Changes in preoperative endoscopic and percutaneous bile drainage in patients with periampullary cancer undergoing pancreaticoduodenectomy in Ontario: effect on clinical practice of a randomized trial.

Background: In 2010, a multicentre randomized controlled trial reported increased postoperative complications in pancreaticoduodenectomy (pde) patients undergoing preoperative biliary decompression (pbd). We evaluated the effect of that publication on rates of pbd at the population level. Methods: This retrospective observational cohort study identified patients undergoing pde for malignancy, 2005-2013, linking them with administrative health care databases covering medical services for a population of 13.5 million. Patients undergoing pbd within 6 weeks before their surgery were identified using physician billing codes and were divided into those undergoing pde before and after article publication, with a 6-month washout period. Chi-square tests were used to compare rates of pbd. Results: Of 1997 pde patients identified, 963 underwent surgery before article publication, and 911, after (123 during the washout period). The rate of pbd was 47.5% before publication, and 41.6% after (p = 0.01). The lowest pbd rates occurred immediately after publication, in 2010 and 2011. Similar results were observed when the cohort was restricted to patients seen preoperatively by a gastroenterologist (n = 1412). Conclusions: Rates of pbd have declined a small, but significant, amount after randomized trial publication. Persistence of pbd might relate to suboptimal knowledge translation, the role of pbd in diagnosis of periampullary malignancy, and treatment of complications (cholangitis, severe hyperbilirubinemia) or anticipation of delay from diagnosis to surgery. The nadir in pbd rates after article publication and the subsequent rise suggest an element of transience in the effect of article publication on clinical practice. Further investigation into the reasons for persistent pbd is needed.

Predictors of adjuvant treatment for pancreatic adenocarcinoma at the population level.

BACKGROUND: In the present study, we aimed to describe, at the population level, patterns of adjuvant treatment use after curative-intent resection for pancreatic adenocarcinoma (pcc) and to identify independent predictors of adjuvant treatment use. METHODS: In this observational cohort study, patients undergoing pcc resection in the province of Ontario (population 13 million) during 2005-2010 were identified using the provincial cancer registry and were linked to administrative databases that include all treatments received and outcomes experienced in the province. Patients were defined as having received chemotherapy (ctx), chemoradiation (crt), or observation (obs). Clinicopathologic factors associated with the use of ctx, crt, or obs were identified by chi-square test. Logistic regression analyses were used to identify independent predictors of adjuvant treatment versus obs, and ctx versus crt. RESULTS: Of the 397 patients included, 75.3% received adjuvant treatment (27.2% crt, 48.1% ctx) and 24.7% received obs. Within a single-payer health care system with universal coverage of costs for ctx and crt, substantial variation by geographic region was observed. Although the likelihood of receiving adjuvant treatment increased from 2005 to 2010 (p = 0.002), multivariate analysis revealed widespread variation between the treating hospitals (p = 0.001), and even between high-volume hepatopancreatobiliary hospitals (p = 0.0006). Younger age, positive lymph nodes, and positive surgical resection margins predicted an increased likelihood of receiving adjuvant treatment. Among patients receiving adjuvant treatment, positive margins and a low comorbidity burden were associated with crt compared with ctx. CONCLUSIONS: Interinstitutional medical practice variation contributes significantly to differential patterns in the rate of adjuvant treatment for pcc. Whether such variation is warranted or unwarranted requires further investigation.

Negative predictive value of preoperative computed tomography in determining pathologic local invasion, nodal disease, and abdominal metastases in gastric cancer.

