Reduced physical work capacity at high altitude—a role for left ventricular dysfunction

Physical work capacity is reduced in sea level residents—lowlanders (LL) as compared to high altitude residents—highlanders (HL). To determine possible etiologies, cardiac performance was studied in two groups of healthy male volunteers (13 LL and 11 HL) utilizing systolic time intervals during rest, submaximal and maximal exercise. The LL were studied at sea level and subsequently during 10 days of residence at an altitude of 3658 m. The HL were studied at high altitude alone. The LL were restudied 30–45 min after administration of intravenous furosemide at high altitude. Mean maximal oxygen uptake ( ) was reduced by 26% in the LL group at high altitude in comparison to sea level values and by 20% in relation to the HL group. Cardiac performance was estimated by the pre-ejection period/left ventricular ejection time ratio. This index was significantly increased in the LL group at high altitude in comparison to sea level values during submaximal and maximal exercise (P < 0.01). Intravenous furosemide in the LL group increased the heart rate (P < 0.05) at rest and during exercise but and cardiac performance were unchanged.It is hypothesized that reduced physical work capacity at high altitude in the LL group may be related to depression of cardiac performance in these subjects. Administration of intravenous furosemide did not influence cardiac performance in the LL group at high altitude.     

Therapy‐related acute myeloid leukaemia and myelodysplastic syndrome in Victoria,Australia 2003–2014

Background

The burden of therapy‐related acute myeloid leukaemia (tAML)/therapy‐related myelodysplastic syndrome (tMDS) in Australia has not been characterised.

Aims

To provide insights into the incidence, associated cancers, latency and survival outcomes of patients with tAML/tMDS in Victoria, Australia, based on a state‐wide cancer registry and to assess if these features are different in tAML/tMDS compared with de novo AML/MDS.

Methods

We analysed adults aged ≥20 years at diagnosis of AML/MDS reported to the Victorian Cancer Registry (VCR) between 2003 and 2014.

Results

In total, 73 of 3120 (2.3%) AML cases were classified tAML. tAML patients were younger than non‐tAML patients at diagnosis (median age 66 vs 71 years, P = 0.000). Median overall survival was similar (6 months). Median latency to tAML was 82 months, with two incidence peaks at 1–4 and 7–8 years. In total, 59 of 73 patients had recorded cancers, the most frequent being non‐Hodgkin lymphoma (NHL, 32.2%) and breast cancer (16.9%). In total, 532 of 3120 (14.1%) additional AML cases had ≥1 prior cancer (confirmation of chemoradiotherapy unavailable). tAML incidence increased (0.0/100 000 persons in 2003, 0.5/100 000 persons in 2014), as did the incidence of non‐tAML with previous cancer (0.8/100 000 persons in 2003, 1.1/100 000 persons in 2014). In total, 101 of 4435 (2.3%) MDS cases were classified tMDS. Although tMDS incidence fluctuated (range 0–0.4/100 000 persons/year), the incidence of non‐tMDS with prior cancer rose (1.4/100 000 persons in 2003, 1.9/100 000 persons in 2014). Compared to tAML, the tMDS cohort was older (median age 70 vs 66 years, P = 0.007). Median latency to tMDS was 42.5 months. NHL was also the most common cancer preceding tMDS, but the second most common cancer was myeloma (17.8%). In total, 1287 of 5061 (20.3%) non‐tMDS patients had a prior cancer.

Conclusions

The burden of tAML/tMDS in Victoria is likely to be underestimated. Linkage between VCR and clinical registries is needed to provide more accurate insights.     

Multiple myeloma: 2014 Update on diagnosis,risk‐stratification,and management

Disease overview : Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis : The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. If end‐organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. Risk stratification : In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk. Risk‐adapted intial therapy : Standard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy : After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease : Patients with indolent relapse can be treated first with 2‐drug or 3‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 89:998–1009, 2014. © 2014 Wiley Periodicals, Inc.     

