Effect of small bowel resection on the intestinal surface acid microclimate in the rat

The effect of extensive (65%) proximal and middle small bowel resection on the intestinal surface acid microclimate (ISAM) of the remaining ileum in the rat was examined and the results were compared to those of sham-operated rats. ISAM pH measurements were performed in vivo using a pH microelectrode; incubation was performed in Krebs-Ringer phosphate buffer (pH 7.40 +/- 0.02). In the resected rats, ISAM pH of 6.03 +/- 0.07 and 7.22 +/- 0.03 were recorded in the proximal and distal part of the remaining ileum, respectively. In the sham-operated rats, ISAM pH of 6.04 +/- 0.07, 6.98 +/- 0.03 and 7.28 +/- 0.02 were recorded in the proximal jejunum and in the proximal and distal part of the corresponding ileal segment. ISAM pH was significantly lower (p less than 0.01) in the proximal part of the remaining ileum of the resected rats as compared to the corresponding part in the sham-operated rats but was similar in distal ileum. In fact, the ISAM pH of the proximal part of the remaining ileum of resected rats was as acidic as that of the jejunum of the sham-operated rats. These results clearly demonstrate that adaptation in the ISAM occurs in the remaining ileum following extensive resection of proximal and middle small intestine.     

Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes

BACKGROUND & AIMS: Studies on the early steps in the life cycle of hepatitis B virus have been hampered by the lack of readily available target cells. In this study, we mapped a defined virus attachment site to primary hepatocytes that is essential for infection. METHODS: We used purified virus particles from human carrier plasma as an inoculum and primary cultures of tupaia hepatocytes as susceptible target cells and studied the inhibitory effect of amino-terminally acylated preS1-derived lipopeptides on infection interference. RESULTS: Infectivity of virus could be blocked efficiently in this system by amino-terminally acylated peptides containing amino acids 2-18 from the preS1 domain. The addition of amino acids 28-48 enhanced the inhibitory capacity, whereas amino acids 49-78 did not contribute to inhibition. Myristoylated preS1 peptides 2-48 bound strongly to tupaia hepatocytes but not to nonhepatic cells or rodent hepatocytes and thereby inhibited infection even at concentrations of 1 nmol/L completely. Particles consisting only of the small hepatitis B surface protein-the active component of current hepatitis B vaccines-did not bind at all to tupaia hepatocytes, but the addition of the preS1 domain to the particles allowed binding. CONCLUSIONS: The preS1 sequence 2-48 mediates attachment of the virus to its target cells, whereas the small surface protein seems to be involved in other steps. These findings indicate that the current subunit hepatitis B vaccines may be improved by the addition of distinct preS1 epitopes. Moreover, preS1 lipopeptides are promising candidates for specific antiviral therapy against hepatitis B infections.     

An overview of the endocrinology of skeletal muscle.

Endocrine regulation of the balance between skeletal muscle anabolism and catabolism has been investigated extensively. Factors determining whether hormones exert anabolic or catabolic influences are multifaceted and often unclear. Testosterone, growth hormone, insulin and insulin-like growth factor-I have complex anabolic effects, some of which have only recently been elucidated, and are important regulators of muscle remodeling, whereas glucocorticoids have direct catabolic effects and induce muscle protein loss. The effects of estrogen are poorly understood and warrant further study. We review recent literature and evaluate the hormones driving skeletal muscle anabolism and catabolism, which ultimately dictate the endocrinology and metabolism of skeletal muscle in humans. Understanding hormonal regulation of skeletal muscle remodeling might facilitate development of improved hormone-mediated therapies for muscle wasting conditions.     