BACKGROUND: Before undergoing curative-intent resection of gastric adenocarcinoma (ga), most patients undergo abdominal computed tomography (ct) imaging to determine contraindications to resection (local invasion, distant metastases). However, the ability to detect contraindications is variable, and the literature is limited to single-institution studies. We sought to assess, on a population level, the clinical relevance of preoperative ct in evaluating the resectability of ga tumours in patients undergoing surgery. METHODS: In a provincial cancer registry, 2414 patients with ga diagnosed during 2005-2008 at 116 institutions were identified, and a primary chart review of radiology, operative, and pathology reports was performed for all patients. Preoperative abdominal ct reports were compared with intraoperative findings and final pathology reports (reference standard) to determine the negative predictive value (npv) of ct in assessing local invasion, nodal involvement, and intra-abdominal metastases. RESULTS: Among patients undergoing gastrectomy, the npv of ct imaging in detecting local invasion was 86.9% (n = 536). For nodal metastasis, the npv of ct was 43.3% (n = 450). Among patients undergoing surgical exploration, the npv of ct for intra-abdominal metastases was 52.3% (n = 407). CONCLUSIONS: Preoperative abdominal ct imaging reported as negative is most accurate in determining local invasion and least accurate in nodal assessment. The poor npv of ct should be taken into account when selecting patients for staging laparoscopy.

The "ART" of thromboembolism: a review of assisted reproductive technology and thromboembolic complications.

Since its development over 25 years ago, the use of assisted reproductive technology (ART) is on the increase. Along with its use, are also reports of thromboembolic complications (TEC); these events could resulted in significant maternal morbidity and even mortality. In this article, we reviewed the general principles of ART. We also performed a search of all published cases of TEC associated with ART, and summarized the results of studies investigating underlying hemostatic changes with ART. The goal of this article is to provide non-fertility specialists an understanding of ART, so as to better manage TEC when they occur in predisposed patients. The most common ART procedure performed today, is in-vitro fertilization-embryo transfer (IVF-ET). The process of IVF involves the use of exogeneous hormones to achieve cycle control, stimulate the ovaries, and support implantation. During this process, supraphysiological estradiol levels can result. One major complication of this intervention, ovarian hyperstimulation syndrome (OHSS), can be associated with both arterial and venous thrombotic complications. These events (especially venous thrombosis) have also been reported to occur weeks after OHSS has resolved; and they can present in unusual sites (upper extremities) resulting in treatment challenges. From current available studies, it is clear that with ovarian stimulation, both the coagulation and fibrinolytic systems are activated. This activation appears to be exaggerated and prolonged with the development of OHSS. Whether these changes are sufficient by themselves to explain the occurrence of TEC is yet unknown. Future studies should be focused on defining the frequency and risk factors of these complications; provide a closer examination of the resultant changes in the coagulation cascade during ART, OHSS and early pregnancy; and investigating the appropriate treatment and thromboprophylaxis for patients undergoing a procedure considered "elective".

Reduced plasma homocysteine in obese red wine consumers: a potential contributor to reduced cardiovascular risk status.

BACKGROUND: Moderate alcohol consumption is associated with improved vascular risk profile and decreased mortality in the middle aged. An elevated homocysteine concentration is an independent risk factor for cardiovascular disease. OBJECTIVE: To examine the relationship between alcohol consumption and homocysteine concentrations in severely obese patients (body mass index (BMI)>35). DESIGN: A careful alcohol history was obtained from 350 (male:female 1:5) consecutive patients as part of preoperative assessment for surgical treatment of obesity. Data were obtained concerning amount, frequency, timing and type of alcohol consumption. Fasting homocysteine, serum folate and vitamin B(12) concentrations were measured. Differences between groups were assessed using Student t-test, and ANOVA. Linear regression was used to assess factors influencing homocysteine concentration. RESULTS: There is a U-shaped relationship between alcohol consumption and homocysteine concentrations, with light to moderate consumption being associated with lower concentrations. Those consuming <100 g/week (n=165) of alcohol had geometric mean (95% CI of mean) serum homocysteine concentrations of 8.5 (8.2-8.9) micromol/l compared with 9.5 (9.1-9.9) micromol/l for non or rare consumers (n=153; P=0.001). The lower concentrations of homocysteine in regular consumers were associated with higher folate concentrations of 9.4 (8.6-10.2) ng/ml when compared with non-consumers 7.5 (7.1-7.8) ng/ml (P=0.001). Red wine consumers (n=42) had lower fasting concentrations of homocysteine 7.8 (7.5-8.1) micromol/l compared with 153 non-consumers 9.4 (9.0-9.8) micromol/l (P<0.001), 82 beer and spirit consumers 9.0 (8.4-9.7) micromol/l (P=0.005) and 73 white wine consumers 8.8 (8.2-9.4 micromol/l (P=0.013). Red wine consumption was an independent predictor for lower homocysteine concentrations. CONCLUSION: Mild to moderate alcohol consumption, especially red wine consumption, in obese subjects is associated with lower fasting homocysteine concentrations. This may reduce cardiovascular risk and help explain the 'French paradox'.