Cutaneous T‐cell lymphoma: 2014 Update on diagnosis,risk‐stratification,and management

Disease overview : Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). Diagnosis : The diagnosis of MF or SS requires the integration of clinical and histopathologic data. Risk‐adapted therapy : TNMB (tumor, node, metastasis, and blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral or blood involvement are generally approached with biologic‐response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy (e.g., CHOP) may be employed for those patients with extensive visceral involvement requiring rapid disease control. In highly selected patients, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol. 89:837–851, 2014. © 2014 Wiley Periodicals, Inc.     

Primary myelofibrosis: 2014 update on diagnosis,risk‐stratification,and management

Disease overview : Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell‐derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Diagnosis : Diagnosis is based on bone marrow morphology. The presence of JAK2, CALR, or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are “triple‐negative.” None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. Risk Stratification : The Dynamic International Prognostic Scoring System‐plus (DIPSS‐plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10⁹/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10⁹/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, ?7/7q?, i(17q), inv(3), ?5/5q?, 12p?, or 11q23 rearrangement). The presence of 0, 1, “2 or 3,” and ≥4 adverse factors defines low, intermediate‐1, intermediate‐2, and high‐risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined by CALR^?/ASXL1⁺ mutational status. Risk‐Adapted Therapy : Observation alone is adequate for asymptomatic low/intermediate‐1 risk disease, especially with CALR⁺/ASXL1^? mutational status. Stem cell transplant is considered for DIPSS‐plus high risk disease or any risk disease with CALR^?/ASXL1⁺ mutational status. Investigational drug therapy is reasonable for symptomatic intermediate‐1 or intermediate‐2 risk disease. Splenectomy is considered for drug‐refractory splenomegaly. Involved field radiotherapy is most useful for post‐splenectomy hepatomegaly, non‐hepatosplenic EMH, PMF‐associated pulmonary hypertension, and extremity bone pain. Am. J. Hematol. 89:916–925, 2014. © 2014 Wiley Periodicals, Inc.     

Bring the old boys—and girls—Back home

• What the article teaches. Patients who are not discharged home after transcatheter aortic valve replacement have higher mortality during follow‐up
• How it will impact practice. Implementation of hospital protocols aimed at reducing rates of un‐necessary nonhome discharge is desirable.
• What new research/study would help answer the question posed. The reasons for worse outcomes after nonhome discharge should be further investigated, as well as the cause of higher likelihood of nonhome discharge in some patients' subgroups, like women.

     

Acute myeloid leukemia: 2014 Update on risk‐stratification and management

Overview: Evidence suggest that even patients aged 70 or above benefit from specific AML therapy. The fundamental decision in AML then becomes whether to recommend standard or investigational treatment. This decision must rest on the likely outcome of standard treatment. Hence we review factors that predict treatment related mortality and resistance to therapy, the latter the principal cause of failure even in patients aged 70 or above. We emphasize the limitations of prediction of resistance based only on pre‐treatment factors and stress the need to incorporate post‐treatment factors, for example indicators of minimal residual disease. We review various newer therapeutic options and considerations that underlie the decision to recommend allogeneic hematopoietic cell transplant. Am. J. Hematol. 89:1064–1081, 2014. © 2014 Wiley Periodicals, Inc.     

