The impact of consanguinity on neonatal and infant health.

Marriage between biological relatives is widely popular in many parts of the world, with over 1000 million people living in countries where 20-50+% of unions are contracted between couples related as second cousins or closer. Consanguinity is, however, a controversial topic, in part due to public misunderstanding, complicated by often exaggerated past estimates of the adverse health outcomes. While some consanguineous couples are at high risk of conceiving a child with a genetic disorder, they are a small minority. Thus a multi-population meta-analysis has indicated an excess infant death rate of 1.1% in the progeny of first cousins, and even this figure may be compromised by inadequate control for non-genetic variables. The benefits as well as the disadvantages of consanguineous marriage are assessed and discussed, with specific consideration given to the health of migrant communities in Western countries, among whom first cousin marriage remains preferential.

A descriptive profile of ß-thalassaemia mutations in India, Pakistan and Sri Lanka.

Thalassaemia is a common and debilitating autosomal recessive disorder affecting many populations in South Asia. To date, efforts to create a regional profile of ß-thalassaemia mutations have largely concentrated on the populations of India. The present study updates and expands an earlier profile of ß-thalassaemia mutations in India, and incorporates comparable data from Pakistan and Sri Lanka. Despite limited data availability, clear patterns of historical and cultural population movements were observed relating to major ß-thalassaemia mutations. The current regional mutation profiles of ß-thalassaemia have been influenced by historical migrations into and from the Indian sub-continent, by the development and effects of Hindu, Buddhist, Muslim and Sikh religious traditions, and by the major mid-twentieth century population translocations that followed the Partition of India in 1947. Given the resultant genetic complexity revealed by the populations of India, Pakistan and Sri Lanka, to ensure optimum diagnostic efficiency and the delivery of appropriate care, it is important that screening and counselling programmes for ß-thalassaemia mutations recognise the underlying patterns of population sub-division throughout the region.

Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases.

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F >or= 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is approximately 3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates.

Profiling ß-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes.

UNLABELLED: Thalassaemia and sickle cell disease have been recognized by the World Health Organization as important inherited disorders principally impacting on the populations of low income countries. To create a national and regional profile of ß-thalassaemia mutations in the population of India, a meta-analysis was conducted on 17 selected studies comprising 8,505 alleles and offering near-national coverage for the disease. At the national level 52 mutations accounted for 97.5% of all ß-thalassaemia alleles, with IVSI-5(G>C) the most common disease allele (54.7%). Population stratification was apparent in the mutation profiles at regional level with, for example, the prevalence of IVSI-5(G>C) varying from 44.8% in the North to 71.4% in the East. A number of major mutations, such as Poly A(T>C), were apparently restricted to a particular region of the country, although these findings may in part reflect the variant test protocols adopted by different centres. Given the size and genetic complexity of the Indian population, and with specific mutations for ß-thalassaemia known to be strongly associated with individual communities, comprehensive disease registries need to be compiled at state, district and community levels to ensure the efficacy of genetic education, screening and counselling programmes. At the same, time appropriately designed community-based studies are required as a health priority to correct earlier sampling inequities which resulted in the under-representation of many communities, in particular rural and socioeconomically under-privileged groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11568-010-9132-3) contains supplementary material, which is available to authorized users.

Physical anthropology and ethnicity in Asia: the transition from anthropometry to genome-based studies.

Initial physical anthropology studies into ethnic diversity were largely dependent on comparative whole body and craniometric measurements, and through time assessments of ethnic diversity based on these measures exhibited increasing statistical sophistication. Since the 1990s, in Asia as elsewhere in the world, human diversity studies have increasingly utilized DNA-based analyses, with Y-chromosome and mtDNA markers providing complementary perspectives on the origins and gene pool structures of different ethnic groups. This approach is illustrated in a study of population genetic structure in PR China, in which DNA samples from the Han majority and eight ethnic minorities were analyzed. The Y-chromosome and mtDNA data showed multiple paternal geographical and ethnic origins but restricted maternal ancestries. However, interpretive problems were apparent in the definition of a number of the ethnic study populations, which appear to reflect political as well as genetic influences. In all anthropological studies, whether based on anthropometry or genomic analysis, unambiguous and appropriate community identification is a prerequisite.