Vagotomy and gallbladder function

The effect of vagotomy on gallbladder function was investigated in a clinical and experimental study. In the clinical study both the size of the gallbladder and its capacity to respond to cholecystokinin were evaluated radiologically before and after vagotomy. In studies in the rabbit, both the immediate effect of vagotomy on the gallbladder and the effect of varying doses of cholecystokinin on gallbladder pressure were studied before and after vagotomy. In studies in the cat the long-term effect of vagotomy was studied with respect to the histology of the gallbladder and the composition of bile.The clinical investigation showed that vagotomy was followed by a significant increase in the volume of the gallbladder and that the effect of the cholecystokinin on the gallbladder remained unchanged after vagotomy. In experiments in the rabbit it was found that cholecystokinin in a dose of 1 unit/kg body weight exerted a somewhat lesser effect on gallbladder pressure after vagotomy than before, while after vagotomy a dose, approximately four times greater, resulted in a stronger gallbladder response. Further, the experiments showed that the chemical composition of the bile seemed to be altered after vagotomy, while the gallbladder remained histologically essentially unchanged.     

Neuroendocrinology of aging in the male and female.

Many changes in the neuroendocrine axis occur with healthy normal aging in humans. Women cease ovarian follicle maturation and menstrual cycles entering the estrogen-deficient state termed menopause. Although not without risk, estrogen and progesterone replacement in postmenopausal women has been shown to ameliorate the complications of lowered estradiol concentrations, such as hot flushes and osteoporsis, while improving the risk of cardiovascular complications. Aging men have lowered serum free and total testosterone concentrations and may experience a less well defined symptom complex termed andropause. Both signs and symptoms of thyroid disease and interpretation of thyroid function tests are difficult in aging humans. Specifically, TSH secretion is diminished in aging so that suppressed serum TSH concentrations are indicative of but not specific for hyperthyroidism. Cortisol secretion is not altered in aging, although serum concentrations of DHEA-S are lower. Prolactin concentrations are increased in both men and women, with the increase being more pronounced in men. The clinical significance of this increase has not yet been determined. Finally, elderly humans are more likely to develop difficulties with fluid and electrolyte balance. Although some alterations in AVP secretion have been shown in the elderly, plasma concentrations are similar in young and elderly subjects. Other mechanisms, such as decreased glomerular filtration rate and a decreased sensitivity of the thirst mechanism in response to hypertonicity, may be important contributors to fluid and electrolyte imbalances.     

Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first‐degree relatives of Type 2 diabetes patients and control subjects

AIMS: To investigate dysregulation of the autonomic nervous system as a potential mechanism for early insulin resistance in the development of Type 2 diabetes. METHODS: Thirteen healthy individuals with first-degree relatives with Type 2 diabetes (R) were compared with 14 control subjects without family history of diabetes (C), matched for age, body mass index and sex. An oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp were performed. Analysis of heart rate variability during rest, controlled breathing, an orthostatic manoeuvre and a standardized physical stress (cold pressor test (CPT)), were used to evaluate the activity of the autonomic nervous system. RESULTS: Fasting blood glucose, HbA1c and serum insulin were similar in the R and C groups. The M-value, reflecting insulin sensitivity, did not differ significantly between the groups. Total spectral power and high-frequency power were lower in R during controlled breathing (P = 0.05 and P = 0.07, respectively), otherwise there were no significant differences between R and C in heart rate variability. However, low-frequency (LF)/high-frequency (HF) spectral power ratio during CPT, reflecting sympathetic/parasympathetic balance, was negatively associated with insulin sensitivity (r = -0.53, P = 0.006). When all subjects were divided into two groups by the mean M-value, the low M-value group displayed an overall higher LF/HF ratio (P = 0.04). HF power was lower in the low M-value group during controlled breathing and CPT (P = 0.01 and P = 0.03, respectively). CONCLUSION: An altered balance of the parasympathetic and sympathetic nervous activity, mainly explained by an attenuated parasympathetic activity, might contribute to the development of insulin resistance and Type 2 diabetes.     