Dissecting Japan's Dengue Outbreak in 2014

Despite Japan''s temperate climate, a dengue outbreak occurred in Tokyo for the first time in over 70 years in 2014. We dissected this dengue outbreak based on phylogenetic analysis, travel interconnectivity, and environmental drivers for dengue epidemics. Comparing the available dengue virus 1 (DENV1) E gene sequence from this outbreak with 3,282 unique DENV1 sequences in National Center for Biotechnology Information suggested that the DENV might have been imported from China, Indonesia, Singapore, or Vietnam. With travelers arriving into Japan, Guangzhou (China) may have been the source of DENV introduction, given that Guangzhou also reported a large-scale dengue outbreak in 2014. Coinciding with the 2014 outbreak, Tokyo''s climate conditions permitted the amplification of Aedes vectors and the annual peak of vectorial capacity. Given suitable vectors and climate conditions in addition to increasing interconnectivity with endemic areas of Asia, Tokyo''s 2014 outbreak did not come as a surprise and may foretell more to come.Endemic in at least 100 countries, dengue is currently regarded as world''s most important mosquito-borne viral disease.¹ Although most of the disease burden is limited to areas with tropical and subtropical climates, evidence suggests that temperate areas may be increasingly at risk as the geographic distribution of relevant vectors expands.^2–4 Although Japan has a temperate climate, the first dengue outbreak in over 70 years occurred in 2014.^5,6 The outbreak was due to dengue virus serotype 1 (DENV-1) and occurred in Tokyo, resulting in 160 dengue cases reported between August and October 2014.^5,6 For an outbreak to occur in a previously dengue-free country, several factors must converge, such as importation of the DENV, presence of the vector, and favorable ecological and climatic conditions for the transmission of virus by vectors.As Japan is geographically close to many countries in Asia that are highly endemic for dengue, it follows that the virus responsible for the 2014 dengue outbreak was likely imported from a country with high connectivity to Japan. Viral genetic information can assist in identifying the most likely country of importation,² as can travel information.^2,7 The probability of importation events occurring depends on the dengue activity in departure countries and the volume of travelers arriving.^2,7Vectorial capacity is the vector''s ability to spread disease among humans and is dependent on vector density, mosquito-to-human biting rate, vector survival rate, and extrinsic incubation period; all of which are highly temperature-sensitive parameters.⁴ Relative vectorial capacity (rVc) has been proposed as an indicator for dengue epidemic potential.⁴ rVc for Aedes mosquitoes, the main vectors for DENVs, is thought to now have reached levels that are conducive for DENV transmission even in some temperate countries.^3,4We examined the factors that may have facilitated the dengue outbreak in Tokyo during 2014 by analyzing the available viral genetic information and data on travelers arriving in Japan from dengue-endemic Asian countries. We also calculated the rVc of Aedes mosquitoes in the months preceding the Tokyo outbreak. Finally, we assessed the seasonal rVc to explore the dengue epidemic potential in Japan.Multiple sequence alignment of the available DENV-1 E gene sequence from the 2014 dengue outbreak in Tokyo and 3,282 unique DENV-1 sequences present in National Center for Biotechnology Information was carried out using a fast Fourier transformation method in MAFFT v6.940b (Kyoto, Japan).⁸ The approximately maximum likelihood phylogenetic tree was generated using generalized time-reversible model of nucleotide evolution in FastTree v2.1.7 (Berkeley, CA).⁹ FastTree uses SH-like local supports with 1,000 resamples to estimate and validate the reliability of each split in the tree. From the tree, the branch containing the sequence from the Japan 2014 outbreak (DENV-1/JP/Hu/Saitama/NIID100/2014, GI:686207807) was selected and a more robust maximum likelihood phylogenetic tree was created using RAXML with 100 bootstrap replications.