Augmentation index in resistance to thyroid hormone (RTH)

Objective  Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes.
Design  An observational study.
Patients  Twelve RTH patients were recruited from the thyroid clinic (mean value ± SD), age 40·8 ± 18·7 years; BMI 27·2 ± 4·2 kg/m² and compared with 12 healthy, euthyroid, age-matched controls (age 41·4 ± 19·3; BMI 24·8 ± 4·4 kg/m²) with no history of cardiovascular disease. No interventional measures were instituted.
Measurements  Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls.
Results  The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21·0% ± 14·1% vs. 5·4% ± 18·2%, P  < 0·03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3·0 ± 0·6 vs. 2·1 ± 0·5 mmol/l; P  < 0·002).
Conclusion  RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.     

Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia

Cytosine arabinoside (ara-C) is irreversibly deaminated to a non-toxic metabolite by cytidine deaminase (CDA). A common polymorphism, A79C, in the gene encoding cytidine deaminase ( CDA ) changes a lysine residue to glutamine resulting in decreased enzyme activity. CDA A79C genotypes were determined in 457 children with acute myeloid leukaemia (AML) treated on the Children's Cancer Group (CCG) 2941 and 2961 protocols and analyzed the impact of CDA genotype on therapy outcomes. Postinduction treatment-related mortality (TRM) was significantly elevated in children with the CC genotype (5-year TRM 17 ± 13% CC vs. 7 ± 4% AA, 5 ± 4% AC, P  = 0·05). This was more notable in children who received idarubicin, fludarabine, ara-C, and granulocyte colony-stimulating factor (IDA-FLAG; ara-C = 7590 mg/m²) (5-year TRM 24 ± 21% CC vs. 6 ± 6% AA, 6 ± 7% AC, P  = 0·07) as consolidation therapy compared to idarubicin, dexamethasone, cytarabine, thioguanine, etoposide and daunomycin (IDA-DCTER; ara-C = 800 mg/m²) (5-year TRM 15 ± 20% CC vs. 8 ± 6% AA, 4 ± 6% AC; P  = 0·29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 ± 20% CC vs. 59 ± 12% AA and 55 ± 14% AC; P  = 0·40). These data indicate that children with a low activity CDA genotype are at increased risk of TRM with ara-C based therapy for AML.     

Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow

S ummary . Eighteen patients with small cell carcinoma of the lung received high dose cyclophosphamide (180–200 mg/kg) intensification following five pulses of 'CHOP' chemotherapy (cyclophosphamide 750 mg/m² i.v., adriamycin 50 mg/m² i.v., vincristine 1·4 mg/m² i.v., prednisolone 40 mg orally for 5 d). They received infusions of autologous bone marrow which had been stored at 4°C for 34 h. Pancytopenia was predictable in onset and its duration acceptable. Recovery of neutrophils to greater than 1·0 × 10⁹/l was achieved in 17·5 ± 0·9 d (mean ± SEM) and platelets to greater than 100 × 10⁹/l in 17·5 ± 0·8 d. Four patients with acute myeloid leukaemia in complete remission received intensification with the supralethal combination of cyclophosphamide and total body irradiation followed by infusion of autologous marrow which had been stored at 4°C for 54 h. Haematological reconstitution in these patients was acceptable but slower (greater than 1·0 × 10⁹/l neutrophils between days 26 and 40; greater than 20 × 10⁹/l platelets between days 23 and 77). Except in one case, normal peripheral counts were attained in all patients.
It is concluded that bone marrow stored at 4°C for up to 54 h is a simple and practical source of viable stem cells which have the capacity for acceptable haematological reconstitution.     

Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m² on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m²) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m² and bortezomib 1·3 mg/m². The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD ( n  = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD ( P  < 0·05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.     