Quality of life after lap-band placement: influence of time, weight loss, and comorbidities.

OBJECTIVE: To assess the quality of life (QOL) in severely obese subjects before and after Lap-Band gastric restrictive surgery and identify factors that may influence change. RESEARCH METHODS AND PROCEDURES: All patients, over a 3-year period, attending for preoperative assessment (n = 459) or annual review after surgery (n = 641) have completed the Short Form-36 (SF-36) health survey. Eight domain and physical component summary (PCS) and mental component summary (MCS) scores were calculated. Scores were analyzed in groups based on time after surgery and compared with community normal (CN) values. Paired preoperative and 1-year scores (n = 218) data were used to find predictors of QOL change. RESULTS: All preoperative mean scores (n = 459) were lower than CN values, with greater impairment in the PCS (36.8 +/- 9.5 vs. CN: 51.3 +/- 8.3, p < 0.001) than in the MCS (45.7 +/- 8.2 vs. CN: 48.8 +/- 9.5, p < 0.001) scores. After 1 year, scores were closer to CN scores (PCS: 52.4 +/- 8.2 and MCS: 48.4 +/- 7.7), and these remained closer for 4 years. Preoperative obesity comorbidity, especially physical disability, was the best predictor of poor preoperative SF-36 scores and of improvement in scores at 1 year. The percentage of excess weight loss at 1 year (46 +/- 16%) was of little predictive value of improved QOL. DISCUSSION: Severely obese subjects have poor health-related QOL as measured by the SF-36 health survey. Lap-Band surgery for this group has provided a dramatic and sustained improvement in all measures of the SF-36. Improvement is greater in those with greater preoperative disability, and the extent of weight loss is not a good predictor of improved QOL.

Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism.

PURPOSE: To identify the gene causing tarsal/carpal coalition syndrome (TCC). METHODS: Individuals from three kindreds with TCC and normal hearing were used to map TCC and screen for mutations in Noggin (NOG). RESULTS: Three different missense mutations in NOG were found. Two of these mutations are identical to mutations previously reported to cause proximal symphalangism (SYM1). CONCLUSIONS: TCC is allelic to SYM1, and at least two different mutations in NOG can result in either TCC or SYM1 in different families. This finding suggests that phenotypic differences between these conditions are caused by epistatic modifiers of NOG.

Elevated homocysteine levels with weight loss after Lap-Band surgery: higher folate and vitamin B12 levels required to maintain homocysteine level.

