Social touch during development: Long-term effects on brain and behavior.

In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and "natural experiments", such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.

International collaborative study for the calibration of proposed International Standards for thromboplastin, rabbit, plain, and for thromboplastin, recombinant, human, plain.

Essentials Two candidate International Standards for thromboplastin (coded RBT/16 and rTF/16) are proposed. International Sensitivity Index (ISI) of proposed standards was assessed in a 20-centre study. The mean ISI for RBT/16 was 1.21 with a between-centre coefficient of variation of 4.6%. The mean ISI for rTF/16 was 1.11 with a between-centre coefficient of variation of 5.7%. SUMMARY: Background The availability of International Standards for thromboplastin is essential for the calibration of routine reagents and hence the calculation of the International Normalized Ratio (INR). Stocks of the current Fourth International Standards are running low. Candidate replacement materials have been prepared. This article describes the calibration of the proposed Fifth International Standards for thromboplastin, rabbit, plain (coded RBT/16) and for thromboplastin, recombinant, human, plain (coded rTF/16). Methods An international collaborative study was carried out for the assignment of International Sensitivity Indexes (ISIs) to the candidate materials, according to the World Health Organization (WHO) guidelines for thromboplastins and plasma used to control oral anticoagulant therapy with vitamin K antagonists. Results Results were obtained from 20 laboratories. In several cases, deviations from the ISI calibration model were observed, but the average INR deviation attributabled to the model was not greater than 10%. Only valid ISI assessments were used to calculate the mean ISI for each candidate. The mean ISI for RBT/16 was 1.21 (between-laboratory coefficient of variation [CV]: 4.6%), and the mean ISI for rTF/16 was 1.11 (between-laboratory CV: 5.7%). Conclusions The between-laboratory variation of the ISI for candidate material RBT/16 was similar to that of the Fourth International Standard (RBT/05), and the between-laboratory variation of the ISI for candidate material rTF/16 was slightly higher than that of the Fourth International Standard (rTF/09). The candidate materials have been accepted by WHO as the Fifth International Standards for thromboplastin, rabbit plain, and thromboplastin, recombinant, human, plain.

Pregnancy in type 2B VWD: a case series.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

Marked elevation of thrombin generation in patients with elevated FVIII:C and venous thromboembolism.

Elevated plasma factor VIII coagulant activity (FVIII:C, > 150 IU/dl) is a risk factor for venous thromboembolism (VTE). We hypothesized that increased FVIII:C may exert a prothrombotic effect by increasing basal thrombin generation. To test this hypothesis we have measured prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex (TAT) in three groups: (i) patients with objectively confirmed VTE and elevated FVIII:C; (ii) patients with VTE and no detectable thrombophilia; and (iii) healthy age- and sex-matched control subjects. In the group of patients with elevated FVIII:C, TAT and F1 + 2 levels were increased in 85% and 78% of individuals respectively. This frequency of coagulation activation is dramatically higher than that reported for other recognized constitutional thrombophilias. In the group of patients with VTE but no proven thrombophilia, increased thrombin generation was present in 30% of individuals. Basal thrombin generation was significantly higher in patients with elevated FVIII:C compared with individuals with VTE but no documented thrombophilia (median TAT = 8.65 microg/l versus 2.95 microg/l, median F1 + 2 = 1.5 nmol/l versus 0.87 nmol/l; P < 0.0001, P < 0.001). Overall FVIII:C levels were strongly correlated with levels of thrombin generation (r= 0.5, P < 0001). The clinical significance of such markedly increased F1 + 2 and TAT levels in patients with high FVIII:C levels remains unclear.

Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.

Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light-chain (AL)-amyloidosis, in whom whole-body serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0.0012), but this was independent of the whole-body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0.00001), with proteinuria (P < 0.001) and low serum albumin (P < 0.00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2.5, range 0.81-9.25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0.96, range 0.65-1.29, n = 28, P < 0.0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL-amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag.

Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response.

Recent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to determine whether the increased FVIII:C precedes the thrombosis or represents a secondary reactive phenomenon. In an attempt to address this question, we followed 35 patients with confirmed VTED, raised FVIII:C level (>1.5 iu/ml) and no other thrombotic tendency. Serial measurements of FVIII:C, vWF:Ag, C-reactive protein and fibrinogen were performed. We hypothesized that a persistent increase in FVIII:C in the absence of any other measures of ongoing acute phase response, would support the idea that elevation of FVIII:C is a constitutional phenomenon. Of this initial group, 94% continued to have an elevated FVIII:C level throughout the period of follow up (median 8 months; range 3 to 39 months), with no significant difference between the FVIII:C levels determined at first estimation and those obtained during follow up (p = 0.58). Conversely, only 18% had evidence of an acute phase reaction when first assessed, and nonparametric ranking analysis demonstrated no correlation between FVIII:C and either C-reactive protein or fibrinogen (p = 0.315 and 0.425 respectively).We conclude that increased FVIII:C levels following VTED are persistent, independent of the acute phase reaction, and thus may represent a constitutional risk factor for VTED.

Activated protein C resistance in normal pregnancy.

This prospective cross-sectional (10 women on each occasion) and longitudinal (20 women) study investigated activated protein C (APC) ratio in normal pregnancy. The APC ratio was measured at booking, 20, 30 and 36 weeks of gestation, and compared with a sample of normal nonpregnant women. No significant difference was found between APC ratios for pregnant women at any gestation and those of the nonpregnant population in either the longitudinal or cross-sectional studies. There was a significant decrease in APC ratios throughout pregnancy, but in all but one case values remained within the normal nonpregnant range. The APC ratio can therefore be used as a screening test for the factor V Leiden mutation during pregnancy.

Identification of uroliths by infrared spectroscopy.

Wet chemical tests have deficiencies when applied to mixtures containing silica, which are common in the uroliths of some domestic animals. Consequently, the applicability of an infrared spectroscopic method was tested on 104 uroliths obtained from cattle, sheep, goats, horses, pigs, dogs, a chicken and a rabbit during diagnostic investigations. The following components were satisfactorily identified: silica, calcium oxalate, calcium carbonate, calcium phosphate, magnesium ammonium phosphate, magnesium phosphate and urates. The infrared characteristics of these compounds and their mixtures are described.