Systemic Hemodynamic Changes in Elderly Hypertensive Patients After Ingesting Foods With Lipid, Protein, and Carbohydrate Contents

Aging is associated with changes in cardiovascular structure and function, which predisposes elderly people to reduced blood pressure levels after meals. The authors studied cardiac systolic function in elderly hypertensive patients after eating meals with different contents of lipids, proteins, and carbohydrates. Ten elderly male hypertensive patients were studied (mean age, 69 years; range 60–80 years). No patients had a previous history of orthostatic or postprandial hypotension. Patients ate 1 of 3 pre-prepared meals: lipid meal (LM), protein meal (PM), or carbohydrate meal (CM), on different days. Mean arterial pressure, total peripheral resistance index (TPRi), cardiac index (CI), and stroke index were recorded at the end of the fasting period and then at 5, 15, 30, 45, and 60 minutes after food ingestion. After ingestion of a CM, the CI increased from 2.30±0.21 L/min/m² to 2.61±0.24 L/min/m² and the TPRi decreased from 3212±226 dynes/sec² to 2793±255 dynes/sec² at 45 minutes (P<.05). After the LM, the CI increased from 2.15±0.15 to 2.84±0.27 L/min/m² and the TPRi decreased from 3630±274 L/min/m² to 2666±282 dynes/sec² at 45 minutes (P<.05). After the PM, no systemic hemodynamic changes were observed. When all 3 meals were compared, the highest values of CI and the lowest values of TPRi were observed for the LM and CM. The authors' results show that fat- and carbohydrate-rich foods cause changes in the systemic hemodynamic of the elderly hypertensive patients.     

Recombinant factor VIIa in continuous infusion during central line insertion in a child with factor VIII high-titre inhibitor

Recombinant factor VIIa (rFVIIa) is a recently added new tool for the treatment of haemophilia patients with inhibitors. A major drawback in the use of rFVIIa is its short half-life, which necessitates frequent bolus injections. Thus the use of rFVIIa in continuous infusion appears to be a good alternative. We describe the use of rFVIIa, administered by continuous infusion with a minipump during the insertion of a central venous catheter in a child with a high-titre factor VIII inhibitor. rFVIIa was administered as an intravenous bolus (90 μg kg⁻¹ [4.5 kIU kg⁻¹]), 1 h prior to central line insertion, after which the continuous infusion was immediately started for 5 days. The infusion rate was based on the clearance obtained from a previous pharmacokinetic study. Effective haemostasis and normal healing of surgical incisions were achieved after central line insertion. No local thrombophlebitis nor evidence of generalized activation of the coagulation cascade was observed. Single-dose pharmacokinetic parameter values were clearance (Cl) 34.6 mL h⁻¹ kg⁻¹, volume of distribution (Vd) 40.6 mL kg⁻¹ and mean residence time (MRT) 1.17 h. The recovery was 2.27% U⁻¹ kg⁻¹. rFVIIa showed a monophasic decay. Cl during continuous infusion was 23.4 ± 6.9 mL h⁻¹ kg⁻¹. The administration of rFVIIa by continuous infusion is effective, safe and more convenient when compared to other clotting factors. Moreover, continuous infusion provides significant economic savings (77% decrease in rFVIIa requirements).     

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision

Background  The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma.
Objective  To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour.
Subjects and methods  FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data.
Results  Si was lower in insulinoma patients before, compared with after surgery (3·37 ± 0·62 vs. 6·24 ± 1·09 SE [×10⁻⁴] min⁻¹µU⁻¹ ml, P  < 0·05). Sg was similar in patients pre- and post-surgery (3·0 ± 0·67 vs. 2·4 ± 0·6 [×10⁻²] min⁻¹, NS).
Conclusions  Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.     

Prognostic relevance of TLX3 (HOX11L2) expression in childhood T-cell acute lymphoblastic leukaemia treated with Berlin–Frankfurt–Münster (BFM) protocols containing early and late re-intensification elements

TLX3 expression ( TLX3+ ) in childhood T-cell acute lymphoblastic leukaemia (T-ALL) seems to be associated with a poor prognosis when treated with regimens that lack early and/or late re-intensification therapy elements. Because such elements are essential components of the ALL-BFM (Berlin–Frankfurt–Münster) protocols, we evaluated whether TLX3+ T-ALL patients benefit from this type of therapy. Thirty-one/131 childhood T-ALL cases (24%) enrolled into four population-based Austrian ALL-BFM therapy studies were TLX3+. The male to female ratio was 3·5:1 and median age and leucocyte count at diagnosis were 8·7 years and 58·9 × 10⁹/l, respectively. Twenty-four patients (77%) were good responders to prednisone. All were in complete remission after induction therapy. After a median observation time of 4·9 years (range 0·4–16·1 years) 28/31 TLX3 + cases remained in first complete remission after chemotherapy with one after additional stem cell transplantation. Although molecular disease was frequently present after a 4-drug induction therapy, final treatment outcome was excellent indicating that TLX3 + T-ALL cases may benefit from a BFM-type of ALL therapy with early and late re-intensification elements. Moreover, the fact that 2/3 relapses were also NUP214-ABL1 + suggests that these cases might represent the particular risk-prone TLX3 + subgroup that could benefit from a targeted tyrosine kinase inhibitor therapy.     