OBJECTIVE: To investigate homocysteine levels and their relationship with serum folate and vitamin B12 concentrations with weight loss after the Lap-Band form of gastric restrictive surgery, with the view to minimizing risk. METHODS: We measured levels of fasting plasma homocysteine (tHcy), folate (serum and RBC) and vitamin B12 in two groups. The study group was 293 consecutive patients at 12 (n=192) or 24 (n=101) months review after surgery. The controls were 244 consecutive patients presenting for this surgery. RESULTS: The group losing weight had higher geometric mean tHcy levels: 10.4 (95% CI, 9.8-10.8) micromol/l compared with 9.2 (95% CI, 8.9-9.7) in controls (P<0.001). This occurred with higher folate levels and unchanged vitamin B12 levels. Levels of folate and B12 together explained 35% (r (2)) of the homocysteine variance in the weight loss group compared with only 9% (r (2)) in controls (P<0.001). Those taking regular multivitamin supplements had lower tHcy levels: 9.6 (9.1-10.0) micromol/l vs 12.3 (11.4-13.3) in those not taking supplements (P<0.001). A low normal plateau of tHcy levels occurred at levels of folate >15 ng/l and B12)600 ng/ml. A curvilinear relationship exists between these cofactors and tHcy levels, with the dose-response relationship shifted to the right in the weight loss group. CONCLUSION: This study shows elevated tHcy levels with weight loss, without lower serum folate or vitamin B(12) levels. There is an altered dose-response relationship with higher serum B(12) and folate levels required to maintain recommended tHcy levels. Patients losing weight have significant health benefits; however, they may be at greater risk of vascular events or fetal abnormality in association with raised tHcy levels. Multivitamin supplementation is effective in lowering tHcy levels.

Pre-operative predictors of weight loss at 1-year after Lap-Band surgery.

BACKGROUND: The authors studied a range of preoperative factors for their predictive value of effectiveness of Lap-Band placement, using the percentage of excess weight loss at 1-year as the outcome measure (%EWL1). METHODS: All factors were measured and recorded prior to surgery. Factors included: patient demographics, family, medical and weight history. Laboratory measures and the responses to the SF-36 Health Survey were also assessed. Factors were assessed for correlation with %EWL1. RESULTS: The group (N=440, F:M 383:57) had mean age 40.0+/-9.5 years, weight of 126+/-25 kg, and BMI 45.6+/-7.5 kg/m2 pre-operatively. At 1-year follow-up, the group had mean weight 97.6< or =20 kg, BMI 35.6 = 6.3 kg/m2, and %EWL1 45.8< or =17%. Increasing age (R= -0.13, p<0.01) and preoperative BMI (R=-0.22, p<0.001) were significantly associated with less %EWL1 and all other factors were controlled for these before assessing significance. Important factors associated with a lower %EWL1 included: hyperinsulinemia (R=-0.36, p<0.001), insulin resistance (R=-0.33, p<0.001) and disease associated with insulin resistance, poor physical ability, pain, and poor general health responses to the SF-36 Health Survey. Patients who consumed alcohol regularly had a better rate of weight loss (R= 0.23, p<0.005). Factors that had no influence included gender, a history of mental illness and measures of mental health, previous bariatric surgery, and a history of many medical conditions associated with obesity. CONCLUSION: Important physical factors have been found to influence the rate of weight loss. Those with increased age, pain, physical disability and insulin resistance have a great deal to gain from weight loss. Although this study has identified factors that are associated with less weight loss, we have not found any factor that predicts an unacceptably low weight loss and thus provides a contraindication to Lap-Band placement. The findings of this study allow us to set more realistic goals for the rate of weight loss in specified sub-groups of our patients.

Genetic evidence on the origins of Indian caste populations.

