A technotypological analysis of the Ahmarian and Levantine Aurignacian assemblages from Manot Cave (area C) and the interrelation with site formation processes.

For more than a century, prehistoric research has focused on cave sites and rock shelters, mostly because of good preservation of organic remains associated with stratified anthropogenic layers. Manot Cave in the Western Galilee, Israel offers the possibility of studying prehistoric assemblages in pristine condition because of the collapse of the cave entrance some 30 thousand years ago. Nine years of excavations have uncovered an Early Upper Paleolithic archaeological sequence. Area C, situated at the bottom of the talus, was exposed to fast and slow depositional and postdepositional processes affecting sediment accumulation. The central part of area C was selected for this study, as it was least disturbed. Following a technotypological analysis, and taking postdepositional processes into consideration, the assemblages were defined and assigned to the Levantine Aurignacian, and Ahmarian traditions. The two archaeological horizons are separated by a mixed horizon within which indicative artifacts of both traditions alternately appear. The Ahmarian assemblage, dated to 46-42 ka cal BP, fits within the northern Mediterranean Ahmarian sites, which technotypologically differs from and is currently dated earlier than the southern desert region Ahmarian sites. The main technotypological characteristics of the assemblage from the Levantine Aurignacian Horizon, dated to 38-34 ka cal BP, are comparable to those from Manot Cave area E layers V-VI, and Ksâr 'Akil levels VII-VIII. Yet, several technotypological elements seem more compatible with the unnamed assemblage from Ksâr 'Akil levels XI-XIII and possibly layer IX from area E.

The challenge of antimicrobial resistance: new regulatory tools to support product development.

The antibiotic pipeline is thin and lacks diversity, particularly for agents targeting Gram-negative pathogens. The reasons for our anemic global development pipeline are often summarized as (i) discovery of new antibiotics is difficult, (ii) clinical development of new antibiotics is difficult, and (iii) the economics for new antibiotics are unfavorable for the developer. Here, we review recent efforts directed at the second of these challenges.

ASCPT Task Force for advancing pharmacometrics and integration into drug development.

Traditionally, medical and biostatistical experts have played a central role in ensuring validity of pharmaceutical testing. The science of pharmacometrics provides powerful approaches for supporting important drug development and regulatory decisions. Numerous case studies published by academic, industry, and US Food and Drug Administration scientists attest to the significant contribution of pharmacometrics to decision making. The economic and public health benefits of applying this discipline to clinical trials far outweigh the cost associated with its implementation. The purpose of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Task Force is to build on the momentum and accelerate dissemination of its impact and adoption into drug development. We describe briefly the contributions of pharmacometrics and the specific goals of the Task Force.

Internal transcardiac pericardiocentesis for acute tamponade.

If the catheter is still in the pericardium when tamponade is recognized during catheterization or electrophysiologic procedures, it can be used for definitive aspiration and relief of tamponade. This is physiologically beneficial to the patient, and psychologically beneficial to both patient and medical staff.

Impact of thrombolysis, intra-aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?

OBJECTIVES: We sought to investigate the potential benefit of thrombolytic therapy (TT) and intra-aortic balloon pump counterpulsation (IABP) on in-hospital mortality rates of patients enrolled in a prospective, multi-center Registry of acute myocardial infarction (MI) complicated by cardiogenic shock (CS). BACKGROUND: Retrospective studies suggest that patients suffering from CS due to MI have lower in-hospital mortality rates when IABP support is added to TT. This hypothesis has not heretofore been examined prospectively in a study devoted to CS. METHODS: Of 1,190 patients enrolled at 36 participating centers, 884 patients had CS due to predominant left ventricular (LV) failure. Excluding 26 patients with IABP placed prior to shock onset and 2 patients with incomplete data, 856 patients were evaluated regarding TT and IABP utilization. Treatments, selected by local physicians, fell into four categories: no TT, no IABP (33%; n = 285); IABP only (33%; n = 279); TT only (15%; n = 132); and TT and IABP (19%; n = 160). RESULTS: Patients in CS treated with TT had a lower in-hospital mortality than those who did not receive TT (54% vs. 64%, p = 0.005), and those selected for IABP had a lower in-hospital mortality than those who did not receive IABP (50% vs. 72%, p < 0.0001). Furthermore, there was a significant difference in in-hospital mortality among the four treatment groups: TT + IABP (47%), IABP only (52%), TT only (63%), no TT, no IABP (77%) (p < 0.0001). Patients receiving early IABP (< or = 6 h after thrombolytic therapy, n = 72) had in-hospital mortality similar to those with late IABP (53% vs. 41%, n = 64, respectively, p = 0.172). Revascularization rates differed among the four groups: no TT, no IABP (18%); IABP only (70%); TT only (20%); TT and IABP (68%, p < 0.0001); this influenced in-hospital mortality significantly (39% with revascularization vs. 78% without revascularization, p < 0.0001). CONCLUSIONS: Treatment of patients in cardiogenic shock due to predominant LV failure with TT, IABP and revascularization by PTCA/CABG was associated with lower in-hospital mortality rates than standard medical therapy in this Registry. For hospitals without revascularization capability, a strategy of early TT and IABP followed by immediate transfer for PTCA or CABG may be appropriate. However, selection bias is evident and further investigation is required.

