Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene

Background Familial partial lipodystrophy (FPLD) is a monogenic form of diabetes characterised by a dominantly inherited disorder of adipose tissue associated with the loss of subcutaneous fat from the limbs and trunk, with excess fat deposited around the face and neck. The lipodystrophy causes severe insulin resistance, resulting in acanthosis nigricans, diabetes, dyslipidaemia, and increased risk of cardiovascular disease. Preliminary results from animals and man suggest that increasing subcutaneous fat by treatment with thiazolidinediones should improve insulin resistance and the associated features of this syndrome. Case report We report a 24-year-old patient with FPLD caused by a mutation in the LMNA gene (R482W) treated with 12 months of rosiglitazone. Subcutaneous fat increased following rosiglitazone treatment as demonstrated by a 29% generalised increase in skin-fold thickness. Leptin levels increased from 5.8 to 11.2 ng/ml. Compared with treatment on Metformin, there was an increase in insulin sensitivity (HOMA S% 17.2–31.6) but no change in glycaemic control. The lipid profile worsened during the follow-up period. Conclusion This initial case suggests that, for modification of cardiovascular risk factors, there are no clear advantages in treating patients with FPLD with rosiglitazone despite increases in subcutaneous adipose tissue. Larger series will be needed to identify moderate beneficial effects and treatment may be more effective in patients with generalised forms of lipodystrophy.     

植酸磷的测定──离子交换法

介绍用离子交换法测定植酸磷的含量。对消化终点、最适的提取时间、离子交换树脂的分离效果进行了试验。黄豆粉、窝窝头、豆腐干植酸测得值的变异系数分别为２．１６％、４．９２％、１．７８％，回收率依次为１０３．３８％、１０２．８１％、１０３．４１％。植酸标准品的植酸含量理论值为５７．６４％，本法测定值为５５．２３％，相对误差为２．１４％。本法的精密度及准确度均符合要求。     

The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse

Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is generally reversible. However, there is evidence that MMC may also cause a late-stage or residual bone marrow injury. The present study in female CD-1 mice investigated the haematological and bone marrow changes induced by MMC in a repeat dose study lasting 50 days. Control and MMC-treated mice were dosed intraperitoneally on eight occasions over 18 days with vehicle, or MMC at 2.5 mg/kg, autopsied (n = 6-12) at 1, 7, 14, 28, 42 and 50 days after the final dose and haematological changes investigated. Femoral nucleated bone marrow cell counts and levels of apoptosis were also evaluated and clonogenic assays carried out; serum levels of FLT3 ligand (FL) were assessed. At day 1 post-dosing, MMC induced significant reductions in RBC, Hb and haematocrit (HCT) values, and there were decreases in reticulocyte, platelet, and femoral nucleated cell counts (FNCC); neutrophil, lymphocyte and monocyte values were also significantly reduced. On days 7 and 14 post-dosing, all haematological parameters showed evidence of a return towards normal values, but at these times, and at day 28, values for RBC and FNCC remained significantly reduced in comparison with controls. At days 42 and 50 post-dosing, many haematological parameters in MMC-treated mice had returned to control levels; however, there remained evidence of late-stage effects on RBC, Hb and HCT values, and FNCC also continued to be significantly decreased. Results for granulocyte-macrophage colony-forming units and erythroid colonies showed a profound decrease immediately post-dosing, but a return to normal values was evident at day 50. Serum FL concentrations demonstrated very significant increases in the immediate post-dosing period, but a return to normal was seen at day 50 post-dosing; a relatively similar pattern was seen in the number of apoptotic femoral marrow nucleated cells. The histopathological examination of kidney tissues from MMC animals at day 42 and 50 post-dosing showed evidence of hydronephrosis with cortical glomerular/tubular atrophy and degeneration. It is therefore concluded that MMC administered on eight occasions over 18 days to female CD-1 mice at 2.5 mg/kg induced profound changes in haematological and bone marrow parameters in the immediate post-dosing period with a return to normal levels at day 50 post-dosing; however, there was evidence of mild but significant late-stage/residual effects on RBC and FNCC, and on cells of the erythroid lineage in the bone marrow.     