The origins and affinities of the approximately 1 billion people living on the subcontinent of India have long been contested. This is owing, in part, to the many different waves of immigrants that have influenced the genetic structure of India. In the most recent of these waves, Indo-European-speaking people from West Eurasia entered India from the Northwest and diffused throughout the subcontinent. They purportedly admixed with or displaced indigenous Dravidic-speaking populations. Subsequently they may have established the Hindu caste system and placed themselves primarily in castes of higher rank. To explore the impact of West Eurasians on contemporary Indian caste populations, we compared mtDNA (400 bp of hypervariable region 1 and 14 restriction site polymorphisms) and Y-chromosome (20 biallelic polymorphisms and 5 short tandem repeats) variation in approximately 265 males from eight castes of different rank to approximately 750 Africans, Asians, Europeans, and other Indians. For maternally inherited mtDNA, each caste is most similar to Asians. However, 20%-30% of Indian mtDNA haplotypes belong to West Eurasian haplogroups, and the frequency of these haplotypes is proportional to caste rank, the highest frequency of West Eurasian haplotypes being found in the upper castes. In contrast, for paternally inherited Y-chromosome variation each caste is more similar to Europeans than to Asians. Moreover, the affinity to Europeans is proportionate to caste rank, the upper castes being most similar to Europeans, particularly East Europeans. These findings are consistent with greater West Eurasian male admixture with castes of higher rank. Nevertheless, the mitochondrial genome and the Y chromosome each represents only a single haploid locus and is more susceptible to large stochastic variation, bottlenecks, and selective sweeps. Thus, to increase the power of our analysis, we assayed 40 independent, biparentally inherited autosomal loci (1 LINE-1 and 39 Alu elements) in all of the caste and continental populations (approximately 600 individuals). Analysis of these data demonstrated that the upper castes have a higher affinity to Europeans than to Asians, and the upper castes are significantly more similar to Europeans than are the lower castes. Collectively, all five datasets show a trend toward upper castes being more similar to Europeans, whereas lower castes are more similar to Asians. We conclude that Indian castes are most likely to be of proto-Asian origin with West Eurasian admixture resulting in rank-related and sex-specific differences in the genetic affinities of castes to Asians and Europeans.

Pregnancy after Lap-Band surgery: management of the band to achieve healthy weight outcomes.

BACKGROUND: Severely obese women have higher obstetric risks and poorer neonatal outcomes. Weight loss reduces obstetric risk. The introduction of a laparoscopically-placed adjustable gastric band, a safe and effective method of weight loss, has given us the ability and responsibility to adjust the band in relation to pregnancy. OBJECTIVE: Our aim was to devise a safe management plan to achieve healthy maternal weight gain (Institute of Medicine 1990) during pregnancy. METHODS: In a cohort group of 650 patients to have a Lap-Band placement for severe obesity, we have reviewed the management of the band and pregnancy outcomes of all women (n=20) to complete a pregnancy (n=22) with a band in-situ. RESULTS: All 22 pregnancies were singleton, with no primary caesarean sections (3 for recurring indications). The mean maternal weight gain was 8.3 kg compared with 15.2 kg for the 15 previous pregnancies of women in this group (p<0.05). There was no difference in birth weights. Obstetric complications were minimal, and there were no premature or low birth weight infants. 11 of 15 subjects with active management of the band achieved a maternal weight gain within the advised range compared with only 2 of 7 prior to this. CONCLUSION: The ability to adjust gastric restriction allows optimal control of maternal weight change in pregnancy and should help avoid the risks of excessive weight change.

Mitochondrial DNA variation in Nicobarese Islanders.

The aboriginal populations living in the Nicobar Islands are hypothesized to be descendants of people who were part of early human dispersals into Southeast Asia. However, analyses of ethnographic histories, languages, morphometric data, and protein polymorphisms have not yet resolved which worldwide populations are most closely related to the Nicobarese. Thus, to explore the origins and affinities of the Nicobar Islanders, we analyzed mitochondrial DNA (mtDNA) hypervariable region 1 sequence data from 33 Nicobarese Islanders and compared their mtDNA haplotypes to those of neighboring East Asians, mainland and island Southeast Asians, Indians, Australian aborigines, Pacific Islanders, and Africans. Unique Nicobarese mtDNA haplotypes, including five Nicobarese mtDNA haplotypes linked to the COII/tRNA(Lys) 9-bp deletion, are most closely related to mtDNA haplotypes from mainland Southeast Asian Mon-Kmer-speaking populations (e.g., Cambodians). Thus, the dispersal of southern Chinese into mainland Southeast Asia may have included a westward expansion and colonization of the islands of the Andaman Sea.