A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity

We studied the pharmacokinetics and toxicity of 220 mg/m² melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m², total body clearance 313 ml/min/m², elimination half-life 46 min) were the same as those of 140 or 200 mg/m² melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia <25 × 10⁹/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.     

Impact of Baseline Renal Function on Outcomes of Renal Artery Stenting in Hypertensive Patients

Renal artery stenting may improve blood pressure (BP) and renal function in resistant hypertension patients; however, benefit may differ depending on the degree of renal dysfunction. The authors analyzed 67 consecutive patients receiving stenting for obstructive renal artery disease between 2002 and 2005. Patients were categorized as normal or mildly impaired according to estimated glomerular filtration rate (eGFR) (≥60 mL/min/1.73 m²), moderately impaired (eGFR 30 to 59 mL/min/1.73 m²), and severely impaired (eGFR <30 mL/min/1.73 m²). In patients with eGFR ≥60, systolic BP did not significantly improve from baseline. However, in patients with an eGFR between 30 and 59 mL/min/1.73 m², systolic BP decreased by 12 mm Hg at 6 months (P=.02) and 14 mm Hg at 12 months (P=.01). Greater benefit was observed in patients with eGFR <30 mL/min/1.73 m², with a 16 mm Hg (P=.10) and 21 mm Hg (P=.02) decrease at 6 and 12 months, respectively. Renal function was stable across all groups. Renal artery stenting reduced BP and produced greatest benefit in patients with baseline impaired renal function.     

Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders – medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1–18 years were enrolled in the Israel National Studies (INS) 89 ( n  = 84) and INS 98 ( n  = 59) trials, based on ALL-Berlin–Frankfurt–Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 ( n  = 60) was 70 ± 5·9% and the INS 98 ( n  = 43), 83·7 ± 5·6% ( P  = 0·12); the cumulative incidence (CI) of any CNS relapse was 5·0 ± 2·8% and 2·3 ± 2·3% ( P  = 0·50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) ≥100 × 10⁹/l treated with extended TIT ( n  = 17) or pCRT ( n  = 10). For all T-ALL patients, 5-year EFS was 61·9 ± 5·3% in INS 89 and 72·9 ± 5·8% in INS 98, ( P  = 0·21); the CI of any CNS relapse was 7·1 ± 2·8% and 1·7 ± 1·7% ( P  = 0·142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.     

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome

Background  Prader–Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited.
Objective  To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls.
Design/patients  Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group ( n  = 15) receiving 1 mg/m²/day GH or a non-GH-treated control group ( n  = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated.
Results  Infants in the GH group had a median age of 2·3 years [interquartile range (IQR) 1·7–3·0] and in the control group of 1·5 years (IQR 1·2–2·7) ( P =  0·17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9·3% (–5·3 to 13·3) vs. –2·9% (–8·1 to 4·9) ( P  < 0·05) in mental development and +11·2% (–4·9 to 22·5) vs. –18·5% (–27·9 to 1·8) ( P  < 0·05) in motor development, respectively.
Conclusion  One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.     

The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma

Relapsed/refractory myeloma has a poor outcome because of multi-drug resistance, patient low-performance status and toxicity of conventional chemotherapy. To improve results, standard chemotherapeutics and drugs targeting the microenvironment are applied at the same time. Bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to other drugs and overcome drug-resistance. Notably, doxorubicin and bortezomib may reciprocally increase their efficacy. Thus, to improve outcome whilst minimizing therapy-related toxicity, liposomal doxorubicin was added to a bortezomib-based combination. From January 2004, relapsed/refractory myeloma patients referred to our Institution received bortezomib 1·0 mg/m² i.v. twice weekly for 2 weeks in a 28-d cycle for up to six cycles, oral dexamethasone 24 mg with the standard scheduling and thalidomide 100 mg continuously (VTD). From January 2005, liposomal doxorubicin, 50 mg/m² (30 mg/m² for patients older than 75 years), was added on day 4 of each cycle [VTD plus Myocet (MyVTD)]. In total, 70 patients were treated: 28 received VTD and 42 MyVTD. Baseline demographic and clinical characteristics were similar between the two groups. Toxicity was manageable although more pronounced with MyVTD. The overall response rate (81% vs. 50%, P  = 0·009), time to progression (19 vs. 11 months, P  = 0·01) and progression-free survival (15 vs. 8 months, P  = 0·001) were significantly higher with MyVTD regimen, suggesting an improved quality of response.     