¹⁰ Trees were visualized using FigTree v1.4.2 (Edinburgh, Scotland; http://tree.bio.ed.ac.uk/software/figtree/). Results of the phylogenetic analysis suggest a strong relationship between the Japan 2014 virus and a virus that was first identified in the Singapore dengue epidemic of 2005 (also seen in 2004–2006 and 2008–2009) and then circulated for a number of years in Asia: Vietnam (2008), Indonesia (2010, 2013), and China (2005, 2013) (Figure 1 , Supplemental Table 1).Open in a separate windowFigure 1.Phylogenetic tree of 2014 dengue index case. Phylogenetic tree for similarity of the strain of dengue virus serotype 1 (DENV-1) isolated from the 2014 outbreak in Tokyo, Japan, with other reported strains; the cases are labeled according to dengue viral serotype (DENV-1), country of isolation in International Organization for Standardization two-letter code (JP), laboratory identifiers of the isolate (Hu/Saitam/NIID100), and year of isolation (2014). The index case isolates from the outbreak in Tokyo are DENV-1/JP/Hu/Saitama/NIID100/2014 (marked in red) shown with neighboring sequences including DENV-1/CN/GD-{"type":"entrez-nucleotide","attrs":{"text":"D13202","term_id":"286095","term_text":"D13202"}}D13202(Guangzhou)/2013 from China (CN) in 2013, DENV-1/RO/599/2013 imported to Romania (RO) from Indonesia (ID) in 2013, numerous strains from Singapore (SG) since 2004, and a few strains from Vietnam (VN) in 2008, among others. See also Supplemental Table 1 for GenBank Identifiers.Furthermore, we obtained the Japan National Tourism Organization''s data¹¹ on inbound travelers between January and September 2014 from dengue-endemic countries in the southeast and east Asia arriving in Japan. Taiwan, China, and Hong Kong had by far the highest travel volume to Japan, followed by Malaysia and Singapore. Figure 2 shows that May–September coincides with the highest travel volume into Japan from all dengue-endemic countries combined.Open in a separate windowFigure 2.Conditions facilitating the 2014 outbreak of dengue in Tokyo, Japan. Red line: temperature (15-day moving average, degree Celsius, 4.0–29.8°C); blue lines: rainfall (daily millimeters of precipitation, blue bars, 0–244 mm/day); purple line: relative vectorial capacity (rVc), 0–1; and pink shaded box: dengue epidemic potential from May to early October in Tokyo, based on relative vectorial capacity being above threshold. Black line: reported incoming travelers from countries reporting dengue cases in 2014 arriving in Japan (monthly total, 492,300–790,046); green line: epidemiological curve of the 2014 outbreak of Tokyo; and green shaded box: period of the dengue outbreak in Tokyo (early August to early October).Finally, we calculated the rVc for Aedes vectors to quantify the dengue epidemic potential based on temperature-dependent parameters. Our calculations followed a modified Ross–McDonald model: where a is the average daily vector biting rate, b_h the probability of vector to human transmission per bite, b_m the probability of human to vector infection per bite, n the duration of the extrinsic incubation period, and μ_m the vector mortality rate, all of which vary according to temperature.⁴ The temperature-dependent parameters for each of these variables needed to calculate rVc were derived from published experiments on Aedes aegypti according to methods described in detail previously, which included diurnal variation.