Combining genetics and population history in the study of ethnic diversity in the People's Republic of China.

Genomic data have increasingly been used to complement linguistic, archeological, and anthropological evidence in reconstructing the origins and migratory patterns of modern humans. East Asia is a particular hotspot of human migration, especially mainland China, where a large number of human fossils have been unearthed and more than 20% of the world's population now resides. There are 56 officially recognized ethnic populations (minzu) in China. In the present study we investigated the ancestry and genetic diversity of nine populations: the majority Han of Liaoning Province; the Miao, Yao, Kucong, and Tibetan communities of Yunnan Province in southwest China; and four Muslim populations, the Hui, Bonan, Dongxiang, and Sala from central and northern China. We used both biparental and uniparental markers to determine patterns of diversity at autosomal, mitochondrial, and Y-chromosome loci. The study populations displayed several paternal origins but restricted maternal ancestries. From the Y-chromosome data in particular, major demographic changes, such as the Neolithic population expansion and more recent historical events including migration along the Silk Road, could be inferred. Specific aspects of the internal structure and organization of the study populations, including endogamy and consanguinity, were uncovered using autosomal markers. However, we encountered interpretive problems in terms of the definition of the present-day ethnic study populations in China, which appear to reflect past and present political as well as genetic influences.

Genetic ancestries in northwest Cambodia.

A survey of the genetic ancestry of 125 Cambodian children resident in Siem Reap province was undertaken, based on eight Y-chromosome binary polymorphisms and sequencing of the mtDNA HV1 region. The data indicated a largely East Asian paternal ancestry and a local Southeast Asian maternal ancestry. The presence of Y-chromosomes P* and R1al* was suggestive of a small but significant Indo-European male ancestral component, which probably reflects the history of Indian, and later European, influences on Cambodia.

A genome-based study of the Muslim Hui community and the Han population of Liaoning Province, PR China.

To investigate the proposed historical origins of the Hui, a Chinese Muslim minority resident in Liaoning Province, PR China, DNA samples obtained from 53 individuals were analyzed at ten autosomal and six Y-chromosome microsatellite loci. As reference sources, equivalent samples were investigated from the coresident Han majority population. Both the Hui and the Han exhibited appreciable genetic heterogeneity in terms of the size, number, and size range of alleles, suggestive of population substructure resulting from their particular cultural and historical backgrounds. The contrast in the patterns of autosomal and Y-chromosome diversity of the two communities was obvious. Analysis of molecular variance showed that only 4.6% of total autosomal molecular variance was due to differences between the Hui and Han. The comparable value for Y-chromosome haplotype distributions of 14.0% indicated that the Hui and Han of Liaoning have separate paternal genetic histories.

Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers.

BACKGROUND: The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug. METHODS: Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. RESULTS: Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. CONCLUSIONS: The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.

Reinforcing, subjective, and psychomotor effects of sevoflurane and nitrous oxide in moderate-drinking healthy volunteers.

AIMS: To characterize the reinforcing, subjective and psychomotor effects of sevoflurane, a volatile anesthetic, across a range of subanesthetic concentrations in non-drug-abusing humans. In addition, a concentration of nitrous oxide was included in the design in order to compare and contrast behavioral effects of a gaseous to a volatile anesthesic. DESIGN: Repeated measures, double-blind, placebo control experiment. SETTING: Human psychopharmacology laboratory. PARTICIPANTS: Fourteen moderate-drinking healthy volunteers. INTERVENTION: In each of four sessions, subjects first sampled placebo-oxygen and an active drug (end-tidal concentrations of 0.2, 0.4, 0.6% sevoflurane and 30% nitrous oxide in oxygen) and then chose between the two MEASUREMENTS: Mood and psychomotor performance during the sampling trials, and choice of drug or placebo-oxygen during choice trial. FINDINGS: Nitrous oxide was chosen by 71% of the subjects, and 0.2, 0.4 and 0.6% sevoflurane were chosen by 50%, 57% and 50% of the subjects, respectively. Neither drug was chosen at levels that exceeded that of chance. Sevoflurane and nitrous oxide both impaired psychomotor performance and produced changes in mood. There were several differences in subjective effects between sevoflurane and nitrous oxide at concentrations which were considered to be equivalent in anesthetic effect. Finally, although sevoflurane did not function as a reinforcer in the majority of individuals tested, there was evidence that sevoflurane functioned as a reinforcer in some volunteers: subjects who chose to inhale sevoflurane over placebo-oxygen tended to report a positive spectrum of subjective effects during the sevoflurane sampling trial, relative to those subjects who chose placebo-oxygen over sevoflurane. CONCLUSIONS: Although sevoflurane did not function as a reinforcer in the majority of subjects tested, the correspondence between positive subjective effects of sevoflurane and subsequent sevoflurane choice suggests that the volatile anesthetic drug can function as a reinforcer in some moderate drinkers.

Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of pentazocine in non-drug-abusing volunteers and to compare and contrast the effects of pentazocine with those of morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 7.5, 15 or 30 mg/70 kg pentazocine or 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. Pentazocine increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "sweating" and "turning of stomach" and increased visual analog scale ratings of "difficulty concentrating," "drunk" and "having unpleasant bodily sensations." Pentazocine (30 mg) had a greater propensity to increase ratings associated with dysphoria than did 10 mg of morphine. Pentazocine produced impairment on four measures of psychomotor performance. Ten milligrams of morphine produced minimal psychomotor impairment. Both pentazocine and morphine induced miosis, but 10 mg of morphine had a greater magnitude of effect than 30 mg of pentazocine. The results of the present study demonstrate that 7.5 to 30 mg of pentazocine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of pentazocine, 30 mg, produced a greater magnitude of dysphoric subjective effects than did 10 mg of morphine, which is consistent with the literature reporting that pentazocine has a greater likelihood of inducing psychotomimesis than do other opioids.

Successful treatment of severe refractory idiopathic thrombocytopenic purpura with liposomal doxorubicin.

Idiopathic thrombocytopenic purpura (ITP) is refractory to initial treatment (steroids and splenectomy) in 25 to 30% of patients. These patients have a significant risk of fatal hemorrhage. Two patients with ITP refractory to multiple interventions and severe depression of platelet counts responded to treatment with liposomal doxorubicin with a return of platelet counts to normal. The drug is easily administered and was well tolerated. Use of this drug in refractory ITP merits further study.

Intussuscepted Meckel diverticulum: radiologic-pathologic correlation.

Nine cases of Meckel diverticulum presenting with intussusception were reviewed and correlated clinically, radiologically and pathologically. The appearance of intussuscepted Meckel diverticulum by small bowel series is not specific. However, by CT, a central fat density surrounded by a thick collar of soft tissue was noted in one case correlating well with the gross pathologic appearance. The pathologic material in all our cases suggests that this CT appearance is characteristic of an inverted Meckel diverticulum.

Computed tomographic appearance of pulmonary alveolar proteinosis in adults.

Two cases of adult pulmonary alveolar proteinosis are presented with emphasis on the computed tomographic findings in both cases. Each patient demonstrated a pattern of diffusely increased lung density on both standard radiographic and computed tomographic examinations of the lung. There was no evidence of adenopathy, pleural effusion, or cardiomegaly in either patient. The diagnosis of pulmonary alveolar proteinosis was established in both patients by open lung biopsy. The optical microscopy and electron microscopy examinations of the biopsy material in each instance demonstrated marked filling of the alveoli with periodic-acid-Schiff-positive material and intraalveolar lamellar bodies. The diagnosis of sarcoid was entertained prior to the open lung biopsy in one patient, a young adult black male. Although the computed tomographic appearance was similar in each case and of no value in the diagnosis of pulmonary alveolar proteinosis, it was helpful in assessing the extent of the disease within the lung.

Evaluation of transsphenoidal hypophysectomy in the management of patients with advanced malignant melanoma.

Transsphenoidal hypophysectomy was performed in 13 patients with advanced malignant melanoma. Although three minor responses were observed, there were no complete or partial responses. All three patients with bone pain had a decrease in discomfort lasting 1-2 months. All five patients with minor responses or stable disease had postoperative decreases in the excretion of the dihydroxyphenylalanine (DOPA) metabolite 3-O-methyldopamine; all but one patient with clinical progression had postoperative increases in excretion. Average survival of those whose postoperative excretion fell (143 +/- days; range, 60-217+) was significantly longer (P less than 0.004) than that of those whose postsurgical values rose (30 days; range, 15-58).