TISSUE CHARACTERIZATION TO DIFFERENTIATE PATHOLOGICAL FROM PHYSIOLOGICAL HYPERTROPHY IN PATIENTS WITH HYPERTENSION AND ATHLETES

Precedents: In pathological left ventricular (LV) hypertrophy (H) of hypertensive patients (P) there is a deposition of collagen. Myocardial fibrosis is one of the factors responsible for systolic and diastolic dysfunction. Athletes increase their ventricular mass as physiological ventricular H. Integrated backscatter (IB) demonstrates changes in myocardial acoustic properties, depending upon their composition and function.
Objectives: (1).Assess the capability of IB to differentiate physiological from pathological H. (2).Correlate IB with overall and regional systolic and diastolic functions.
Methods: Group I(GI):13 hypertensive P with an LV mass index (LVMI)>124 gr/m², Group II(G2):11 athletes, Group III(G3): 8 volunteers. We determined overall systolic and diastolic functions and regional function of the basal septum, IB and cyclic variation of the IB (CVIB) of the posterior wall.
Results: Age (years): G1:52 ± 15, G2:28 ± 8 G3:35 ± 8 p = 0.000; Sex: G1:m/f 12/1, G2: m/f 9/2, G3: m/f 4/4, LVMI: G1: 180.1 ± 58 gr/m², G2:130.2 ± 20 gr/m² G3: 90.2 ± 16 gr/m² p = 0.000. Left atrial area (LAA): G1: 22 ± 4 cm², G2: 18.8 ± 1.8 cm², G3: 15.8 cm² p = 0.001, mid-wall shortening fraction (MWSF): G1:26.9 ± 3.5, G2:27.5 ± 4 G3:25 ± 3 p = NS; CVIB: G1:5,3 ± 2,5 G2:7.6 ± 2,1 G3:6.4 ± 1.1 P = 0.048.Correlation of IB and MWSF, p = NS; IB and MWSF p = NS, IB and CVIB:-0.56 p = 0.005.  

  TABLE     

15.

The Effect of Cimetidine on Gastrin Release in Ulcer Disease     

M. G. Korman  J. Hansky †  J. Waugh ‡ 《Internal medicine journal》1979,9(4):367-369

Summary: The effect of cirnetidine on gastrin release in ulcer disease. M. G. Korman. J. Hansky and J. Waugh, Aust. N.Z. J. Med., 1979, 9, pp. 367–369.
The effect of a single dose of 400 mg of the H₂-receptor antagonist cimetidine on protein meal stimulated immunoreactive gastrin was assessed in ten patients with gastric ulcer and ten patients with duodenal ulcer. In gastric ulcer patients, serum gastrin (mean±SE) rose from 34±2·2 pmol∖l^-1 to a peak of 80±5·0 pmol∖l^-1 at 45 minutes without and from 36±2·2 to 107±8·0 pmol∖l^-1 at 60 minutes with cimetidine; in duodenal ulcer it rose from 26±3·0 to 47±5·1 pmol∖l^-1 at 45 minutes without and 26±3·2 to 52±5·1 pmol∖l^-1 at 60 minutes with cimetidine. Integrated gastrin responses in gastric ulcer were 4900±800 pmol∖l^-1 720 minutes without and 7000±900 pmol∖l^-1 720 minutes with cimetidine and 1560±300 pmol∖l^-1 720 minutes without and 2620±400 pmol∖l^-1 720 minutes with cimetidine in duodenal ulcer patients. These gastrin increases after cimetidine are comparable to those achieved with continuous intragastric neutralisation with alkali.     

16.