^4,12,13 We used the Ross–McDonald equation using the same temperature-dependent parameters for calculating rVc as given by Liu-Helmersson and others,⁴ but with updated temperature time-series datasets: the Met Office Integrated Data Archive System dataset¹⁴ for Tokyo and Climatic Research Unit (CRU) dataset¹⁵ for the time period leading up to the 2014 outbreak in Tokyo (Figure 2). In addition, we obtained the daily precipitation and mean temperatures for Tokyo,¹⁴ which were displayed alongside calculated rVc, the incoming travel volume from countries reporting dengue in 2014,¹¹ and the epidemic curve of the 2014 dengue outbreak in Tokyo⁵ to show the temporal alignment of multiple factors (Figure 2). Figure 2 highlights the time window in 2014 that was most conducive for dengue epidemics in Tokyo. Taking into account travel volume, rVc, mean temperature, and precipitation, May–October was the most probable period for a dengue outbreak.Using gridded (0.5° latitude × 0.5° longitude) climate data for the whole country of Japan (2004–2013) from the CRU 3.22 dataset,¹⁵ we also calculated decadal average rVc for Japan, which we aggregated and mapped by season (Figure 3 ). We found that rVc varied by season and geographical location in Japan. Figure 3 shows dengue epidemic potential as measured by rVc peaked during the summer months of June–August and was highest in southern Japan, while parts of northern Japan remained below the epidemic threshold. Despite the fact that we used rVc calculations based on Ae. aegypti, our results mirror previous findings¹⁶ of Aedes albopictus'' seasonal activity and spatial extent in Japan and also correspond to the outbreak timing in 2014. A minor limitation of the rVc calculations is that the methods were originally developed based on Ae. aegypti not Ae. albopictus.⁴ As there is a lack of published data for Ae. albopictus on temperature-driven variations in the five parameters that constitute rVc, we had to rely on such data for Ae. aegypti. Although we would expect differences between the two vectors with regard to rVc, such differences are likely to be small, as a study on global temperature constraints of these two vectors points out.³Open in a separate windowFigure 3.Seasonal mapping of dengue epidemic potential in Japan, 2004–2013. Relative vectorial capacity (rVc) ≥ 0.2 (orange-red) represent above threshold outbreak potential; rVc ≤ 0.2 (blue-yellow) represent below threshold outbreak potential; winter: December–February; spring: March–May, summer: June–August, and autumn: September–November.In conclusion, the phylogenetic similarity of DENV-1 E gene isolated from the 2014 outbreak in Japan with viruses from China, Indonesia, Singapore, and Vietnam renders any of these four countries a likely source of importation. Taking into account the high travel volume into Japan, Guangzhou could well have been the source of DENV introduction that triggered Tokyo''s outbreak, given that Guangzhou had a large-scale dengue outbreak in 2014.¹⁷Our findings show that several conducive factors converged preceding and during the time of the dengue outbreak in Tokyo, from August until October 2014. Climate conditions, particularly temperature and precipitation, were favorable for the amplification of Aedes vectors. Furthermore, the ability of the vector to transmit dengue, as measured by the rVc, was highest at the time of the 2014 outbreak. A previous global study showed small increasing trends for Aedes mosquitoes'' vectorial capacity over the past century; and large increases are expected by the end of this century in temperate Northern Hemisphere regions using climate change projections.⁴ Therefore, despite Japan''s temperate climate, dengue epidemic potential not only already exists but also is likely to increase over the next decades, exacerbated by the ongoing geographic expansion of Aedes vectors within Japan.¹⁶ Under scenarios of changing climate and increasing regional travel, these findings suggest that Japan will face more dengue outbreaks in the future. Considering the difficulties in controlling endemic and epidemic dengue activity in countries such as Singapore despite the expenditure of considerable resources, Japan should continue to be proactive about preventing and immediately mitigating future outbreaks. Enhanced vector surveillance and more stringent vector control measures may be necessary to preemptively combat this threat to ensure that dengue transmission in Japan does not become commonplace. However, the most important strategy to prevent dengue in Japan would be more effectively controlling dengue in all dengue-endemic countries, facilitated by an efficacious and safe vaccine, once available.     