Clinical outcome after subtalar arthroscopy.

We investigated the clinical outcomes of patients with specific symptoms and physical findings of subtalar pathology with nonspecific radiographic findings after subtalar arthroscopy. Preoperative workup included plain radiographs in all of the patients, magnetic resonance imaging in seven patients, and bone scan in six patients. Based on these studies, no patient had significant subtalar arthrosis. Twelve patients underwent subtalar arthroscopy. Clinical outcome was rated with the American Orthopaedic Foot and Ankle Society Hindfoot Score. Preoperatively, the score ranged from 54 to 75, with a mean of 60. Postoperative scores ranged from 53 to 85, with a mean of 71. The follow-up averaged 17.5 months. Preoperative magnetic resonance imaging and bone scan uniformly underestimated the degree of articular damage. There were no operative complications. Three patients improved their scores by 10 points or greater. Two of these patients had debridement of a cartilage flap to a stable base performed. The third patient had an arthroscopically assisted removal of a loose body. Three of the four patients whose scores decreased have progressed to subtalar arthrodesis. We conclude from this small series of patients that arthroscopy is the most accurate method of diagnosing subtalar articular cartilage damage, but that it has limited therapeutic benefit in the treatment of early degenerative joint disease.

Successful intracoronary thrombolysis in cocaine-associated acute myocardial infarction.

We describe a case of cocaine-associated acute myocardial infarction managed by cardiac catheterization and intracoronary thrombolysis. Based on this and other reported cases, it appears that an invasive approach to the management of cocaine-associated acute myocardial infarction is advantageous over intravenous thrombolysis. Such a strategy would define the pathophysiology of acute myocardial infarction in the setting of cocaine use and allow mechanical intervention should pharmacologic therapy be unsuccessful.

Urologic injuries in pelvic ring disruptions.

Pelvic ring disruptions are the result of high energy blunt trauma and are associated with other significant injuries in greater than 50% of the cases. These injuries may involve neurovascular structures and other organ systems. Lower urinary tract injuries may occur in as much as 25% of patients with pelvic ring disruptions. Coordinated care between the orthopaedist and urologist is required for successful treatment of the urologic and pelvic injury. Of primary importance to the orthopaedist is the potential for infection after open stabilization of the anterior arch. When contaminated urine communicates with the anterior arch, the possibility of infection exists. Early repair of bladder disruptions with simultaneous anterior arch plating minimizes this risk. The treatment of urethral disruptions and the safest method for urinary drainage remain controversial, however.

Development of locomotor behavior in the spinal kitten.

This study was undertaken to determine the locomotor capability of kittens whose spinal cords were transected at birth. The postnatal development of reflex and goal-directed locomotion was examined during the first 5 postnatal months in kittens that received low thoracic spinal cord transections as newborns. Some spinal kittens developed aberrant quadrupedal forms of locomotion. The onset of quadrupedal locomotion, however, was delayed by 2-3 months compared to the normal kitten (42) and deteriorated by 5 months of age. Qualitative and quantitative analyses demonstrated that the quadrupedal locomotion was abnormal. Although some step cycles were characterized by full weight support, the typical hindlimb step cycle of the best performing cat showed inadequate weight support and balance. No spinal cat was able to coordinate the hindlimbs with the forelimbs during overground locomotion on a runaway or during quadrupedal locomotion on a treadmill. Neuroanatomical tracing with WGA-HRP and immunocytochemical techniques showed no axonal regeneration or growth into or across the lesion sites. The aberrant form of quadrupedal locomotion developed without descending input to the caudal spinal cord. The variability in performance among animals suggested that compensatory strategies were important factors in the spinal kitten's achievement of quadrupedal locomotion. Hindlimb weight-supported stepping during quadrupedal locomotion in some animals underscored the capacity of the isolated caudal spinal cord to generate both rhythmical stepping movements and weight support. The maintenance of developmentally immature, but functional, hindlimb postures suggested that the development of the isolated caudal spinal cord was arrested in the absence of descending input.

Transplants enhance locomotion in neonatal kittens whose spinal cords are transected: a behavioral and anatomical study.