IVE (ifosfamide, epirubicin and etoposide) is a more effective stem cell mobilisation regimen than ICE (ifosphamide, carboplatin and etoposide) in the context of salvage therapy for lymphoma     

Fox CP  McMillan AK  Bishton MJ  Haynes AP  Russell NH 《British journal of haematology》2008,141(2):244-248

Two commonly used chemotherapy regimens for lymphoma salvage therapy were compared: ICE (ifosphamide, carboplatin and etoposide) ± rituximab and IVE (ifosfamide, epirubicin and etoposide) ± rituximab, for their efficacy in mobilising peripheral blood stem cells for autologous transplantation. Significant differences were observed between the cohorts in terms of number of patients mobilising the stipulated minimum >2 × 10⁶ CD34⁺/kg (99·2% in IVE group versus 83% in ICE group: P  =   0·0002) and also in terms of the number of patients achieving the predetermined target of >5 × 10⁶ CD34⁺/kg, both in total and during the first apheresis procedure (72% in IVE versus 51% in ICE group and 49% in IVE versus 7% in ICE group: P  =   0·02 and P  <   0·0001 respectively). This analysis of two similar groups of patients treated within a single-centre appears to demonstrate that the IVE regimen is a more effective stem cell mobilisation regimen than ICE in the context of salvage therapy for Hodgkin and non-Hodgkin lymphoma, allowing more patients to achieve the target CD34⁺ cell collection and proceed to high-dose therapy and autologous stem cell transplantation.     

17.

A pilot study of low-dose recombinant human granulocyte-macrophage colony-stimulating factor in chronic neutropenia     

R. S. Kaczmarski    A. Pozniak  A. Lakhani  †  E. Harvey  ‡ G. J. Mufti 《British journal of haematology》1993,84(2):338-340

Summary. Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) is under investigation for the treatment of a wide range of haematological disorders. At commonly used doses of > 120 μg/m²/d, extramedullary toxicity is common. We report the effects of low-dose (LD) rhGM-CSF in patients with chronic neutropenia related to HIV infection, myelodysplastic syndrome and idiopathic neutropenia. Nine patients with a mean pre-treatment neutrophil count of 0·6 × 10⁹/1 (range 0·2–1·4 × 10⁹/1) received daily rhGM-CSF at doses of between 5 and 15 μg/m², Eight patients responded with a mean post-treatment ANC of 3·2 × 10⁹/1 (range 1·9–4·6 × 10⁹/1). There was no significant therapy-related morbidity. We conclude that in chronic neutropenia, LD rhGM-CSF is an acceptable treatment which has important cost/benefit implications.     

18.

Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome     

Cho LW  Kilpatrick ES  Keevil BG  Coady AM  Atkin SL 《Clinical endocrinology》2009,70(2):233-237

Context  Mean insulin resistance (IR) is greater and it is also more variable in overweight women with polycystic ovarian syndrome (PCOS) compared to weight matched controls. Whilst treatment will reduce the mean IR, it is not known if the IR variability is also reduced.
Objective  To compare the change in IR and its variability before and after treatment with insulin sensitization through metformin and pioglitazone, compared to that induced by weight loss with orlistat.
Design  Randomized, open labelled parallel study.
Setting  Endocrinology outpatient clinic at a referral centre.
Patients  Thirty obese PCOS patients [BMI 36·0 ± 1·2 kg/m² (mean ± SEM)] participated in the study.
Intervention  The change in biological variability (BV) was assessed by measuring IR (homeostasis model assessment method) at 4-day intervals on 10 consecutive occasions before and 12 weeks after randomization to metformin, pioglitazone or orlistat.
Outcome measured  The primary end point of the study was a change in BV of IR.
Results  Treatment with pioglitazone, orlistat and metformin reduced the overall IR by 41·0 ± 4·1%, 19·7 ± 6·4% and 16·1 ± 6·8% ( P =  0·005, P  = 0·013, P  = 0·17, respectively) and IR variability by 28·5 ± 18·0%, 41·8 ± 11·6% and 23·7 ± 17·0 ( P =  0·20, P  = 0·015 and P  = 0·28, respectively). Free androgen index reduced significantly with all treatments.
Conclusion  Only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12-week period of the study.     

19.

Pathogen reduction technology (Mirasol^®) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS     

K. Janetzko  K. Hinz  S. Marschner  R. Goodrich  & H. Klüter 《Vox sanguinis》2009,97(3):234-239

Background and Objectives  Mirasol^® pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS).
Materials and Methods  Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP.
Results  On day 5, PRT units showed a significantly lower pH (7·087 ± 0·105 vs. 7·288 ± 0·200) accompanied by a higher lactate production (0·104 ± 0014 vs. 0·063 ± 0·017 mmol/10¹²/h) and glucose consumption rate (0·039 ± 0005 vs. 0·028 ± 0·009 mmol/10¹² platelets/h). CD62p expression was higher in treated units (44·5 ± 13·0 vs. 16·5 ± 7·6%).
Conclusion  In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible.     