Hodgkin lymphoma: 2014 update on diagnosis,risk‐stratification,and management

Disease overview: Hodgkin lymphoma (HL) is an uncommon B‐cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States. Diagnosis: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte‐predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte‐rich HL are subgroups under the designation of classical HL. Risk stratification: An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Risk‐adapted therapy: Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved‐field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High‐dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. Am. J. Hematol. 89:772–779, 2014. © 2014 Wiley Periodicals, Inc.     

Clinical phenotype in heterozygote and biallelic Bernard‐Soulier syndrome—A case control study

Bernard‐Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi‐quantitative questionnaire, platelet parameters, PFA‐100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61‐platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P = 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF. Am. J. Hematol. 90:149–155, 2015. © 2014 Wiley Periodicals, Inc.     

The pattern of basal and stimulated insulin responses to intravenous glucose in first degree relatives of Type 1 (insulin-dependent) diabetic children and unrelated adults aged 5 to 50 years

Summary The pattern of insulin secretion was studied in 107 normal individuals aged 5 to 50 years. Intravenous glucose tolerance tests were performed on 64 islet-cell antibody negative siblings of diabetic children and on 43 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I — stage 1 (n=22), II — stages 2 and 3 (n=18), III — stages 4 and 5 (n=20), IV — adults >17 years (n=47). Basal and stimulated (incremental 0–10 and 10–60 min areas) insulin responses rose throughout puberty (Groups I–III), declined following puberty until the third decade (Groups III and IV) and then appeared constant thereafter. Insulin levels in the 17.6–22.5 year group were lower than in the 12.6–15 year group (p<0.01). Fasting insulin to glucose ratios and incremental 0–60 min insulin to glucose area ratios produced a similar age-related pattern indicating that changes in insulin levels were independent of glucose concentrations. Gender did not affect these changes and multiple regression analysis showed that HLA haplotype sharing did not influence insulin responses in siblings of diabetic patients. Age and pubertal status must be carefully considered when interpreting intravenous glucose tolerance tests from patients suspected of having early abnormalities of carbohydrate metabolism.     

Malaria in Zhejiang Province,China, from 2005 to 2014

To summarize the changing epidemiological characteristics of malaria in Zhejiang Province, China, we collected data on malaria from the Chinese Notifiable Disease Reporting System (NDRS) and analyzed them. A total of 2,738 malaria cases were identified in Zhejiang Province from 2005 to 2014, of which 2,018 were male and 720 were female. Notably, only 7% of malaria cases were indigenous and the other cases were all imported. The number of malaria cases increased from 2005 to 2007, peaked in 2007, and then decreased from 2007 to 2011. There were no indigenous cases from 2012 to 2014. Of all cases, 68% of cases contracted Plasmodium vivax, 27% of cases contracted P. falciparum, and two cases contracted P. malariae. About 88% of malaria cases during 2005–2011 occurred yearly between May and October, but the number of malaria cases in different months during 2012–2014 was similar. The median age was 33 years, and 1,892 cases occurred in persons aged 20–50 years. The proportion of businessmen increased and the proportion of migrant laborers decreased in recent years. The median time from illness onset to confirmation of malaria cases was 5 days and it decreased from 2005 to 2014. Some epidemiological characteristics of malaria have changed, and businessmen are the emphases to surveillance in every month.     

Inhibition of intestinal absorption and improvement of oral glucose tolerance by biguanides in the normal and in the streptozotocin-diabetic rat

Summary In the rat the assumption of a primary effect of moderate doses of biguanides on intestinal absorption is supported by the following results: 1. The tolerance to parenteral glucose administration was not improved. — 2. Afteroral pretreatment the hyperglycaemia induced byoral glucose was decreased. — 3. After pretreatmentin vivo the transport of glucose through the intestinal wall was inhibited. — 4. The intestinal glucose transport was inhibited alsoin vitro in the presence of biguanides at concentrations to be expected in intestinal tissuein vivo after efficient doses. — 5. In the streptozoocin-diabetic rat there was a strong correlation between the feeding state and the hypoglycaemie effect of biguanides. In streptozotocin-diabetic rats previously starved and then refed, the hypoglycaemie effect decreased with decreasing doses of the diabetogenic agent. — 6. The relative potency of various biguanides was similar with regard to their effects on hyperglycaemia and on the intestinal glucose transport. — The results suggest, however, that in the rat further events, probably triggered by the inhibition of intestinal absorption, are involved in the mechanism of action of biguanides.

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Hemmung der intestinalen Glucoseresorption und Verbesserung der oralen Glucosetoleranz durch Biguanide bei normalen und Streptozotocin-diabetischen Ratten