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy,non-mycobacterium bovis BCG-vaccinated Malawian young adults

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M. bovis (MPB70), M. bovis BCG (Ag85), and M. leprae (65 kDa, 35 kDa, and 18 kDa) in >600 non-M. bovis BCG-vaccinated young adults in the Karonga District of northern Malawi. IFN-gamma was measured by enzyme-linked immunosorbent assay (ELISA) in day 6 supernatants of diluted whole-blood cultures. The recombinant M. leprae 35-kDa and 18-kDa and purified native M. bovis BCG Ag85 antigens induced the highest percentages of responders, though both leprosy and bovine tuberculosis are now rare in this population. The M. tuberculosis antigens ESAT-6 and MPT64 and the M. bovis antigen MPB70 induced the lowest percentages of responders. One of the subjects subsequently developed extrapulmonary tuberculosis; this individual had a 15-mm-diameter reaction to the Mantoux test and responded to M. tuberculosis PPD, Ag85, MPT64, and ESAT-6 but not to any of the leprosy antigens. We conclude that in this rural African population, exposure to M. tuberculosis or M. bovis is much less frequent than exposure to environmental mycobacteria such as M. avium, which have antigens homologous to the M. leprae 35-kDa and 18-kDa antigens. M. tuberculosis ESAT-6 showed the strongest association with the size of the Mantoux skin test induration, suggesting that among the three M. tuberculosis antigens tested it provided the best indication of exposure to, or infection with, M. tuberculosis.     

Relapsing diabetes can result from moderately activating mutations in KCNJ11

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.     

Cocoa Flavanols Adjuvant to an Oral Nutritional Supplement Acutely Enhances Nutritive Flow in Skeletal Muscle without Altering Leg Glucose Uptake Kinetics in Older Adults

Ageing is associated with postprandial muscle vascular and metabolic dysfunction, suggesting vascular modifying interventions may be of benefit. Reflecting this, we investigated the impact of acute cocoa flavanol (450–500 mg) intake (versus placebo control) on vascular (via ultrasound) and glucose/insulin metabolic responses (via arterialised/venous blood samples and ELISA) to an oral nutritional supplement (ONS) in twelve healthy older adults (50% male, 72 ± 4 years), in a crossover design study. The cocoa condition displayed significant increases in m. vastus lateralis microvascular blood volume (MBV) in response to feeding at 180 and 240-min after ONS consumption (baseline: 1.00 vs. 180 min: 1.09 ± 0.03, p = 0.05; 240 min: 1.13 ± 0.04, p = 0.002), with MBV at these timepoints significantly higher than in the control condition (p < 0.05). In addition, there was a trend (p = 0.058) for MBV in m. tibialis anterior to increase in response to ONS in the cocoa condition only. Leg blood flow and vascular conductance increased, and vascular resistance decreased in response to ONS (p < 0.05), but these responses were not different between conditions (p > 0.05). Similarly, glucose uptake and insulin increased in response to ONS (p < 0.05) comparably between conditions (p > 0.05). Thus, acute cocoa flavanol supplementation can potentiate oral feeding-induced increases in MBV in older adults, but this improvement does not relay to muscle glucose uptake.     

Distal oblique osteotomy versus cheilectomy for moderate-advanced hallux rigidus: A 2-year propensity-score-matched study

BackgroundThe surgical treatment of moderate-advanced hallux rigidus is controversial. Cheilectomy is widely used but has recurrence rates of up to 30%. Dorsal oblique metatarsal osteotomy (DOO) has also shown good results, however, there is no study comparing outcomes of the DOO against cheilectomy.MethodsThis was a retrospective propensity score matched study based on registry data from a single tertiary institution. Between 2007 and 2017, all patients who had undergone dorsal cheilectomy or DOO for hallux rigidus were included. Patients with previous foot surgery, revision surgeries, and concomitant surgical procedures were excluded. Clinical outcomes, complication rates, revision rates and patient satisfaction were assessed at 2 years postoperatively.ResultsThere were 44 patients (34 cheilectomy, 10 DOO). After propensity score matching, 17 cheilectomy and all 10 DOO cases were selected for comparison. Patients in both groups had a significant improvement in visual analogue pain scores (VAS) and AOFAS 1st toe scores 2-years post-operatively (P < 0.001) with high levels of post-operative satisfaction (85.1%). Overall there were no statistically significant differences in post-operative scores, improvement in scores, complication rates, revision rates, and levels of patient satisfaction between groups.ConclusionsBoth the DOO and cheilectomy give similarly good outcomes for moderate-advanced hallux rigidus. Further studies are needed to elucidate differences in indications for each procedure.