20.

Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia     

Franco Locatelli  Anna M. Testi  Maria Ester Bernardo  Carmelo Rizzari  Alice Bertaina  Pietro Merli  rea Pession  Eugenia Giraldi  Rosanna Parasole  Walter Barberi  Marco Zecca 《British journal of haematology》2009,147(3):371-378

The safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblastic leukaemia (ALL). The study enrolled 25 paediatric patients (median age 12·5 years) with either refractory ( n  = 17; 68%) or multiple relapsed ( n  = 8; 32%) ALL to receive clofarabine 40 mg/m², cyclophosphamide 400 mg/m² and etoposide 150 mg/m², daily for 5 consecutive days. No patient died from treatment-related complications. The most common adverse events were febrile neutropenia, mucositis and reversible liver toxicity; no case of liver veno-occlusive disease was reported. The overall remission rate was 56%: 13 patients (52%) achieved complete remission (CR) and one (4%) CR without platelet recovery (CRp). In seven of the 13 (54%) patients achieving CR, remissions were of sufficient duration to allow patients to receive allogeneic haematopoietic stem cell transplantation. The probability of CR/CRp was greater in the 17 patients with B cell precursor ALL than in the eight with T-ALL (76% vs. 12%, respectively, P  <   0·01). The 18-month overall survival probability was 39% and 0% in patients who did or did not respond to the treatment, respectively ( P  <   0·01). These data suggest that the clofarabine/cyclophosphamide/etoposide regimen is well tolerated and can induce clinical response in a relevant proportion of children with refractory/multiple relapsed ALL.     

The Effect of Cimetidine on Gastrin Release in Ulcer Disease

Summary: The effect of cirnetidine on gastrin release in ulcer disease. M. G. Korman. J. Hansky and J. Waugh, Aust. N.Z. J. Med., 1979, 9, pp. 367–369.
The effect of a single dose of 400 mg of the H₂-receptor antagonist cimetidine on protein meal stimulated immunoreactive gastrin was assessed in ten patients with gastric ulcer and ten patients with duodenal ulcer. In gastric ulcer patients, serum gastrin (mean±SE) rose from 34±2·2 pmol∖l^-1 to a peak of 80±5·0 pmol∖l^-1 at 45 minutes without and from 36±2·2 to 107±8·0 pmol∖l^-1 at 60 minutes with cimetidine; in duodenal ulcer it rose from 26±3·0 to 47±5·1 pmol∖l^-1 at 45 minutes without and 26±3·2 to 52±5·1 pmol∖l^-1 at 60 minutes with cimetidine. Integrated gastrin responses in gastric ulcer were 4900±800 pmol∖l^-1 720 minutes without and 7000±900 pmol∖l^-1 720 minutes with cimetidine and 1560±300 pmol∖l^-1 720 minutes without and 2620±400 pmol∖l^-1 720 minutes with cimetidine in duodenal ulcer patients. These gastrin increases after cimetidine are comparable to those achieved with continuous intragastric neutralisation with alkali.     

IVE (ifosfamide, epirubicin and etoposide) is a more effective stem cell mobilisation regimen than ICE (ifosphamide, carboplatin and etoposide) in the context of salvage therapy for lymphoma

Two commonly used chemotherapy regimens for lymphoma salvage therapy were compared: ICE (ifosphamide, carboplatin and etoposide) ± rituximab and IVE (ifosfamide, epirubicin and etoposide) ± rituximab, for their efficacy in mobilising peripheral blood stem cells for autologous transplantation. Significant differences were observed between the cohorts in terms of number of patients mobilising the stipulated minimum >2 × 10⁶ CD34⁺/kg (99·2% in IVE group versus 83% in ICE group: P  =   0·0002) and also in terms of the number of patients achieving the predetermined target of >5 × 10⁶ CD34⁺/kg, both in total and during the first apheresis procedure (72% in IVE versus 51% in ICE group and 49% in IVE versus 7% in ICE group: P  =   0·02 and P  <   0·0001 respectively). This analysis of two similar groups of patients treated within a single-centre appears to demonstrate that the IVE regimen is a more effective stem cell mobilisation regimen than ICE in the context of salvage therapy for Hodgkin and non-Hodgkin lymphoma, allowing more patients to achieve the target CD34⁺ cell collection and proceed to high-dose therapy and autologous stem cell transplantation.     