Zusammenfassung Folgende Befunde lassen darauf schließen, daß Biguanide in mäßiger Dosierung bei der Ratte primär die intestinale Absorption beeinflussen: 1. Die parenterale Glucosetoleranz wurde nicht verbessert. — 2. Nachoraler Vorbehandlung wurde die durchorale Glucosegabe induzierte Hyperglykämie vermindert. — 3. NachIn-vivo-Vorbehandlung war der Glucosetransport durch die Darmwand gehemmt. — 4. Der intestinale Glucosetransport wurde auchin vitro in Gegenwart von Biguanid-Konzentrationen gehemmt, die man im intestinalen Gewebe nach Applikation wirksamer Dosen erwarten kann. — 5. In der Streptozotocin-diabetischen Ratte bestand eine strenge Korrelation zwischen Fütterungszust and und hypoglykämischem Effekt. In wiedergefütterten Streptozotocin-Ratten nahm die hypoglykämische Wirkung mit abnehmenden Dosen des diabetogenen Agens ab. — 6. Die relative Wirkungsstärke verschiedener Biguanide bezüglich Verminderung der Hyperglykämie und Hemmung der intestinalen Glucoseaufnahme war vergleichbar. — Die erhobenen Befunde deuten jedoch darauf hin, daß in der Ratte zusätzliche Vorgänge, die möglicherweise durch die Absorptionshemmung ausgelöst werden, am Wirkungsmechanismus der Biguanide wesentlich beteiligt sind.

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Inhibition de l'absorption intestinale et amélioration de la tolérance orale au glucose avec des biguanides chez le rat normal et chez le rat rendu diabétique par le streptozotocine

Résumé Les constatations suivantes permettent la conclusion que l'application de faibles doses de biguanides influence chez le rat premièrement l'absorption intestinale: 1. Aucune amélioration de la tolérance parentérale au glucose. 2. Après un prétraitementoral l'hyperglycémie induite par l'administrationorale de glucose est diminuée. — 3. Après un prétraitementin vivo le transport de glucose par la paroi intestinale est freiné. — 4. Des concentrations de biguanides que l'on pourrait rencontrerin vivo dans le tissu intestinal (après traitement avec des dosages efficaces) provoque également une inhibition du transport de glucose dans l'intestinin vitro. — 5. Chez le rat rendu diabétique par streptozotocine il existe une forte corrélation entre l'alimentation et l'effet hypoglycémique. Chez le rat réalimenté l'effet hypoglycémique diminue après l'administration de doses décroissantes de l'agent diabétogène. — 6. La puissance relative de divers biguanides par rapport à la diminution de l'hypoglycémie et l'inhibition du transport intestinal de glucose peut être comparée. — Les résultats trouvés chez le rat font cependant allusion au fait que l'inhibition de l'absorption intestinale n'est pas la seule action des biguanides. Il semble qu'il y a encore d'autres facteurs reliés à cette inhibition.

     

Bone marrow histopathologic patterns and immunologic phenotype in B-cell chronic lymphocytic leukaemia

Summary The present work analyzes the clinicobiological and immunological characteristics — the latter hitherto unexplored — of the different bone marrow histopathological patterns of the B-cell chronic lymphocytic leukaemia (B-CLL). In addition, we studied whether any or some of these parameters were able to predict the probability of a particular pattern of bone marrow involvement appearing. Of the 100 B-CLL cases studied 41 had a diffuse pattern and 59 were non-diffuse — interstitial 27, nodular 11 and mixed 21 —. Neither clinical nor immunological differences were observed among the distinct non-diffuse patterns. The patients in the diffuse group displayed an increased incidence of µ⁺ isotype and a higher proportion of HLA-DR and HAN-PC1 positive cells while, conversely, reactivity with the FMC8 McAb was lower. In addition, patients with a diffuse pattern of BM involvement displayed features of a more extensive disease: a higher incidence of adenopathies (p<0.05), hepatomegaly (p<0.01), splenomegaly (p<0.01), anaemia (p<0.01) and thrombopenia (p<0.01) as well as higher levels of peripheral blood lymphocytosis (p<0.05) and a higher percentage of BM lymphocytic infiltration (p<0.001). Multiple regression analysis showed that thrombopenia and splenomegaly were the two most important features in predicting the probability of a diffuse pattern.     