Evaluation of the Paradoxical Sphincter Contraction by a Strain/Squeeze Index in Constipated Patients

PURPOSE One finding in patients with constipation is the paradoxical puborectalis contraction, i.e. , activation of the sphincter muscles during straining instead of relaxation. The aims of this study were to evaluate the importance of needle placement in sphincter-electromyography and to evaluate a strain/squeeze index in constipated patients and control subjects. METHODS We investigated consecutively 194 constipated patients and 16 control subjects with integrated electromyography during straining and squeezing and calculated a strain/squeeze index. The examination was performed in the puborectalis and in the external anal sphincter muscle through hook-electrodes. RESULTS There was a strong correlation between indices in the puborectalis muscle and in the external anal sphincter muscle (r = 0.70–0.80, P < 0.001). Forty-seven patients (24 percent) had a mean index of greater than 50 compared with none in the control group (P = 0.01). Mean overall index in patients was 24 (range, 0–306) vs. 18 (range, 0–45) in controls (P = 0.12). Patients with an index greater than 50 had impaired rectal evacuation (P < 0.001), increased threshold for urge (P < 0.05), and tended to have fewer stools (P = 0.06). CONCLUSION Quantification of paradoxical contraction in the puborectalis and external anal sphincter with a strain/squeeze index differentiates patients in whom paradoxical activity may be a cause of constipation. An index above 50 may be of pathologic significance. Correlations between activity in the puborectalis and external anal sphincter muscle were strong which suggests that investigation in one of them is sufficient. Reprints are not available.     

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia

Conditioning including total body/lymphoid irradiation is widely used to prevent graft rejection in patients with refractory severe aplastic anemia (SAA) undergoing hemopoietic cell transplantation (HCT) from alternative donors and or after graft manipulation. To reduce regimen-related toxicity we transplanted three children with refractory SAA after conditioning with radiotherapy-free regimens. Conditioning included fludarabine 175-180 mg/m2 in all patients. In addition, patient 1 (failing two previous grafts) received thiotepa 10 mg/kg and Campath-1H 60 mg/m2; patient 2 cyclophosphamide 120 mg/kg, thiotepa 15 mg/kg and OKT-3 0.1 mg/kg/day for 4 weeks; and patient 3 cyclophosphamide 120 and ATG 90 mg/kg. Stem cell source was unmanipulated marrow from the same unrelated donor as for the two previous transplantations in patient 1 and CD34+-purified peripheral blood stem cells from an HLA-matched unrelated donor and from the haploidentical mother in patients 2 and 3. Only patient 1 received graft-versus-host disease (GVHD) prophylaxis with cyclosporine A and mycophenolate mofetil. Follow-up is now 30, 51, and 15 months. None of the patients developed GVHD. All patients have normal counts with complete donor chimerism. Fludarabine-based conditioning is powerfully immunosuppressive and may be used for children with refractory SAA undergoing HCT from alternative donors even after rejection following previous HCT.     

Preservation of pulsatile luteinizing hormone release during postpartum lactational amenorrhea

To evaluate the pulsatile mode of immunoactive LH release during physiological lactational amenorrhea, we withdrew blood samples at 10-min intervals for 24 h from breastfeeding women (n = 9) at both 3 weeks and 3 months postpartum. Nonlactating women (n = 7) were sampled similarly in the early follicular phase of the normal menstrual cycle. Objective LH pulse analysis revealed that the mean frequencies of pulsatile LH release were similar at both times postpartum and in menstruating young women. By 3 months postpartum, mean serum PRL concentrations had declined 50%, and serum LH peak areas doubled. In contrast, LH interpulse interval, peak duration, and maximal, incremental, and fractional LH pulse amplitude did not change significantly. When deconvolution analysis was used to assess pituitary responses to two pulses of exogenous GnRH at 3 months (vs. 3 weeks) postpartum, we found significant increases in maximal LH secretory rates and the total mass of LH secreted. There was no change in the duration or timing of the evoked LH secretory burst and/or the estimated half-life of endogenous LH. In summary, during lactational amenorrhea, pulsatile LH release occurs at a mean frequency no different from that in the normal early follicular phase. As hyperprolactinemia wanes, there is increased pituitary responsiveness to exogenously administered GnRH and a doubling of spontaneous serum LH concentration peak areas. Such amplitude changes are consistent with the hypothesis of increased endogenous GnRH drive (e.g. augmented GnRH secretion per burst and/or increased pituitary responsiveness to available GnRH) during recovery of the postpartum hypothalamopituitary-ovarian axis.