A pilot study of low-dose recombinant human granulocyte-macrophage colony-stimulating factor in chronic neutropenia

Summary. Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) is under investigation for the treatment of a wide range of haematological disorders. At commonly used doses of > 120 μg/m²/d, extramedullary toxicity is common. We report the effects of low-dose (LD) rhGM-CSF in patients with chronic neutropenia related to HIV infection, myelodysplastic syndrome and idiopathic neutropenia. Nine patients with a mean pre-treatment neutrophil count of 0·6 × 10⁹/1 (range 0·2–1·4 × 10⁹/1) received daily rhGM-CSF at doses of between 5 and 15 μg/m², Eight patients responded with a mean post-treatment ANC of 3·2 × 10⁹/1 (range 1·9–4·6 × 10⁹/1). There was no significant therapy-related morbidity. We conclude that in chronic neutropenia, LD rhGM-CSF is an acceptable treatment which has important cost/benefit implications.     

Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome

Context  Mean insulin resistance (IR) is greater and it is also more variable in overweight women with polycystic ovarian syndrome (PCOS) compared to weight matched controls. Whilst treatment will reduce the mean IR, it is not known if the IR variability is also reduced.
Objective  To compare the change in IR and its variability before and after treatment with insulin sensitization through metformin and pioglitazone, compared to that induced by weight loss with orlistat.
Design  Randomized, open labelled parallel study.
Setting  Endocrinology outpatient clinic at a referral centre.
Patients  Thirty obese PCOS patients [BMI 36·0 ± 1·2 kg/m² (mean ± SEM)] participated in the study.
Intervention  The change in biological variability (BV) was assessed by measuring IR (homeostasis model assessment method) at 4-day intervals on 10 consecutive occasions before and 12 weeks after randomization to metformin, pioglitazone or orlistat.
Outcome measured  The primary end point of the study was a change in BV of IR.
Results  Treatment with pioglitazone, orlistat and metformin reduced the overall IR by 41·0 ± 4·1%, 19·7 ± 6·4% and 16·1 ± 6·8% ( P =  0·005, P  = 0·013, P  = 0·17, respectively) and IR variability by 28·5 ± 18·0%, 41·8 ± 11·6% and 23·7 ± 17·0 ( P =  0·20, P  = 0·015 and P  = 0·28, respectively). Free androgen index reduced significantly with all treatments.
Conclusion  Only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12-week period of the study.     

Pathogen reduction technology (Mirasol®) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS

Background and Objectives  Mirasol^® pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS).
Materials and Methods  Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP.
Results  On day 5, PRT units showed a significantly lower pH (7·087 ± 0·105 vs. 7·288 ± 0·200) accompanied by a higher lactate production (0·104 ± 0014 vs. 0·063 ± 0·017 mmol/10¹²/h) and glucose consumption rate (0·039 ± 0005 vs. 0·028 ± 0·009 mmol/10¹² platelets/h). CD62p expression was higher in treated units (44·5 ± 13·0 vs. 16·5 ± 7·6%).
Conclusion  In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible.     

Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia

The safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblastic leukaemia (ALL). The study enrolled 25 paediatric patients (median age 12·5 years) with either refractory ( n  = 17; 68%) or multiple relapsed ( n  = 8; 32%) ALL to receive clofarabine 40 mg/m², cyclophosphamide 400 mg/m² and etoposide 150 mg/m², daily for 5 consecutive days. No patient died from treatment-related complications. The most common adverse events were febrile neutropenia, mucositis and reversible liver toxicity; no case of liver veno-occlusive disease was reported. The overall remission rate was 56%: 13 patients (52%) achieved complete remission (CR) and one (4%) CR without platelet recovery (CRp). In seven of the 13 (54%) patients achieving CR, remissions were of sufficient duration to allow patients to receive allogeneic haematopoietic stem cell transplantation. The probability of CR/CRp was greater in the 17 patients with B cell precursor ALL than in the eight with T-ALL (76% vs. 12%, respectively, P  <   0·01). The 18-month overall survival probability was 39% and 0% in patients who did or did not respond to the treatment, respectively ( P  <   0·01). These data suggest that the clofarabine/cyclophosphamide/etoposide regimen is well tolerated and can induce clinical response in a relevant proportion of children with refractory/multiple relapsed ALL.