Efficacy of Triple Therapy Plus Cetraxate for the Helicobacter pylori Eradication in Partial Gastrectomy Patients

In the present study, we aimed to establish an additional standardized protocol with a higher H. pylori eradication rate in the remnant stomach. Fifty-five H. pylori–positive patients were randomly allocated to one of three regimens: LAC—lansoprazole, amoxicillin, and clarithromycin b.i.d. for 7 days (n = 17); LAC+CET—LAC b.i.d. plus cetraxate q.i.d. for 7 days (n = 20); and LEFT—LAC for 7 days in a horizontal body position on the left side for 30 min (n = 18). Patient compliance and side effects were checked via interviews. H. pylori eradication was successful in 75, 72, and 41% in LAC+CET, LEFT, and LAC, respectively. The eradication rate was significantly higher in LAC+CET than in LAC (P = 0.024) but not in LEFT (P = 0.058). Adverse events that occurred in each group were almost all mild ones. Cetraxate plus LAC for 1 week is a safe and effective regime for the eradication of H. pylori in patients after partial gastrectomy.     

Mutations in the ABCC8 gene can cause autoantibody-negative insulin-dependent diabetes

Activating mutations in genes KCNJ11 and ABCC8, which form the ATP-sensitive K + channel (K_ATP channel), have been shown to cause transient or permanent neonatal diabetes. We describe here a rather different phenotype: two cases of adult diabetic patients—considered and treated as insulin-dependent diabetic patients since adolescence—who, in fact, turned out to be heterozygous for an ABCC8 mutation and able to successfully discontinue insulin while taking sulphonylurea treatment.     

Microstructural Evolution,Tensile Failure,Fatigue Behavior and Wear Properties of Al2O3 Reinforced Al2014 Alloy T6 Heat Treated Metal Composites

The paper focused on an experimental study on the microstructural, mechanical, and wear characteristics of 15 wt.% alumina (Al₂O₃) particulates with an average particle size of 20 µm, reinforced in Al2014 alloy matrix composite as-cast and heat-treated samples. The metal matrix composite (MMC)samples were produced via a novel two-stage stir-casting technique. The fabricated composite samples were subjected to evaluate hardness, tensile strength, fatigue behavior and wear properties for both as cast and T6 heat-treated test samples. The Al2014 alloy and Al2014-15 wt.% Al₂O₃ MMCs were in solution for 1 h at a temperature of 525 °C, quenched instantly in cold water, and then artificially aged for 10 h at a temperature of 175 °C. SEM and X-ray diffraction analyses were used to investigate the microstructure and dispersion of the reinforced Al₂O₃ particles in the composite and the base alloy Al2014. The obtained results indicated that the hardness, tensile and fatigue strength and wear resistance increased when an amount of Al₂O₃ particles was added, compared to the as-cast Al2014 alloy and it was observed that after subjecting the same composite samples to heat treatment, there was further enhancement in the mechanical and wear properties in the Al2014 matrix alloy and Al2014-15 wt.% Al₂O₃ composite samples.     

Chronic neutrophilic leukemia 2014: Update on diagnosis,molecular genetics,and management

Disease Overview : Chronic neutrophilic leukemia (CNL) is a myeloproliferative neoplasm characterized by sustained, mature neutrophilic leukocytosis, splenomegaly, and bone marrow granulocytic hyperplasia. Diagnosis : Key diagnostic criteria include leukocytosis of > 25 × 10⁹/l (of which >80% are neutrophils) with <10% and <1% circulating immature granulocytes and myeloblasts, respectively. There should be no dysplasia, monocytosis, molecular evidence of BCR‐ABL1, PDGFRA, PDGFRB, or FGRF1 rearrangements and no identifiable cause for physiologic neutrophilia or, if present, demonstration of myeloid clonality. Developments in Molecular Genetics : Recently, CNL has been shown to be specifically driven by somatic activating mutations of CSF3R, most commonly CSF3R T618I. As such, the diagnosis of CNL will no longer be one of exclusion only, and revision of the current WHO classification is anticipated to include the molecular criterion of mutated CSF3R. Am. J. Hematol. 89:651–658, 2014. © 2014 Wiley Periodicals, Inc.