The distribution of human genetic diversity: a comparison of mitochondrial, autosomal, and Y-chromosome data.

We report a comparison of worldwide genetic variation among 255 individuals by using autosomal, mitochondrial, and Y-chromosome polymorphisms. Variation is assessed by use of 30 autosomal restriction-site polymorphisms (RSPs), 60 autosomal short-tandem-repeat polymorphisms (STRPs), 13 Alu-insertion polymorphisms and one LINE-1 element, 611 bp of mitochondrial control-region sequence, and 10 Y-chromosome polymorphisms. Analysis of these data reveals substantial congruity among this diverse array of genetic systems. With the exception of the autosomal RSPs, in which an ascertainment bias exists, all systems show greater gene diversity in Africans than in either Europeans or Asians. Africans also have the largest total number of alleles, as well as the largest number of unique alleles, for most systems. GST values are 11%-18% for the autosomal systems and are two to three times higher for the mtDNA sequence and Y-chromosome RSPs. This difference is expected because of the lower effective population size of mtDNA and Y chromosomes. A lower value is seen for Y-chromosome STRs, reflecting a relative lack of continental population structure, as a result of rapid mutation and genetic drift. Africa has higher GST values than does either Europe or Asia for all systems except the Y-chromosome STRs and Alus. All systems except the Y-chromosome STRs show less variation between populations within continents than between continents. These results are reassuring in their consistency and offer broad support for an African origin of modern human populations.

Comparisons of pressure and temperature activation parameters for amide hydrogen exchange in T4 lysozyme.

Activation enthalpies and entropies are reported for proton-deuteron exchange at 42 amide sites in T4 lysozyme and compared with activation volumes for the same residues obtained earlier [Hitchens, T. K., and Bryant, R. G. (1998) Biochemistry 37, 5878-5887]. There is no correlation found between activation volume and activation entropy or activation enthalpy. The activation enthalpy is linearly related to the activation entropy in part as a consequence of a relatively narrow sampling window for the rate constants that corresponds to a narrow range of activation free energy. A consequence of the entropy-enthalpy compensation is preservation of rank order of proton exchange. Variations in DeltaH, DeltaS, and DeltaV for residues that are structurally close together in the folded protein suggest that there may be a variety of energetically distinct pathways for the access of solvent to these structurally related exchange sites.

Deep common ancestry of indian and western-Eurasian mitochondrial DNA lineages.

About a fifth of the human gene pool belongs largely either to Indo-European or Dravidic speaking people inhabiting the Indian peninsula. The 'Caucasoid share' in their gene pool is thought to be related predominantly to the Indo-European speakers. A commonly held hypothesis, albeit not the only one, suggests a massive Indo-Aryan invasion to India some 4,000 years ago [1]. Recent limited analysis of maternally inherited mitochondrial DNA (mtDNA) of Indian populations has been interpreted as supporting this concept [2] [3]. Here, this interpretation is questioned. We found an extensive deep late Pleistocene genetic link between contemporary Europeans and Indians, provided by the mtDNA haplogroup U, which encompasses roughly a fifth of mtDNA lineages of both populations. Our estimate for this split is close to the suggested time for the peopling of Asia and the first expansion of anatomically modern humans in Eurasia [4] [5] [6] [7] [8] and likely pre-dates their spread to Europe. Only a small fraction of the 'Caucasoid-specific' mtDNA lineages found in Indian populations can be ascribed to a relatively recent admixture.

Multiple origins of the mtDNA 9-bp deletion in populations of South India.