We have studied the locomotor development of kittens that received complete low thoracic spinal cord transections and embryonic spinal cord transplants as newborns. Embryonic spinal cord (E21-E26) transplanted into the site of a transection integrated well with the host spinal cord and promoted the development of overground locomotion. Spinalized kittens with transplants were first distinguished from spinalized kittens during the 2nd and 3rd postnatal weeks when kittens with transplants positioned their hindlimbs underneath their bodies which promoted support of the hindquarters. By postnatal Week 6, kittens with transplants exhibited overground locomotion characterized by full weight support and moderate balance control. By 20 weeks of age, as many as 96% of the step cycles showed full weight support and as few as 2% of the step cycles were interrupted by a fall. Most kittens also showed coordination between the forelimbs and the hindlimbs. They differed from normal in the precocious onset of reflex stepping and in the less precise interlimb coordination and more precarious balance during overground locomotion. The overground locomotor performance of kittens with transplants greatly exceeded that of spinal kittens without transplants since few spinalized kittens showed any full-weight-supported step cycles and none showed coordination between the forelimbs and the hindlimbs. In the absence of a transplant, no fibers could grow across the lesion site. In the presence of a transplant, fibers grew across the lesion site and established anatomical connectivity with the host. Host segmental systems identified by the presence of calcitonin gene-related peptide- and substance P-immunoreactive fibers were found throughout the transplants. Descending host systems of supraspinal origin were identified by serotonin- and dopamine beta-hydroxylase-immunoreactive fibers throughout the transplants. The growth of supraspinal axons into the transplant, and in one case into the caudal host spinal cord, provided a possible anatomical basis for the development of coordinated overground locomotion.

The development of quadrupedal locomotion in the kitten.

The development of bipedal treadmill locomotion and overground locomotion has previously been studied in the kitten; the development of quadrupedal treadmill locomotion has not. We evaluated and compared all three forms of locomotion in the normal kitten and present quantitative data comparing the development of quadrupedal treadmill and overground locomotion. Overground locomotion was studied from the day of birth to 5 months of age and quadrupedal treadmill locomotion was studied in the same animals from 9 weeks to 5 months of age. Treadmill locomotion was initiated postweaning, since it could not be reliably elicited without a food reward. Three locomotor characteristics (weight support, balance, and coordination between the forelimbs and the hindlimbs) were evaluated quantitatively. Kittens first consistently demonstrated overground steps with the ventral surface of their bodies supported above the walking surface throughout the entire step cycle during the second and third postnatal weeks. By 4 weeks of age, overground locomotion consistently showed full weight support and midline positioning of the hindquarters. Coordination between the forelimbs and the hindlimbs developed differently in the two forms of quadrupedal locomotion evaluated. During overground locomotion, the kittens initially used a single pattern in which only one limb was in swing at any time. As the kittens' weight support and trunk control improved, additional swing phase coordination patterns emerged and these patterns were correlated with the animals' ability to change speeds during locomotion. The consistency with which a dominant interlimb swing phase pattern was used at a particular speed increased with age and, by 6 weeks, the frequency of each speed-related dominant pattern approached 100% during overground locomotion. At 6 weeks, interlimb coordination also was evident in the nearly consistent interlimb phase interval present between the forelimb's initiation of the first extension subphase and the ipsilateral hindlimb's initiation of the flexion phase. The consistent patterns appeared to be fostered by maturation of weight support and balance. In contrast, the interlimb phase interval was inconsistent during quadrupedal treadmill locomotion until 20 weeks of age. Moreover, the interlimb swing phase patterns used during quadrupedal treadmill locomotion differed from those used during overground locomotion. The differences in the developmental time course and patterns of interlimb coordination between overground and quadrupedal treadmill locomotion suggest that different mechanisms regulate the control of interlimb coordination during these two different forms of quadrupedal locomotion.

Plasticity of complex terminals in lamina II in partially deafferented spinal cord: the cat spared root preparation.

Projections to the dorsal horn change in adult mammals in response to complete or partial deafferentation. The number of synaptic terminals remains constant after complete lumbosacral deafferentation, indicating replacement of lost dorsal root terminals by newly formed terminals from spared intrinsic systems. The density of a spared central projection of a dorsal root is increased in dorsal horn after partial deafferentation, consistent with sprouting by the axons in the spared root. In this study, we have used electron microscopy to study morphological changes in a specific class of terminals in the dorsal horn induced by partial deafferentation. Complex terminals (CTs) in the dorsal horn originate exclusively from dorsal roots and are readily distinguished morphologically. The CTs and the postsynaptic densities (PSDs) associated with CTs were measured in lamina II at L5 and L6 in cats subjected to unilateral spared root (L6) dorsal rhizotomies and compared to CTs in the control side. Acutely following partial deafferentation, the number of CT profiles decreased. At more chronic survivals, the number of CT profiles were restored to normal levels, and both the number and the length of PSDs were increased. The changes in CTs and PSDs suggest sprouting and synaptogenesis by the spared dorsal root fibers that produce changes in the postsynaptic neuron. Spared root deafferentation thus elicits compensatory changes in presynaptic terminals of the spared root and also in their postsynaptic target neurons.

