 and 20 msec of the P-wave on the SAE and indices of electrophysiologic measurements, sinus node recovery time (SRT) and sinoatrial conduction time (SACT), obtained from programmed stimuli, was evaluated. It was found that the initial potentials of the P-wave on the SAE correlated negatively with SRT and SACT (-0.37 < or = r < or = -0.30). It was concluded that the initial potentials correlated with indices of electrophysiologic measurements, although the statistical significance was weak.

Cultured human keratinocytes express tropoelastin.

We detected elastin mRNA in cultured normal human keratinocytes by RNase protection assay. The content of elastin mRNA was estimated at approximately one-twentieth of that of cultured skin fibroblasts. Tropoelastin polypeptide with a molecular weight of 68 kDa was detected in the preparation of culture medium of normal human keratinocytes by western blot assays using anti-tropoelastin antibody. Immunohistochemical studies also demonstrated positive staining in cultured normal human keratinocytes as well as in skin fibroblasts. The expression of elastin by normal human keratinocytes was found to reach a maximum level at the quiescent phase of keratinocyte growth. When normal human keratinocytes were cultured on tropoelastin-coated dishes, their growth potential was greatly suppressed compared with other matrix protein-coated dishes. These results suggest that cultured normal human keratinocytes can actively synthesize elastin and that keratinocyte elastin may act as a growth-regulator for keratinocytes.

Expression of the retinoid-inducible polypeptide, midkine, in human epidermal keratinocytes.

Midkine (MK) is a retinoid-inducible and potent cell growth/differentiation factor active during mouse embryogenesis. We studied MK expression in various cell strains established from the skin. MK and its mRNA were detected in cultured keratinocytes but not in melanoma cell lines or dermal fibroblasts by both Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Treatment of cultured keratinocytes with retinoic acid (10(-5) M, 24 h) resulted in an increase in the level of MK mRNA. When added to cultured keratinocytes, MK stimulated cell proliferation fourfold. Immunohistochemistry revealed MK to be present at the epidermal-dermal junction in embryonic mouse skin and in normal human skin. The limited expression of MK in epidermal keratinocytes indicates that this polypeptide may be involved in the differentiation/proliferation of keratinocytes.

Stimulation of collagen expression and glycosaminoglycan synthesis by midkine in human skin fibroblasts.

Midkine is a retinoid-inducible regulator of cell differentiation and cell growth in developing embryonic tissues. The effects of midkine on the expression of the extracellular matrix components, collagens and glycosaminoglycans, in dermal fibroblasts were studied. Midkine did not alter fibroblast proliferation. Collagen synthesis was stimulated in a dose- and exposure time-dependent manner and the maximum two-fold stimulation was achieved at a concentration of 100 ng/ml for 72 h treatment. Midkine increased the synthesis of type I and III collagens to the same extent. Glycosaminoglycan synthesis was also stimulated two-fold, mainly accounted for by an increase in hyaluronan synthesis. Midkine enhanced mRNA levels of alpha 1 (I), alpha 1 (III), alpha 1 (VI) collagens, transforming growth factor beta 1 and matrix metalloprotease-2 but did not alter the mRNA levels of elastin, MMP-1 and tissue inhibitor of metalloproteases-1. These results suggest that midkine is a potent stimulator of collagen and glycosaminoglycan synthesis and may prove useful in the therapy of delayed wound healing.

Self-involuting atrophoderma of the lateral-upper arm. A new benign variant of morphea?

BACKGROUND: Atrophoderma of Pasini-Pierini and morphea are considered to be distinct clinical entities. However, some authors say that they are closely related diseases. We encountered 5 unique cases that did not fit the criteria for both diseases. OBJECTIVE AND METHODS: We report 5 cases with solitary atrophic lesions on the lateral-upper arm. They appeared as white to erythematous, non-indurated and slightly depressed lesions with a smooth surface, and the patients had no history of trauma or injection. RESULTS: Histological examinations showed slight to moderate lower dermal fibrosis without specific changes in adipose tissue. The lesions disappeared spontaneously within a year. CONCLUSION: Our cases may be a benign variant form of morphea. We propose the term 'self-involuting atrophoderma of the lateral-upper arm (SALA)' for these clinical features.

Overexcretion of low-sulphated chondroitin sulphate in the urine of the patient resembling progeroid.

We report an unusual case with mental retardation, short stature, sparse scalp hair, prominence of scalp veins, atrophy of subcutaneous fat, pterygia of the neck and loose skin. The patient excreted greater amounts of low-sulphated chondroitin sulphate (LSC) in the urine than age-matched controls. The pattern of glycosaminoglycan in serum and its synthesis by the patient fibroblasts were normal. Collagen, elastin and decorin mRNA levels in the patient fibroblasts were also unaltered. These results suggest that this patient seems to be different from Lowe's syndrome and decorin-deficient progeroid. An abnormal LSC metabolism may be partially responsible for the pathology of these syndromes.

Chronic white plaque of the vulva in postmenopausal women.

We report 13 cases of white lesions in the vulva in postmenopausal women. Nine cases had clinical and histological features typical of lichen sclerosus et atrophicus (LSA). Two cases exhibited mild histological changes suggestive of LSA. Two cases of normal-appearing histology without significant histological changes. Considering the relatively short duration of the disease and relatively small lesions in the last two cases, they may be considered to represent the initial stage of LSA.

A case of acrogeria associated with late-onset focal dermal elastosis.

We report a case of acrogeria. Biochemical analysis of patient fibroblasts demonstrated unaltered type III collagen synthesis. An RNA hybridization assay demonstrated that the levels of type I and elastin mRNAs were normal. The patient had multiple yellow papules on the neck, axilla and inguinal area which clinically and histologically resembled late-onset focal dermal elastosis. Both diseases may have some similar abnormal metabolism of connective tissue.

Systemic scleroderma and perforating granuloma annulare: differential diagnosis from calcinosis.

BACKGROUND: Systemic scleroderma is a disorder of unknown etiology with skin sclerosis. Its major histological features are swollen and homogenized collagen bundles. OBJECTIVE AND METHODS: We describe 2 patients with systemic sclerosis who have multiple umbilicated nodules indistinguishable from calcinosis cutis. RESULTS: Histological examinations including Von Kossa staining revealed features of perforating granuloma annulare, but not of calcinosis cutis. CONCLUSION: The association may not be fortuitous but both diseases may be etiologically related.

A case of CREST syndrome associated with sick sinus syndrome.

Cardiac manifestations of the CREST syndrome or limited systemic sclerosis (ISSc) are very rare. We report a case of CREST syndrome associated with sick sinus syndrome. Histopathology of cardiac muscle revealed fibrotic changes, suggesting that such changes may be pathogenetically related to CREST syndrome.

Characterization of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjögren's syndrome.

BACKGROUND: Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare disease, and its pathogenesis of amyloid deposition is still unknown. OBJECTIVE: The purpose of this study was to know the origin of amyloid in PLCNA. METHODS: Water-soluble amyloid fibrils were isolated from the skin and resolved on SDS-PAGE, then subjected to immunoblot analysis. RESULTS: The major amyloid fibril protein was a 29-kD peptide which reacted with both anti-lambda- and anti-kappa-light-chain antibodies. CONCLUSION: Amyloids in this particular case of PLCNA are derived from the polyclonal immunoglobulin light chain and some cases of PLCNA could be reactive diseases rather than neoplastic ones.