The origins and genetic affinities of the more than 500 tribal populations living in South Asia are widely disputed. This may reflect differential contributions that continental populations have made to tribal groups in South Asia. We assayed for the presence of the intergenic COII/tRNALys 9-bp deletion in human mtDNA in 646 individuals from 12 caste and 14 tribal populations of South India and compared them to individuals from Africa, Europe, and Asia. The 9-bp deletion is observed in four South Indian tribal populations, the Irula, Yanadi, Siddi, and Maria Gond, and in the Nicobarese. Length polymorphisms of the 9-bp motif are present in the Santal, Khonda Dora, and Jalari, all of whom live in a circumscribed region on the eastern Indian coast. Phylogenetic analyses of mtDNA control region sequence from individuals with the 9-bp deletion indicate that it has arisen independently in some Indian tribal populations. Other 9-bp deletion haplotypes are likely to be of Asian and African origin, implying multiple origins of the 9-bp deletion in South India. These results demonstrate varying genetic affinities of different South Indian tribes to continental populations and underscore the complex histories of the tribal populations living in South Asia.

The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.

Ulnar-mammary syndrome (UMS) is a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development. Mutations that disrupt the DNA-binding domain of the T-box gene, TBX3, have been demonstrated to cause UMS. However, the 3' terminus of the open reading frame (ORF) of TBX3 was not identified, and mutations were detected in only two families with UMS. Furthermore, no substantial homology outside the T-box was found among TBX3 and its orthologues. The subsequent cloning of new TBX3 cDNAs allowed us to complete the characterization of TBX3 and to identify alternatively transcribed TBX3 transcripts, including one that interrupts the T-box. The complete ORF of TBX3 is predicted to encode a 723-residue protein, of which 255 amino acids are encoded by newly identified exons. Comparison of other T-box genes to TBX3 indicates regions of substantial homology outside the DNA-binding domain. Novel mutations have been found in all of eight newly reported families with UMS, including five mutations downstream of the region encoding the T-box. This suggests that a domain(s) outside the T-box is highly conserved and important for the function of TBX3. We found no obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts.

Reconstructing the history of human limb development: lessons from birth defects.

A major goal of biology has been to understand the developmental mechanisms behind evolutionary trends. This has led to a growing interest in studying the molecular basis of the evolution of developmental programs such as those mediating the diversification of tetrapod limbs. Over the last 10 y, it has become clear that the genes and general developmental programs used to build a limb are strongly conserved among widely disparate species. This finding suggests that altered regulation of the timing and locations of developmental events may be responsible for the morphologic variation observed among some species. However, genetic analyses of the regulatory regions of genes controlling vertebrate developmental programs are very limited. Characterization of the genetic basis of human birth defects of the limb provides an opportunity to dissect the developmental programs used to modify the architecture of the hominoid limb. This may allow us to assess the relative contributions of altered gene regulation to morphologic variation among species and reconstruct the evolutionary history of the hominid limb. Such insight is also important because morphologic differences in the hominid upper limb have been correlated with the use of tools, and tool making is often regarded as the milestone that marked the emergence of the genus Homo.

Granulocyte apheresis in inflammatory bowel disease: possible mechanisms of effect.

We have studied the effects of granulocyte apheresis in 18 patients with ulcerative colitis and 6 with Crohn's disease who had failed to respond to conventional therapy. Patients were treated with weekly apheresis using a granulocyte removal column (GI, Otsuka Pharmaceutical Co., Ltd., London, U.K.). We found a mean reduction in circulating granulocytes of 1.29 x 10(9) cells/L with no significant alterations in red blood cell monocyte, total lymphocyte, absolute T-helper, or T-cytotoxic lymphocyte counts. There were no significant changes in complement levels or immunoglobulin subclasses. There was a significant increase in granulocyte adhesion and a reduction in L-selectin expression. The removal of granulocytes is unlikely to explain the effect of granulocytapheresis. The markedly increased expression of alpha(m) integrin/Mac-1 and low L-selectin expression alter the capability of granulocytes to migrate to sites of inflammation and may be responsible for the improvement observed in patients treated with granulocyte apheresis.