The couch as defense and as potential for enactment.

Use of the couch in psychoanalysis is almost universal because of its many advantages. This paper focuses on situations in which the use of the couch is not beneficial, involving problems of the patient or of the analyst. Interferences with the usefulness of the couch are illustrated by means of vignettes from the analysis of four patients which demonstrate the isolating potential of the couch and the reasons why this may make the couch appeal to some patients and repel others. The distancing potential of the couch may sometimes appeal to analysts, particularly when the face-to-face arrangement is troublesome. The use of the couch for the enactment of conflict is discussed, as are analytic attitudes toward the use or non-use of the couch.

Enactment and play following medical trauma. An analytic case study.

This paper on the four-year analysis of a five-year-old girl with a school phobia details the playroom enactments of medical trauma and its sequelae. Early in the analysis the patient expressed herself almost exclusively through play. Gradually she connected her conflicts, including those over her compulsive masturbation, to her hospital experiences. Only after the traumatic medical experiences were no longer the major issue did other important conflicts become available for analytic work. Physical activity remained prominent in the analysis and generated pressure for mutual enactment. This case again draws our attention to the complex overlap of play, enactments, and verbalization in child analysis.

NMDA receptor blockade rescues Clarke's and red nucleus neurons after spinal hemisection.

Hemisection of the adult rat spinal cord at T9 transects the ascending ipsilateral axons of Clarke's nucleus (CN) neurons and the descending contralateral axons of red nucleus (RN) neurons. Eight weeks following axotomy, 30% of CN neurons and 22% of RN neurons die. Since both nuclei receive glutamatergic input, we wished to examine the possibility that glutamatergic excitotoxicity contributes to axotomy-induced neuronal death in these nuclei. To test this we studied the effects of administration of the NMDA receptor antagonist MK-801 on cell survival after axotomy. When 1 mg/kg body weight MK-801 is administered subcutaneously every day for 1-8 weeks to hemisected rats, cell death is prevented. Treatment with 0.5 mg/kg body weight MK-801 over the same time periods results in only partial rescue of axotomized neurons. Paradoxically, when 1 mg/kg MK-801 administration is restricted to the first week of an 8 week survival period, cell death in both the RN and CN is greatly exaggerated over the cell loss found in saline-treated animals. Withdrawal of 1 mg/kg MK-801 after 1 week of administration induces the loss of 92% of CN neurons, which is 63% greater than that occurring after axotomy alone. If, however, 1 mg/kg MK-801 is withdrawn after 2 weeks post-axotomy in the RN and 3 weeks postaxotomy in CN, all axotomized neurons survive. This rescue is found at 6 months postsurgery, the longest survival period studied, and therefore appears to be permanent. These results suggest that glutamatergic afferent input contributes significantly to the death of axotomized red nucleus and Clarke's nucleus neurons via NMDA receptors located on these neurons.

Grafts of fetal central nervous system tissue rescue axotomized Clarke's nucleus neurons in adult and neonatal operates.

Many conditions are thought to contribute to neuron death after axotomy, including immaturity of the cell at the time of injury, inability to reestablish or maintain target contact, and dependence on trophic factors produced by targets. Exogenous application of neurotrophic factors and transplants of peripheral nerve and embryonic central nervous system (CNS) tissue temporarily rescue axotomized CNS neurons, but permanent rescue may require transplants that are normal targets of the injured neurons. We examined the requirements for survival of axotomized Clarke's nucleus (CN) neurons. Two months after hemisection of the spinal cord at the T8 segment, there was an ipsilateral 30% loss of neurons at the L1 segment in adult operates and a 40% loss in neonates. Transplants of embryonic spinal cord, cerebellum, and neocortex inserted into the T8 segment at the time of hemisection prevented virtually all of the cell death in both adults and neonates, but transplants of embryonic striatum were ineffective. None of the grafts prevented the somal atrophy of CN neurons caused by axotomy. Retrograde transport of fluoro-gold from the cerebellum demonstrated that 33% of all CN neurons at L1 project to the cerebellum, 50% of these died following a T8 hemisection, but all these projection neurons were rescued by a transplant of embryonic spinal cord. These results suggest that the rescue of axotomized CN neurons is relatively specific for the normal target areas of these neurons, but this specificity is not absolute and may depend on the distribution and synthesis of particular neurotrophic agents.